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Understanding reasons for drug use amongst young people: a functional perspective

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Annabel Boys, John Marsden, John Strang, Understanding reasons for drug use amongst young people: a functional perspective, Health Education Research , Volume 16, Issue 4, August 2001, Pages 457–469, https://doi.org/10.1093/her/16.4.457

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This study uses a functional perspective to examine the reasons young people cite for using psychoactive substances. The study sample comprised 364 young poly-drug users recruited using snowball-sampling methods. Data on lifetime and recent frequency and intensity of use for alcohol, cannabis, amphetamines, ecstasy, LSD and cocaine are presented. A majority of the participants had used at least one of these six drugs to fulfil 11 of 18 measured substance use functions. The most popular functions for use were using to: relax (96.7%), become intoxicated (96.4%), keep awake at night while socializing (95.9%), enhance an activity (88.5%) and alleviate depressed mood (86.8%). Substance use functions were found to differ by age and gender. Recognition of the functions fulfilled by substance use should help health educators and prevention strategists to make health messages about drugs more relevant and appropriate to general and specific audiences. Targeting substances that are perceived to fulfil similar functions and addressing issues concerning the substitution of one substance for another may also strengthen education and prevention efforts.

The use of illicit psychoactive substances is not a minority activity amongst young people in the UK. Results from the most recent British Crime Survey show that some 50% of young people between the ages of 16 and 24 years have used an illicit drug on at least one occasion in their lives (lifetime prevalence) ( Ramsay and Partridge, 1999 ). Amongst 16–19 and 20–24 year olds the most prevalent drug is cannabis (used by 40% of 16–19 year olds and 47% of 20–24 year olds), followed by amphetamine sulphate (18 and 24% of the two age groups respectively), LSD (10 and 13%) and ecstasy (8 and 12%). The lifetime prevalence for cocaine hydrochloride (powder cocaine) use amongst the two age groups is 3 and 9%, respectively. Collectively, these estimates are generally comparable with other European countries ( European Monitoring Centre for Drugs and Drug Addiction, 1998 ) and the US ( Johnston et al ., 1997 , 2000 ).

The widespread concern about the use of illicit drugs is reflected by its high status on health, educational and political agendas in many countries. The UK Government's 10-year national strategy on drug misuse identifies young people as a critical priority group for prevention and treatment interventions ( Tackling Drugs to Build a Better Britain 1998 ). If strategies to reduce the use of drugs and associated harms amongst the younger population are to be developed, particularly within the health education arena, it is vital that we improve our understanding of the roles that both licit and illicit substances play in the lives of young people. The tendency for educators, practitioners and policy makers to address licit drugs (such as alcohol) separately from illegal drugs may be unhelpful. This is partly because young illicit drug users frequently drink alcohol, and may have little regard for the illicit and licit distinction established by the law. To understand the roles that drug and alcohol use play in contemporary youth culture, it is necessary to examine the most frequently used psychoactive substances as a set.

It is commonplace for young drug users to use several different psychoactive substances. The terms `poly-drug' or `multiple drug' use have been used to describe this behaviour although their exact definitions vary. The term `poly-drug use' is often used to describe the use of two or more drugs during a particular time period (e.g. over the last month or year). This is the definition used within the current paper. However, poly-drug use could also characterize the use of two or more psychoactive substances so that their effects are experienced simultaneously. We have used the term `concurrent drug use' to denote this pattern of potentially more risky and harmful drug use ( Boys et al. 2000a ). Previous studies have reported that users often use drugs concurrently to improve the effects of another drug or to help manage its negative effects [e.g. ( Power et al ., 1996 ; Boys et al. 2000a ; Wibberley and Price, 2000 )].

The most recent British Crime Survey found that 5% of 16–29 year olds had used more than one drug in the last month ( Ramsay and Partridge, 1999 ). Given that 16% of this age band reported drug use in the month prior to interview, this suggests that just under a third of these individuals had used more than one illicit substance during this time period. With alcohol included, the prevalence of poly-drug use is likely to be much higher.

There is a substantial body of literature on the reasons or motivations that people cite for using alcohol, particularly amongst adult populations. For example, research on heavy drinkers suggested that alcohol use is related to multiple functions for use ( Edwards et al ., 1972 ; Sadava, 1975 ). Similarly, research with a focus on young people has sought to identify motives for illicit drug use. There is evidence that for many young people, the decision to use a drug is based on a rational appraisal process, rather than a passive reaction to the context in which a substance is available ( Boys et al. 2000a ; Wibberley and Price, 2000 ). Reported reasons vary from quite broad statements (e.g. to feel better) to more specific functions for use (e.g. to increase self-confidence). However, much of this literature focuses on `drugs' as a generic concept and makes little distinction between different types of illicit substances [e.g. ( Carman, 1979 ; Butler et al ., 1981 ; Newcomb et al ., 1988 ; Cato, 1992 ; McKay et al ., 1992 )]. Given the diverse effects that different drugs have on the user, it might be proposed that reasons for use will closely mirror these differences. Thus stimulant drugs (such as amphetamines, ecstasy or cocaine) will be used for reasons relating to increased nervous system arousal and drugs with sedative effects (such as alcohol or cannabis), with nervous system depression. The present study therefore selected a range of drugs commonly used by young people with stimulant, sedative or hallucinogenic effects to examine this issue further.

The phrase `instrumental drug use' has been used to denote drug use for reasons specifically linked to a drug's effects ( WHO, 1997 ). Examples of the instrumental use of amphetamine-type stimulants include vehicle drivers who report using to improve concentration and relieve tiredness, and people who want to lose weight (particularly young women), using these drugs to curb their appetite. However, the term `instrumental substance use' seems to be used when specific physical effects of a drug are exploited and does not encompass use for more subtle social or psychological purposes which may also be cited by users. In recent reports we have described a `drug use functions' model to help understand poly-substance use phenomenology amongst young people and how decisions are made about patterns of consumption ( Boys et al ., 1999a , b , 2000a ). The term `function' is intended to characterize the primary or multiple reasons for, or purpose served by, the use of a particular substance in terms of the actual gains that the user perceives that they will attain. In the early, 1970s Sadava suggested that functions were a useful means of understanding how personality and environmental variables impacted on patterns of drug use ( Sadava, 1975 ). This work was confined to functions for cannabis and `psychedelic drugs' amongst a sample of college students. To date there has been little research that has examined the different functions associated with the range of psychoactive substances commonly used by young poly-drug users. It is unclear if all drugs with similar physical effects are used for similar purposes, or if other more subtle social or psychological dimensions to use are influential. Work in this area will help to increase understanding of the different roles played by psychoactive substances in the lives of young people, and thus facilitate health, educational and policy responses to this issue.

Previous work has suggested that the perceived functions served by the use of a drug predict the likelihood of future consumption ( Boys et al ., 1999a ). The present study aims to develop this work further by examining the functional profiles of six substances commonly used by young people in the UK.

Patterns of cannabis, amphetamine, ecstasy, LSD, cocaine hydrochloride and alcohol use were examined amongst a sample of young poly-drug users. Tobacco use was not addressed in the present research.

Sampling and recruitment

A snowball-sampling approach was employed for recruitment of participants. Snowball sampling is an effective way of generating a large sample from a hidden population where no formal sampling frame is available ( Van Meter, 1990 ). A team of peer interviewers was trained to recruit and interview participants for the study. We have described this procedure in detail elsewhere and only essential features are described here ( Boys et al. 2000b ). Using current or ex-drug users to gather data from hidden populations of drug using adults has been found to be successful ( Griffiths et al ., 1993 ; Power, 1995 ).

Study participants

Study participants were current poly-substance users with no history of treatment for substance-related disorders. We excluded people with a treatment history on the assumption that young people who have had substance-related problems requiring treatment represent a different group from the general population of young drug users. Inclusion criteria were: aged 16–22 years and having used two or more illegal substances during the past 90 days. During data collection, the age, gender and current occupation of participants were recorded and monitored to ensure that sufficient individuals were recruited to the groups to permit subgroup analyses. If an imbalance was observed in one of these variables, the interviewers were instructed to target participants with specific characteristics (e.g. females under the age of 18) to redress this imbalance.

Study measures

Data were collected using a structured interviewer-administered questionnaire developed specifically for the study. In addition to recording lifetime substance use, questions profiled consumption patterns of six substances in detail. Data were collected between August and November 1998. Interviews were audiotaped with the interviewee's consent. This enabled research staff to verify that answers had been accurately recorded on the questionnaire and that the interview had been conducted in accordance with the research protocol. Research staff also checked for consistency across different question items (e.g. the total number of days of drug use in the past 90 days should equal or exceed the number of days of cannabis use during the same time period). On the few occasions where inconsistencies were identified that could not be corrected from the tape, the interviewer was asked to re-contact the interviewee to verify the data.

Measures of lifetime use, consumption in the past year and past 90 days were based on procedures developed by Marsden et al . ( Marsden et al ., 1998 ). Estimated intensity of consumption (amount used on a typical using day) was recorded verbatim and then translated into standardized units at the data entry stage.

Functions for substance use scale

The questionnaire included a 17-item scale designed to measure perceived functions for substance use. This scale consisted of items developed in previous work ( Boys et al ., 1999a ) in addition to functions derived from qualitative interviews ( Boys et al ., 1999b ), new literature and informal discussions with young drug users. Items were drawn from five domains (Table I ).

Participants were asked if they had ever used a particular drug in order to fulfil each specific function. Those who endorsed the item were then invited to rate how frequently they had used it for this purpose over the past year, using a five-point Likert-type scale (`never' to `always'; coded 0–4). One item differed between the function scales used for the stimulant drugs and for alcohol and cannabis. For the stimulant drugs (amphetamines, cocaine and ecstasy) the item `have you ever used [named drug] to help you to lose weight' was used, for cannabis and alcohol this item was replaced with `have you ever used [drug] to help you to sleep?'. (The items written in full as they appeared in the questionnaire are shown in Table III , together with abbreviations used in this paper.)

Statistical procedures

The internal reliability of the substance use functions scales for each of the six substances was judged using Chronbach's α coefficient. Chronbach's α is a statistic that reflects the extent to which each item in a measurement scale is associated with other items. Technically it is the average of correlations between all possible comparisons of the scale items that are divided into two halves. An α coefficient for a scale can range from 0 (no internal reliability) to 1 (complete reliability). Analyses of categorical variables were performed using χ 2 statistic. Differences in scale means were assessed using t -tests.

The sample consisted of 364 young poly-substance users (205 males; 56.3%) with a mean age of 19.3 years; 69.8% described their ethnic group as White-European, 12.6% as Black and 10.1% were Asian. Just over a quarter (27.5%) were unemployed at the time of interview; a third were in education, 28.8% were in full-time work and the remainder had part-time employment. Estimates of monthly disposable income (any money that was spare after paying for rent, bills and food) ranged from 0 to over £1000 (median = £250).

Substance use history

The drug with the highest lifetime prevalence was cannabis (96.2%). This was followed by amphetamine sulphate (51.6%), cocaine hydrochloride (50.5%) (referred to as cocaine hereafter) and ecstasy (48.6%). Twenty-five percent of the sample had used LSD and this was more common amongst male participants (χ 2 [1] = 9.68, P < 0.01). Other drugs used included crack cocaine (25.5%), heroin (12.6%), tranquillizers (21.7%) and hallucinogenic mushrooms (8.0%). On average, participants had used a total of 5.2 different psychoactive substances in their lives (out of a possible 14) (median = 4.0, mode = 3.0, range 2–14). There was no gender difference in the number of different drugs ever used.

Table II profiles use of the six target drugs over the past year, and the frequency and intensity of use in the 90 days prior to interview.

There were no gender differences in drug use over the past year or in the past 90 days with the exception of amphetamines. For this substance, females who had ever used this drug were more likely to have done so during the past 90 days than males (χ 2 [1] = 4.14, P < 0.05). The mean number of target drugs used over the past 90 days was 3.2 (median = 3.0, mode = 3.0, range 2–6). No gender differences were observed. Few differences were also observed in the frequency and intensity of use. Males reported drinking alcohol more frequently during the three months prior to interview ( t [307] = 2.48, P < 0.05) and using cannabis more intensively on a `typical using day' ( t [337] = 3.56, P < 0.001).

Perceived functions for substance use

There were few differences between the functions endorsed for use of each drug `ever' and those endorsed for use during `the year prior to interview'. This section therefore concentrates on data for the year prior to interview. We considered that in order to use a drug for a specific function, the user must have first hand knowledge of the drug's effects before making this decision. Consequently, functions reported by individuals who had only used a particular substance on one occasion in their lives (i.e. with no prior experience of the drug at the time they made the decision to take it) were excluded from the analyses. Table III summarizes the proportion of the sample who endorsed each of the functions for drugs used in the past year. Roman numerals have been used to indicate the functions with the top five average scores. Table III also shows means for the total number of different items endorsed by individual users and the internal reliability of the function scales for each substance using Chronbach's α coefficients. There were no significant gender differences in the total number of functions endorsed for any of the six substances.

The following sections summarize the top five most popular functions drug-by-drug together with any age or gender differences observed in the items endorsed.

Cannabis use ( n = 345)

Overall the most popular functions for cannabis use were to `RELAX' (endorsed by 96.8% of people who had used the drug in the last year), to become `INTOXICATED' (90.7%) and to `ENHANCE ACTIVITY' (72.8%). Cannabis was also commonly used to `DECREASE BOREDOM' (70.1%) and to `SLEEP' (69.6%) [this item was closely followed by using to help `FEEL BETTER' (69.0%)]. Nine of the 17 function items were endorsed by over half of those who had used cannabis on more than one occasion in the past year. There were no significant gender differences observed, with the exception of using to `KEEP GOING', where male participants were significantly more likely to say that they had used cannabis to fulfil this function in the past year (χ 2 [1] = 6.10, P < 0.05).

There were statistically significant age differences on four of the function variables: cannabis users who reported using this drug in the past year to help feel `ELATED/EUPHORIC' or to help `SLEEP' were significantly older than those who had not used cannabis for these purposes (19.6 versus 19.0; t [343] = 3.32, P < 0.001; 19.4 versus 19.0; t [343] = 2.01, P < 0.05). In contrast, those who had used cannabis to `INCREASE CONFIDENCE' and to `STOP WORRYING' tended to be younger than those who did not (19.0 versus 19.4; t [343] = –2.26, P < 0.05; 19.1 versus 19.5; t [343] = –1.99, P < 0.05).

Amphetamines ( n = 160)

Common functions for amphetamine use were to `KEEP GOING' (95.6%), to `STAY AWAKE' (91.3%) or to `ENHANCE ACTIVITY' (66.2%). Using to help feel `ELATED/EUPHORIC' (60.6%) and to `ENJOY COMPANY' (58.1%) were also frequently mentioned. Seven of the 17 function items were endorsed by over half of participants who had used amphetamines in the past year. As with cannabis, gender differences were uncommon: females were more likely to use amphetamines to help `LOSE WEIGHT' than male participants (χ 2 [1] = 21.67, P < 0.001).

Significant age differences were found on four function variables. Individuals who reported using amphetamines in the past year to feel `ELATED/EUPHORIC' were significantly older than those who did not (19.9 versus 19.0; t [158] = 2.87, P < 0.01). In contrast, participants who used amphetamines to `STOP WORRYING' (18.8 versus 19.8; t [158] = –2.77, P < 0.01), to `DECREASE BOREDOM' (19.2 versus 19.9; t [158] = –2.39, P < 0.05) or to `ENHANCE ACTIVITY' (19.3 versus 20.1; t [158] = –2.88, P < 0.01) were younger than those who had not.

Ecstasy ( n = 157)

The most popular five functions for using ecstasy were similar to those for amphetamines. The drug was used to `KEEP GOING' (91.1%), to `ENHANCE ACTIVITY' (79.6%), to feel `ELATED/EUPHORIC' (77.7%), to `STAY AWAKE' (72.0%) and to get `INTOXICATED' (68.2%). Seven of the 17 function items were endorsed by over half of those who had used ecstasy in the past year. Female users were more likely to use ecstasy to help `LOSE WEIGHT' than male participants (Fishers exact test, P < 0.001).

As with the other drugs discussed above, participants who reported using ecstasy to feel `ELATED/EUPHORIC' were significantly older than those who did not (19.8 versus 18.9; t [155] = 2.61, P < 0.01). In contrast, those who had used ecstasy to `FEEL BETTER' (19.3 versus 20.0; t [155] = –2.29, P < 0.05), to `INCREASE CONFIDENCE' (19.2 versus 19.9; t [155] = –2.22, P < 0.05) and to `STOP WORRYING' (19.0 versus 19.9; t [155] = –2.96, P < 0.01) tended to be younger.

LSD ( n = 58)

Of the six target substances examined in this study, LSD was associated with the least diverse range of functions for use. All but two of the function statements were endorsed by at least some users, but only five were reported by more than 50%. The most common purpose for consuming LSD was to get `INTOXICATED' (77.6%). Other popular functions included to feel `ELATED/EUPHORIC' and to `ENHANCE ACTIVITY' (both endorsed by 72.4%), and to `KEEP GOING' and to `ENJOY COMPANY' (both endorsed by 58.6%). Unlike the other substances examined, no gender or age differences were observed.

Cocaine ( n = 168)

In common with ecstasy and amphetamines, the most widely endorsed functions for cocaine use were to help `KEEP GOING' (84.5%) and to help `STAY AWAKE' (69.0%). Consuming cocaine to `INCREASE CONFIDENCE' and to get `INTOXICATED' (both endorsed by 66.1%) were also popular. However, unlike the other stimulant drugs, 61.9% of the cocaine users reported using to `FEEL BETTER'. Ten of the 17 function items were endorsed by over half of those who had used cocaine in the past year.

Gender differences were more common amongst functions for cocaine use than the other substances surveyed. More males reported using cocaine to `IMPROVE EFFECTS' of other drugs (χ 2 [1] = 4.00, P < 0.05); more females used the drug to help `STAY AWAKE' (χ 2 [1] = 12.21, P < 0.001), to `LOSE INHIBITIONS' (χ 2 [1] = 9.01, P < 0.01), to `STOP WORRYING' (χ 2 [1] = 8.11, P < 0.01) or to `ENJOY COMPANY' of friends (χ 2 [1] = 4.34, P < 0.05). All participants who endorsed using cocaine to help `LOSE WEIGHT' were female.

Those who had used cocaine to `FEEL BETTER' (18.9 versus 19.8; t [166] = –3.06, P < 0.01), to `STOP WORRYING' (18.6 versus 19.7; t [166] = –3.86, P < 0.001) or to `DECREASE BOREDOM' (18.9 versus 19.6; t [166] = –2.52, P < 0.05) were significantly younger than those who did not endorse these functions. Similar to the other drugs, participants who had used cocaine to feel `ELATED/EUPHORIC' in the past year tended to be older than those who had not (19.6 versus 18.7; t [166] = 3.16, P < 0.01).

Alcohol ( n = 312)

The functions for alcohol use were the most diverse of the six substances examined. Like LSD, the most commonly endorsed purpose for drinking was to get `INTOXICATED' (89.1%). Many used alcohol to `RELAX' (82.7%), to `ENJOY COMPANY' (74.0%), to `INCREASE CONFIDENCE' (70.2%) and to `FEEL BETTER' (69.9%). Overall, 11 of the 17 function items were endorsed by over 50% of those who had drunk alcohol in the past year. Male participants were more likely to report using alcohol in combination with other drugs either to `IMPROVE EFFECTS' of other drugs (χ 2 [1] = 4.56, P < 0.05) or to ease the `AFTER EFFECTS' of other substances (χ 2 [1] = 7.07, P < 0.01). More females than males reported that they used alcohol to `DECREASE BOREDOM' (χ 2 [1] = 4.42, P < 0.05).

T -tests revealed significant age differences on four of the function variables: those who drank to feel `ELATED/EUPHORIC' were significantly older (19.7 versus 19.0; t [310] = 3.67, P < 0.001) as were individuals who drank to help them to `LOSE INHIBITIONS' (19.6 versus 19.0; t [310] = 2.36, P < 0.05). In contrast, participants who reported using alcohol just to get `INTOXICATED' (19.2 versus 20.3; t [310] = –3.31, P < 0.001) or to `DECREASE BOREDOM' (19.2 versus 19.6; t [310] = –2.25, P < 0.05) were significantly younger than those who did not.

Combined functional drug use

The substances used by the greatest proportion of participants to `IMPROVE EFFECTS' from other drugs were cannabis (44.3%), alcohol (41.0%) and amphetamines (37.5%). It was also common to use cannabis (64.6%) and to a lesser extent alcohol (35.9%) in combination with other drugs in order to help manage `AFTER EFFECTS'. Amphetamines, ecstasy, LSD and cocaine were also used for these purposes, although to a lesser extent. Participants who endorsed the combination drug use items were asked to list the three main drugs with which they had combined the target substance for these purposes. Table IV summarizes these responses.

Overall functions for drug use

In order to examine which functions were most popular overall, a dichotomous variable was created for each different item to indicate if one or more of the six target substances had been used to fulfil this purpose during the year prior to interview. For example, if an individual reported that they had used cannabis to relax, but their use of ecstasy, amphetamines and alcohol had not fulfilled this function, then the variable for `RELAX' was scored `1'. Similarly if they had used all four of these substances to help them to relax in the past year, the variable would again be scored as `1'. A score of `0' indicates that none of the target substances had been used to fulfil a particular function. Table V summarizes the data from these new variables.

Over three-quarters of the sample had used at least one target substance in the past year for 11 out of the 18 functions listed. The five most common functions for substance use overall were to `RELAX' (96.7%); `INTOXICATED' (96.4%); `KEEP GOING' (95.9%); `ENHANCE ACTIVITY' (88.5%) and `FEEL BETTER' (86.8%). Despite the fact that `SLEEP' was only relevant to two substances (alcohol and cannabis), it was still endorsed by over 70% of the total sample. Using to `LOSE WEIGHT' was only relevant to the stimulant drugs (amphetamines, ecstasy and cocaine), yet was endorsed by 17.3% of the total sample (almost a third of all female participants). Overall, this was the least popular function for recent substance use, followed by `WORK' (32.1%). All other items were endorsed by over 60% of all participants.

Gender differences were identified in six items. Females were significantly more likely to have endorsed the following: using to `INCREASE CONFIDENCE' (χ 2 [1] = 4.41, P < 0.05); `STAY AWAKE' (χ 2 [1] = 5.36, P < 0.05), `LOSE INHIBITIONS' (χ 2 [1] = 4.48, P < 0.05), `ENHANCE SEX' (χ 2 [1] = 5.17, P < 0.05) and `LOSE WEIGHT' (χ 2 [1] = 29.6, P < 0.001). In contrast, males were more likely to use a substance to `IMPROVE EFFECTS' of another drug (χ 2 [1] = 11.18, P < 0.001).

Statistically significant age differences were identified in three of the items. Those who had used at least one of the six target substances in the last year to feel `ELATED/EUPHORIC' (19.5 versus 18.6; t [362] = 4.07, P < 0.001) or to `SLEEP' (19.4 versus 18.9; t [362] = 2.19, P < 0.05) were significantly older than those who had not used for this function. In contrast, participants who had used in order to `STOP WORRYING' tended to be younger (19.1 versus 19.7; t [362] = –2.88, P < 0.01).

This paper has examined psychoactive substance use amongst a sample of young people and focused on the perceived functions for use using a 17-item scale. In terms of the characteristics of the sample, the reported lifetime and recent substance use was directly comparable with other samples of poly-drug users recruited in the UK [e.g. ( Release, 1997 )].

Previous studies which have asked users to give reasons for their `drug use' overall instead of breaking it down by drug type [e.g. ( Carman, 1979 ; Butler et al ., 1981 ; Newcomb et al ., 1988 ; Cato, 1992 ; McKay et al ., 1992 )] may have overlooked the dynamic nature of drug-related decision making. A key finding from the study is that that with the exception of two of the functions for use scale items (using to help sleep or lose weight), all of the six drugs had been used to fulfil all of the functions measured, despite differences in their pharmacological effects. The total number of functions endorsed by individuals for use of a particular drug varied from 0 to 15 for LSD, and up to 17 for cannabis, alcohol and cocaine. The average number ranged from 5.9 (for LSD) to 9.0 (for cannabis). This indicates that substance use served multiple purposes for this sample, but that the functional profiles differed between the six target drugs.

We have previously reported ( Boys et al. 2000b ) that high scores on a cocaine functions scale are strongly predictive of high scores on a cocaine-related problems scale. The current findings support the use of similar function scales for cannabis, amphetamines, LSD and ecstasy. It remains to be seen whether similar associations with problem scores exist. Future developmental work in this area should ensure that respondents are given the opportunity to cite additional functions to those included here so that the scales can be further extended and refined.

Recent campaigns that have targeted young people have tended to assume that hallucinogen and stimulant use is primarily associated with dance events, and so motives for use will relate to this context. Our results support assumptions that these drugs are used to enhance social interactions, but other functions are also evident. For example, about a third of female interviewees had used a stimulant drug to help them to lose weight. Future education and prevention efforts should take this diversity into account when planning interventions for different target groups.

The finding that the same functions are fulfilled by use of different drugs suggests that at least some could be interchangeable. Evidence for substituting alternative drugs to fulfil a function when a preferred drug is unavailable has been found in other studies [e.g. ( Boys et al. 2000a )]. Prevention efforts should perhaps focus on the general motivations behind use rather than trying to discourage use of specific drug types in isolation. For example, it is possible that the focus over the last decade on ecstasy prevention may have contributed inadvertently to the rise in cocaine use amongst young people in the UK ( Boys et al ., 1999c ). It is important that health educators do not overlook this possibility when developing education and prevention initiatives. Considering functions that substance use can fulfil for young people could help us to understand which drugs are likely to be interchangeable. If prevention programmes were designed to target a range of substances that commonly fulfil similar functions, then perhaps this could address the likelihood that some young people will substitute other drugs if deterred from their preferred substance.

There has been considerable concern about the perceived increase in the number of young people who are using cocaine in the UK ( Tackling Drugs to Build a Better Britain 1998 ; Ramsay and Partridge, 1999 ; Boys et al. 2000b ). It has been suggested that, for a number of reasons, cocaine may be replacing ecstasy and amphetamines as the stimulant of choice for some young people ( Boys et al ., 1999c ). The results from this study suggest that motives for cocaine use are indeed similar to those for ecstasy and amphetamine use, e.g. using to `keep going' on a night out with friends, to `enhance an activity', `to help to feel elated or euphoric' or to help `stay awake'. However, in addition to these functions which were shared by all three stimulants, over 60% of cocaine users reported that they had used this drug to `help to feel more confident' in a social situation and to `feel better when down or depressed'. Another finding that sets cocaine aside from ecstasy and amphetamines was the relatively common existence of gender differences in the function items endorsed. Female cocaine users were more likely to use to help `stay awake', `lose inhibitions', `stop worrying', `enjoy company of friends' or to help `lose weight'. This could indicate that women are more inclined to admit to certain functions than their male counterparts. However, the fact that similar gender differences were not observed in the same items for the other five substances, suggests this interpretation is unlikely. Similarly, the lack of gender differences in patterns of cocaine use (both frequency and intensity) suggests that these differences are not due to heavier cocaine use amongst females. If these findings are subsequently confirmed, this could point towards an inclination for young women to use cocaine as a social support, particularly to help feel less inhibited in social situations. If so, young female cocaine users may be more vulnerable to longer-term cocaine-related problems.

Many respondents reported using alcohol or cannabis to help manage effects experienced from another drug. This has implications for the choice of health messages communicated to young people regarding the use of two or more different substances concurrently. Much of the literature aimed at young people warns them to avoid mixing drugs because the interactive effects may be dangerous [e.g. ( HIT, 1996 )]. This `Just say No' type of approach does not take into consideration the motives behind mixing drugs. In most areas, drug education and prevention work has moved on from this form of communication. A more sophisticated approach is required, which considers the functions that concurrent drug use is likely to have for young people and tries to amend messages to make them more relevant and acceptable to this population. Further research is needed to explore the motivations for mixing different combinations of drugs together.

Over three-quarters of the sample reported using at least one of the six target substances to fulfil 11 out of the 18 functions. These findings provide strong evidence that young people use psychoactive drugs for a range of distinct purposes, not purely dependent on the drug's specific effects. Overall, the top five functions were to `help relax', `get intoxicated', `keep going', `enhance activity' and `feel better'. Each of these was endorsed by over 85% of the sample. Whilst all six substances were associated to a greater or lesser degree with each of these items, there were certain drugs that were more commonly associated with each. For example, cannabis and alcohol were popular choices for relaxation or to get intoxicated. In contrast, over 90% of the amphetamine and ecstasy users reported using these drugs within the last year to `keep going'. Using to enhance an activity was a common function amongst users of all six substances, endorsed by over 70% of ecstasy, cannabis and LSD users. Finally, it was mainly alcohol and cannabis (and to a lesser extent cocaine) that were used to `feel better'.

Several gender differences were observed in the combined functions for recent substance use. These findings indicate that young females use other drugs as well as cocaine as social supports. Using for specific physical effects (weight loss, sex or wakefulness) was also more common amongst young women. In contrast, male users were significantly more likely to report using at least one of the target substances to try to improve the effects of another substance. This indicates a greater tendency for young males in this sample to mix drugs than their female counterparts. Age differences were also observed on several function items: participants who had used a drug to `feel elated or euphoric' or to `help sleep' tended to be older and those who used to `stop worrying about a problem' were younger. If future studies confirm these differences, education programmes and interventions might benefit from tailoring their strategies for specific age groups and genders. For example, a focus on stress management strategies and coping skills with a younger target audience might be appropriate.

Some limitations of the study need to be acknowledged. The sample for this study was recruited using a snowball-sampling methodology. Although it does not yield a random sample of research participants, this method has been successfully used to access hidden samples of drug users [e.g. ( Biernacki, 1986 ; Lenton et al ., 1997 )]. Amongst the distinct advantages of this approach are that it allows theories and models to be tested quantitatively on sizeable numbers of subjects who have engaged in a relatively rare behaviour.

Further research is now required to determine whether our observations may be generalized to other populations (such as dependent drug users) and drug types (such as heroin, tranquillizers or tobacco) or if additional function items need to be developed. Future studies should also examine if functions can be categorized into primary and subsidiary reasons and how these relate to changes in patterns of use and drug dependence. Recognition of the functions fulfilled by substance use could help inform education and prevention strategies and make them more relevant and acceptable to the target audiences.

Structure of functions scales

Profile of substance use over the past year and past 90 days ( n = 364)

Proportion (%) of those who have used [substance] more than once, who endorsed each functional statement for their use in the past year

Combined functional substance use reported by the sample over the past year

Percentage of participants who reported having used at least one of the target substances to fulfil each of the different functions over the past year ( n = 364)

We gratefully acknowledge research support from the Health Education Authority (HEA). The views expressed in this paper are those of the authors and do not necessarily reflect those of the HEA. We would also like to thank the anonymous referees for helpful comments and suggestions on an earlier draft of this paper.

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• March 01, 2024 | VOL. 181, NO. 3 CURRENT ISSUE pp.171-254
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Substance Use Disorders and Addiction: Mechanisms, Trends, and Treatment Implications

• Ned H. Kalin , M.D.

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The numbers for substance use disorders are large, and we need to pay attention to them. Data from the 2018 National Survey on Drug Use and Health ( 1 ) suggest that, over the preceding year, 20.3 million people age 12 or older had substance use disorders, and 14.8 million of these cases were attributed to alcohol. When considering other substances, the report estimated that 4.4 million individuals had a marijuana use disorder and that 2 million people suffered from an opiate use disorder. It is well known that stress is associated with an increase in the use of alcohol and other substances, and this is particularly relevant today in relation to the chronic uncertainty and distress associated with the COVID-19 pandemic along with the traumatic effects of racism and social injustice. In part related to stress, substance use disorders are highly comorbid with other psychiatric illnesses: 9.2 million adults were estimated to have a 1-year prevalence of both a mental illness and at least one substance use disorder. Although they may not necessarily meet criteria for a substance use disorder, it is well known that psychiatric patients have increased usage of alcohol, cigarettes, and other illicit substances. As an example, the survey estimated that over the preceding month, 37.2% of individuals with serious mental illnesses were cigarette smokers, compared with 16.3% of individuals without mental illnesses. Substance use frequently accompanies suicide and suicide attempts, and substance use disorders are associated with a long-term increased risk of suicide.

Addiction is the key process that underlies substance use disorders, and research using animal models and humans has revealed important insights into the neural circuits and molecules that mediate addiction. More specifically, research has shed light onto mechanisms underlying the critical components of addiction and relapse: reinforcement and reward, tolerance, withdrawal, negative affect, craving, and stress sensitization. In addition, clinical research has been instrumental in developing an evidence base for the use of pharmacological agents in the treatment of substance use disorders, which, in combination with psychosocial approaches, can provide effective treatments. However, despite the existence of therapeutic tools, relapse is common, and substance use disorders remain grossly undertreated. For example, whether at an inpatient hospital treatment facility or at a drug or alcohol rehabilitation program, it was estimated that only 11% of individuals needing treatment for substance use received appropriate care in 2018. Additionally, it is worth emphasizing that current practice frequently does not effectively integrate dual diagnosis treatment approaches, which is important because psychiatric and substance use disorders are highly comorbid. The barriers to receiving treatment are numerous and directly interact with existing health care inequities. It is imperative that as a field we overcome the obstacles to treatment, including the lack of resources at the individual level, a dearth of trained providers and appropriate treatment facilities, racial biases, and the marked stigmatization that is focused on individuals with addictions.

This issue of the Journal is focused on understanding factors contributing to substance use disorders and their comorbidity with psychiatric disorders, the effects of prenatal alcohol use on preadolescents, and brain mechanisms that are associated with addiction and relapse. An important theme that emerges from this issue is the necessity for understanding maladaptive substance use and its treatment in relation to health care inequities. This highlights the imperative to focus resources and treatment efforts on underprivileged and marginalized populations. The centerpiece of this issue is an overview on addiction written by Dr. George Koob, the director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), and coauthors Drs. Patricia Powell (NIAAA deputy director) and Aaron White ( 2 ). This outstanding article will serve as a foundational knowledge base for those interested in understanding the complex factors that mediate drug addiction. Of particular interest to the practice of psychiatry is the emphasis on the negative affect state “hyperkatifeia” as a major driver of addictive behavior and relapse. This places the dysphoria and psychological distress that are associated with prolonged withdrawal at the heart of treatment and underscores the importance of treating not only maladaptive drug-related behaviors but also the prolonged dysphoria and negative affect associated with addiction. It also speaks to why it is crucial to concurrently treat psychiatric comorbidities that commonly accompany substance use disorders.

Insights Into Mechanisms Related to Cocaine Addiction Using a Novel Imaging Method for Dopamine Neurons

Cassidy et al. ( 3 ) introduce a relatively new imaging technique that allows for an estimation of dopamine integrity and function in the substantia nigra, the site of origin of dopamine neurons that project to the striatum. Capitalizing on the high levels of neuromelanin that are found in substantia nigra dopamine neurons and the interaction between neuromelanin and intracellular iron, this MRI technique, termed neuromelanin-sensitive MRI (NM-MRI), shows promise in studying the involvement of substantia nigra dopamine neurons in neurodegenerative diseases and psychiatric illnesses. The authors used this technique to assess dopamine function in active cocaine users with the aim of exploring the hypothesis that cocaine use disorder is associated with blunted presynaptic striatal dopamine function that would be reflected in decreased “integrity” of the substantia nigra dopamine system. Surprisingly, NM-MRI revealed evidence for increased dopamine in the substantia nigra of individuals using cocaine. The authors suggest that this finding, in conjunction with prior work suggesting a blunted dopamine response, points to the possibility that cocaine use is associated with an altered intracellular distribution of dopamine. Specifically, the idea is that dopamine is shifted from being concentrated in releasable, functional vesicles at the synapse to a nonreleasable cytosolic pool. In addition to providing an intriguing alternative hypothesis underlying the cocaine-related alterations observed in substantia nigra dopamine function, this article highlights an innovative imaging method that can be used in further investigations involving the role of substantia nigra dopamine systems in neuropsychiatric disorders. Dr. Charles Bradberry, chief of the Preclinical Pharmacology Section at the National Institute on Drug Abuse, contributes an editorial that further explains the use of NM-MRI and discusses the theoretical implications of these unexpected findings in relation to cocaine use ( 4 ).

Treatment Implications of Understanding Brain Function During Early Abstinence in Patients With Alcohol Use Disorder

Developing a better understanding of the neural processes that are associated with substance use disorders is critical for conceptualizing improved treatment approaches. Blaine et al. ( 5 ) present neuroimaging data collected during early abstinence in patients with alcohol use disorder and link these data to relapses occurring during treatment. Of note, the findings from this study dovetail with the neural circuit schema Koob et al. provide in this issue’s overview on addiction ( 2 ). The first study in the Blaine et al. article uses 44 patients and 43 control subjects to demonstrate that patients with alcohol use disorder have a blunted neural response to the presentation of stress- and alcohol-related cues. This blunting was observed mainly in the ventromedial prefrontal cortex, a key prefrontal regulatory region, as well as in subcortical regions associated with reward processing, specifically the ventral striatum. Importantly, this finding was replicated in a second study in which 69 patients were studied in relation to their length of abstinence prior to treatment and treatment outcomes. The results demonstrated that individuals with the shortest abstinence times had greater alterations in neural responses to stress and alcohol cues. The authors also found that an individual’s length of abstinence prior to treatment, independent of the number of days of abstinence, was a predictor of relapse and that the magnitude of an individual’s neural alterations predicted the amount of heavy drinking occurring early in treatment. Although relapse is an all too common outcome in patients with substance use disorders, this study highlights an approach that has the potential to refine and develop new treatments that are based on addiction- and abstinence-related brain changes. In her thoughtful editorial, Dr. Edith Sullivan from Stanford University comments on the details of the study, the value of studying patients during early abstinence, and the implications of these findings for new treatment development ( 6 ).

Relatively Low Amounts of Alcohol Intake During Pregnancy Are Associated With Subtle Neurodevelopmental Effects in Preadolescent Offspring

Excessive substance use not only affects the user and their immediate family but also has transgenerational effects that can be mediated in utero. Lees et al. ( 7 ) present data suggesting that even the consumption of relatively low amounts of alcohol by expectant mothers can affect brain development, cognition, and emotion in their offspring. The researchers used data from the Adolescent Brain Cognitive Development Study, a large national community-based study, which allowed them to assess brain structure and function as well as behavioral, cognitive, and psychological outcomes in 9,719 preadolescents. The mothers of 2,518 of the subjects in this study reported some alcohol use during pregnancy, albeit at relatively low levels (0 to 80 drinks throughout pregnancy). Interestingly, and opposite of that expected in relation to data from individuals with fetal alcohol spectrum disorders, increases in brain volume and surface area were found in offspring of mothers who consumed the relatively low amounts of alcohol. Notably, any prenatal alcohol exposure was associated with small but significant increases in psychological problems that included increases in separation anxiety disorder and oppositional defiant disorder. Additionally, a dose-response effect was found for internalizing psychopathology, somatic complaints, and attentional deficits. While subtle, these findings point to neurodevelopmental alterations that may be mediated by even small amounts of prenatal alcohol consumption. Drs. Clare McCormack and Catherine Monk from Columbia University contribute an editorial that provides an in-depth assessment of these findings in relation to other studies, including those assessing severe deficits in individuals with fetal alcohol syndrome ( 8 ). McCormack and Monk emphasize that the behavioral and psychological effects reported in the Lees et al. article would not be clinically meaningful. However, it is feasible that the influences of these low amounts of alcohol could interact with other predisposing factors that might lead to more substantial negative outcomes.

Increased Comorbidity Between Substance Use and Psychiatric Disorders in Sexual Identity Minorities

There is no question that victims of societal marginalization experience disproportionate adversity and stress. Evans-Polce et al. ( 9 ) focus on this concern in relation to individuals who identify as sexual minorities by comparing their incidence of comorbid substance use and psychiatric disorders with that of individuals who identify as heterosexual. By using 2012−2013 data from 36,309 participants in the National Epidemiologic Study on Alcohol and Related Conditions–III, the authors examine the incidence of comorbid alcohol and tobacco use disorders with anxiety, mood disorders, and posttraumatic stress disorder (PTSD). The findings demonstrate increased incidences of substance use and psychiatric disorders in individuals who identified as bisexual or as gay or lesbian compared with those who identified as heterosexual. For example, a fourfold increase in the prevalence of PTSD was found in bisexual individuals compared with heterosexual individuals. In addition, the authors found an increased prevalence of substance use and psychiatric comorbidities in individuals who identified as bisexual and as gay or lesbian compared with individuals who identified as heterosexual. This was most prominent in women who identified as bisexual. For example, of the bisexual women who had an alcohol use disorder, 60.5% also had a psychiatric comorbidity, compared with 44.6% of heterosexual women. Additionally, the amount of reported sexual orientation discrimination and number of lifetime stressful events were associated with a greater likelihood of having comorbid substance use and psychiatric disorders. These findings are important but not surprising, as sexual minority individuals have a history of increased early-life trauma and throughout their lives may experience the painful and unwarranted consequences of bias and denigration. Nonetheless, these findings underscore the strong negative societal impacts experienced by minority groups and should sensitize providers to the additional needs of these individuals.

Trends in Nicotine Use and Dependence From 2001–2002 to 2012–2013

Although considerable efforts over earlier years have curbed the use of tobacco and nicotine, the use of these substances continues to be a significant public health problem. As noted above, individuals with psychiatric disorders are particularly vulnerable. Grant et al. ( 10 ) use data from the National Epidemiologic Survey on Alcohol and Related Conditions collected from a very large cohort to characterize trends in nicotine use and dependence over time. Results from their analysis support the so-called hardening hypothesis, which posits that although intervention-related reductions in nicotine use may have occurred over time, the impact of these interventions is less potent in individuals with more severe addictive behavior (i.e., nicotine dependence). When adjusted for sociodemographic factors, the results demonstrated a small but significant increase in nicotine use from 2001–2002 to 2012–2013. However, a much greater increase in nicotine dependence (46.1% to 52%) was observed over this time frame in individuals who had used nicotine during the preceding 12 months. The increases in nicotine use and dependence were associated with factors related to socioeconomic status, such as lower income and lower educational attainment. The authors interpret these findings as evidence for the hardening hypothesis, suggesting that despite the impression that nicotine use has plateaued, there is a growing number of highly dependent nicotine users who would benefit from nicotine dependence intervention programs. Dr. Kathleen Brady, from the Medical University of South Carolina, provides an editorial ( 11 ) that reviews the consequences of tobacco use and the history of the public measures that were initially taken to combat its use. Importantly, her editorial emphasizes the need to address health care inequity issues that affect individuals of lower socioeconomic status by devoting resources to develop and deploy effective smoking cessation interventions for at-risk and underresourced populations.

Conclusions

Maladaptive substance use and substance use disorders are highly prevalent and are among the most significant public health problems. Substance use is commonly comorbid with psychiatric disorders, and treatment efforts need to concurrently address both. The papers in this issue highlight new findings that are directly relevant to understanding, treating, and developing policies to better serve those afflicted with addictions. While treatments exist, the need for more effective treatments is clear, especially those focused on decreasing relapse rates. The negative affective state, hyperkatifeia, that accompanies longer-term abstinence is an important treatment target that should be emphasized in current practice as well as in new treatment development. In addition to developing a better understanding of the neurobiology of addictions and abstinence, it is necessary to ensure that there is equitable access to currently available treatments and treatment programs. Additional resources must be allocated to this cause. This depends on the recognition that health care inequities and societal barriers are major contributors to the continued high prevalence of substance use disorders, the individual suffering they inflict, and the huge toll that they incur at a societal level.

Disclosures of Editors’ financial relationships appear in the April 2020 issue of the Journal .

1 US Department of Health and Human Services: Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality: National Survey on Drug Use and Health 2018. Rockville, Md, SAMHSA, 2019 ( https://www.samhsa.gov/data/nsduh/reports-detailed-tables-2018-NSDUH ) Google Scholar

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4 Bradberry CW : Neuromelanin MRI: dark substance shines a light on dopamine dysfunction and cocaine use (editorial). Am J Psychiatry 2020 ; 177:1019–1021 Abstract ,  Google Scholar

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Risk and protective factors of drug abuse among adolescents: a systematic review

• Azmawati Mohammed Nawi 1 ,
• Rozmi Ismail 2 ,
• Fauziah Ibrahim 2 ,
• Mohd Rohaizat Hassan 1 ,
• Mohd Rizal Abdul Manaf 1 ,
• Noh Amit 3 ,
• Norhayati Ibrahim 3 &
• Nurul Shafini Shafurdin 2  

BMC Public Health volume  21 , Article number:  2088 ( 2021 ) Cite this article

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Drug abuse is detrimental, and excessive drug usage is a worldwide problem. Drug usage typically begins during adolescence. Factors for drug abuse include a variety of protective and risk factors. Hence, this systematic review aimed to determine the risk and protective factors of drug abuse among adolescents worldwide.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was adopted for the review which utilized three main journal databases, namely PubMed, EBSCOhost, and Web of Science. Tobacco addiction and alcohol abuse were excluded in this review. Retrieved citations were screened, and the data were extracted based on strict inclusion and exclusion criteria. Inclusion criteria include the article being full text, published from the year 2016 until 2020 and provided via open access resource or subscribed to by the institution. Quality assessment was done using Mixed Methods Appraisal Tools (MMAT) version 2018 to assess the methodological quality of the included studies. Given the heterogeneity of the included studies, a descriptive synthesis of the included studies was undertaken.

Out of 425 articles identified, 22 quantitative articles and one qualitative article were included in the final review. Both the risk and protective factors obtained were categorized into three main domains: individual, family, and community factors. The individual risk factors identified were traits of high impulsivity; rebelliousness; emotional regulation impairment, low religious, pain catastrophic, homework completeness, total screen time and alexithymia; the experience of maltreatment or a negative upbringing; having psychiatric disorders such as conduct problems and major depressive disorder; previous e-cigarette exposure; behavioral addiction; low-perceived risk; high-perceived drug accessibility; and high-attitude to use synthetic drugs. The familial risk factors were prenatal maternal smoking; poor maternal psychological control; low parental education; negligence; poor supervision; uncontrolled pocket money; and the presence of substance-using family members. One community risk factor reported was having peers who abuse drugs. The protective factors determined were individual traits of optimism; a high level of mindfulness; having social phobia; having strong beliefs against substance abuse; the desire to maintain one’s health; high paternal awareness of drug abuse; school connectedness; structured activity and having strong religious beliefs.

The outcomes of this review suggest a complex interaction between a multitude of factors influencing adolescent drug abuse. Therefore, successful adolescent drug abuse prevention programs will require extensive work at all levels of domains.

Peer Review reports

Introduction

Drug abuse is a global problem; 5.6% of the global population aged 15–64 years used drugs at least once during 2016 [ 1 ]. The usage of drugs among younger people has been shown to be higher than that among older people for most drugs. Drug abuse is also on the rise in many ASEAN (Association of Southeast Asian Nations) countries, especially among young males between 15 and 30 years of age. The increased burden due to drug abuse among adolescents and young adults was shown by the Global Burden of Disease (GBD) study in 2013 [ 2 ]. About 14% of the total health burden in young men is caused by alcohol and drug abuse. Younger people are also more likely to die from substance use disorders [ 3 ], and cannabis is the drug of choice among such users [ 4 ].

Adolescents are the group of people most prone to addiction [ 5 ]. The critical age of initiation of drug use begins during the adolescent period, and the maximum usage of drugs occurs among young people aged 18–25 years old [ 1 ]. During this period, adolescents have a strong inclination toward experimentation, curiosity, susceptibility to peer pressure, rebellion against authority, and poor self-worth, which makes such individuals vulnerable to drug abuse [ 2 ]. During adolescence, the basic development process generally involves changing relations between the individual and the multiple levels of the context within which the young person is accustomed. Variation in the substance and timing of these relations promotes diversity in adolescence and represents sources of risk or protective factors across this life period [ 6 ]. All these factors are crucial to helping young people develop their full potential and attain the best health in the transition to adulthood. Abusing drugs impairs the successful transition to adulthood by impairing the development of critical thinking and the learning of crucial cognitive skills [ 7 ]. Adolescents who abuse drugs are also reported to have higher rates of physical and mental illness and reduced overall health and well-being [ 8 ].

The absence of protective factors and the presence of risk factors predispose adolescents to drug abuse. Some of the risk factors are the presence of early mental and behavioral health problems, peer pressure, poorly equipped schools, poverty, poor parental supervision and relationships, a poor family structure, a lack of opportunities, isolation, gender, and accessibility to drugs [ 9 ]. The protective factors include high self-esteem, religiosity, grit, peer factors, self-control, parental monitoring, academic competence, anti-drug use policies, and strong neighborhood attachment [ 10 , 11 , 12 , 13 , 14 , 15 ].

The majority of previous systematic reviews done worldwide on drug usage focused on the mental, psychological, or social consequences of substance abuse [ 16 , 17 , 18 ], while some focused only on risk and protective factors for the non-medical use of prescription drugs among youths [ 19 ]. A few studies focused only on the risk factors of single drug usage among adolescents [ 20 ]. Therefore, the development of the current systematic review is based on the main research question: What is the current risk and protective factors among adolescent on the involvement with drug abuse? To the best of our knowledge, there is limited evidence from systematic reviews that explores the risk and protective factors among the adolescent population involved in drug abuse. Especially among developing countries, such as those in South East Asia, such research on the risk and protective factors for drug abuse is scarce. Furthermore, this review will shed light on the recent trends of risk and protective factors and provide insight into the main focus factors for prevention and control activities program. Additionally, this review will provide information on how these risk and protective factors change throughout various developmental stages. Therefore, the objective of this systematic review was to determine the risk and protective factors of drug abuse among adolescents worldwide. This paper thus fills in the gaps of previous studies and adds to the existing body of knowledge. In addition, this review may benefit certain parties in developing countries like Malaysia, where the national response to drugs is developing in terms of harm reduction, prison sentences, drug treatments, law enforcement responses, and civil society participation.

This systematic review was conducted using three databases, PubMed, EBSCOhost, and Web of Science, considering the easy access and wide coverage of reliable journals, focusing on the risk and protective factors of drug abuse among adolescents from 2016 until December 2020. The search was limited to the last 5 years to focus only on the most recent findings related to risk and protective factors. The search strategy employed was performed in accordance with the Preferred Reporting Items for a Systematic Review and Meta-analysis (PRISMA) checklist.

A preliminary search was conducted to identify appropriate keywords and determine whether this review was feasible. Subsequently, the related keywords were searched using online thesauruses, online dictionaries, and online encyclopedias. These keywords were verified and validated by an academic professor at the National University of Malaysia. The keywords used as shown in Table  1 .

Selection criteria

The systematic review process for searching the articles was carried out via the steps shown in Fig.  1 . Firstly, screening was done to remove duplicate articles from the selected search engines. A total of 240 articles were removed in this stage. Titles and abstracts were screened based on the relevancy of the titles to the inclusion and exclusion criteria and the objectives. The inclusion criteria were full text original articles, open access articles or articles subscribed to by the institution, observation and intervention study design and English language articles. The exclusion criteria in this search were (a) case study articles, (b) systematic and narrative review paper articles, (c) non-adolescent-based analyses, (d) non-English articles, and (e) articles focusing on smoking (nicotine) and alcohol-related issues only. A total of 130 articles were excluded after title and abstract screening, leaving 55 articles to be assessed for eligibility. The full text of each article was obtained, and each full article was checked thoroughly to determine if it would fulfil the inclusion criteria and objectives of this study. Each of the authors compared their list of potentially relevant articles and discussed their selections until a final agreement was obtained. A total of 22 articles were accepted to be included in this review. Most of the excluded articles were excluded because the population was not of the target age range—i.e., featuring subjects with an age > 18 years, a cohort born in 1965–1975, or undergraduate college students; the subject matter was not related to the study objective—i.e., assessing the effects on premature mortality, violent behavior, psychiatric illness, individual traits, and personality; type of article such as narrative review and neuropsychiatry review; and because of our inability to obtain the full article—e.g., forthcoming work in 2021. One qualitative article was added to explain the domain related to risk and the protective factors among the adolescents.

PRISMA flow diagram showing the selection of studies on risk and protective factors for drug abuse among adolescents.2.2. Operational Definition

Drug-related substances in this context refer to narcotics, opioids, psychoactive substances, amphetamines, cannabis, ecstasy, heroin, cocaine, hallucinogens, depressants, and stimulants. Drugs of abuse can be either off-label drugs or drugs that are medically prescribed. The two most commonly abused substances not included in this review are nicotine (tobacco) and alcohol. Accordingly, e-cigarettes and nicotine vape were also not included. Further, “adolescence” in this study refers to members of the population aged between 10 to 18 years [ 21 ].

Data extraction tool

All researchers independently extracted information for each article into an Excel spreadsheet. The data were then customized based on their (a) number; (b) year; (c) author and country; (d) titles; (e) study design; (f) type of substance abuse; (g) results—risks and protective factors; and (h) conclusions. A second reviewer crossed-checked the articles assigned to them and provided comments in the table.

Quality assessment tool

By using the Mixed Method Assessment Tool (MMAT version 2018), all articles were critically appraised for their quality by two independent reviewers. This tool has been shown to be useful in systematic reviews encompassing different study designs [ 22 ]. Articles were only selected if both reviewers agreed upon the articles’ quality. Any disagreement between the assigned reviewers was managed by employing a third independent reviewer. All included studies received a rating of “yes” for the questions in the respective domains of the MMAT checklists. Therefore, none of the articles were removed from this review due to poor quality. The Cohen’s kappa (agreement) between the two reviewers was 0.77, indicating moderate agreement [ 23 ].

The initial search found 425 studies for review, but after removing duplicates and applying the criteria listed above, we narrowed the pool to 22 articles, all of which are quantitative in their study design. The studies include three prospective cohort studies [ 24 , 25 , 26 ], one community trial [ 27 ], one case-control study [ 28 ], and nine cross-sectional studies [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. After careful discussion, all reviewer panels agreed to add one qualitative study [ 46 ] to help provide reasoning for the quantitative results. The selected qualitative paper was chosen because it discussed almost all domains on the risk and protective factors found in this review.

A summary of all 23 articles is listed in Table  2 . A majority of the studies (13 articles) were from the United States of America (USA) [ 25 , 26 , 27 , 29 , 30 , 31 , 34 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ], three studies were from the Asia region [ 32 , 33 , 38 ], four studies were from Europe [ 24 , 28 , 40 , 44 ], and one study was from Latin America [ 35 ], Africa [ 43 ] and Mediterranean [ 45 ]. The number of sample participants varied widely between the studies, ranging from 70 samples (minimum) to 700,178 samples (maximum), while the qualitative paper utilized a total of 100 interviewees. There were a wide range of drugs assessed in the quantitative articles, with marijuana being mentioned in 11 studies, cannabis in five studies, and opioid (six studies). There was also large heterogeneity in terms of the study design, type of drug abused, measurements of outcomes, and analysis techniques used. Therefore, the data were presented descriptively.

After thorough discussion and evaluation, all the findings (both risk and protective factors) from the review were categorized into three main domains: individual factors, family factors, and community factors. The conceptual framework is summarized in Fig.  2 .

Conceptual framework of risk and protective factors related to adolescent drug abuse

DOMAIN: individual factor

Risk factors.

Almost all the articles highlighted significant findings of individual risk factors for adolescent drug abuse. Therefore, our findings for this domain were further broken down into five more sub-domains consisting of personal/individual traits, significant negative growth exposure, personal psychiatric diagnosis, previous substance history, comorbidity and an individual’s attitude and perception.

Personal/individual traits

Chuang et al. [ 29 ] found that adolescents with high impulsivity traits had a significant positive association with drug addiction. This study also showed that the impulsivity trait alone was an independent risk factor that increased the odds between two to four times for using any drug compared to the non-impulsive group. Another longitudinal study by Guttmannova et al. showed that rebellious traits are positively associated with marijuana drug abuse [ 27 ]. The authors argued that measures of rebelliousness are a good proxy for a youth’s propensity to engage in risky behavior. Nevertheless, Wilson et al. [ 37 ], in a study involving 112 youths undergoing detoxification treatment for opioid abuse, found that a majority of the affected respondents had difficulty in regulating their emotions. The authors found that those with emotional regulation impairment traits became opioid dependent at an earlier age. Apart from that, a case-control study among outpatient youths found that adolescents involved in cannabis abuse had significant alexithymia traits compared to the control population [ 28 ]. Those adolescents scored high in the dimension of Difficulty in Identifying Emotion (DIF), which is one of the key definitions of diagnosing alexithymia. Overall, the adjusted Odds Ratio for DIF in cannabis abuse was 1.11 (95% CI, 1.03–1.20).

Significant negative growth exposure

A history of maltreatment in the past was also shown to have a positive association with adolescent drug abuse. A study found that a history of physical abuse in the past is associated with adolescent drug abuse through a Path Analysis, despite evidence being limited to the female gender [ 25 ]. However, evidence from another study focusing at foster care concluded that any type of maltreatment might result in a prevalence as high as 85.7% for the lifetime use of cannabis and as high as 31.7% for the prevalence of cannabis use within the last 3-months [ 30 ]. The study also found significant latent variables that accounted for drug abuse outcomes, which were chronic physical maltreatment (factor loading of 0.858) and chronic psychological maltreatment (factor loading of 0.825), with an r 2 of 73.6 and 68.1%, respectively. Another study shed light on those living in child welfare service (CWS) [ 35 ]. It was observed through longitudinal measurements that proportions of marijuana usage increased from 9 to 18% after 36 months in CWS. Hence, there is evidence of the possibility of a negative upbringing at such shelters.

Personal psychiatric diagnosis

The robust studies conducted in the USA have deduced that adolescents diagnosed with a conduct problem (CP) have a positive association with marijuana abuse (OR = 1.75 [1.56, 1.96], p  < 0.0001). Furthermore, those with a diagnosis of Major Depressive Disorder (MDD) showed a significant positive association with marijuana abuse.

Previous substance and addiction history

Another study found that exposure to e-cigarettes within the past 30 days is related to an increase in the prevalence of marijuana use and prescription drug use by at least four times in the 8th and 10th grades and by at least three times in the 12th grade [ 34 ]. An association between other behavioral addictions and the development of drug abuse was also studied [ 29 ]. Using a 12-item index to assess potential addictive behaviors [ 39 ], significant associations between drug abuse and the groups with two behavioral addictions (OR = 3.19, 95% CI 1.25,9.77) and three behavioral addictions (OR = 3.46, 95% CI 1.25,9.58) were reported.

Comorbidity

The paper by Dash et al. (2020) highlight adolescent with a disease who needs routine medical pain treatment have higher risk of opioid misuse [ 38 ]. The adolescents who have disorder symptoms may have a risk for opioid misuse despite for the pain intensity.

Individual’s attitudes and perceptions

In a study conducted in three Latin America countries (Argentina, Chile, and Uruguay), it was shown that adolescents with low or no perceived risk of taking marijuana had a higher risk of abuse (OR = 8.22 times, 95% CI 7.56, 10.30) [ 35 ]. This finding is in line with another study that investigated 2002 adolescents and concluded that perceiving the drug as harmless was an independent risk factor that could prospectively predict future marijuana abuse [ 27 ]. Moreover, some youth interviewed perceived that they gained benefits from substance use [ 38 ]. The focus group discussion summarized that the youth felt positive personal motivation and could escape from a negative state by taking drugs. Apart from that, adolescents who had high-perceived availability of drugs in their neighborhoods were more likely to increase their usage of marijuana over time (OR = 11.00, 95% CI 9.11, 13.27) [ 35 ]. A cheap price of the substance and the availability of drug dealers around schools were factors for youth accessibility [ 38 ]. Perceived drug accessibility has also been linked with the authorities’ enforcement programs. The youth perception of a lax community enforcement of laws regarding drug use at all-time points predicted an increase in marijuana use in the subsequent assessment period [ 27 ]. Besides perception, a study examining the attitudes towards synthetic drugs based on 8076 probabilistic samples of Macau students found that the odds of the lifetime use of marijuana was almost three times higher among those with a strong attitude towards the use of synthetic drugs [ 32 ]. In addition, total screen time among the adolescent increase the likelihood of frequent cannabis use. Those who reported daily cannabis use have a mean of 12.56 h of total screen time, compared to a mean of 6.93 h among those who reported no cannabis use. Adolescent with more time on internet use, messaging, playing video games and watching TV/movies were significantly associated with more frequent cannabis use [ 44 ].

Protective factors

Individual traits.

Some individual traits have been determined to protect adolescents from developing drug abuse habits. A study by Marin et al. found that youth with an optimistic trait were less likely to become drug dependent [ 33 ]. In this study involving 1104 Iranian students, it was concluded that a higher optimism score (measured using the Children Attributional Style Questionnaire, CASQ) was a protective factor against illicit drug use (OR = 0.90, 95% CI: 0.85–0.95). Another study found that high levels of mindfulness, measured using the 25-item Child Acceptance and Mindfulness Measure, CAMM, lead to a slower progression toward injectable drug abuse among youth with opioid addiction (1.67 years, p  = .041) [ 37 ]. In addition, the social phobia trait was found to have a negative association with marijuana use (OR = 0.87, 95% CI 0.77–0.97), as suggested [ 31 ].

According to El Kazdouh et al., individuals with a strong belief against substance use and those with a strong desire to maintain their health were more likely to be protected from involvement in drug abuse [ 46 ].

DOMAIN: family factors

The biological factors underlying drug abuse in adolescents have been reported in several studies. Epigenetic studies are considered important, as they can provide a good outline of the potential pre-natal factors that can be targeted at an earlier stage. Expecting mothers who smoke tobacco and alcohol have an indirect link with adolescent substance abuse in later life [ 24 , 39 ]. Moreover, the dynamic relationship between parents and their children may have some profound effects on the child’s growth. Luk et al. examined the mediator effects between parenting style and substance abuse and found the maternal psychological control dimension to be a significant variable [ 26 ]. The mother’s psychological control was two times higher in influencing her children to be involved in substance abuse compared to the other dimension. Conversely, an indirect risk factor towards youth drug abuse was elaborated in a study in which low parental educational level predicted a greater risk of future drug abuse by reducing the youth’s perception of harm [ 27 , 43 ]. Negligence from a parental perspective could also contribute to this problem. According to El Kazdouh et al. [ 46 ], a lack of parental supervision, uncontrolled pocket money spending among children, and the presence of substance-using family members were the most common negligence factors.

While the maternal factors above were shown to be risk factors, the opposite effect was seen when the paternal figure equipped himself with sufficient knowledge. A study found that fathers with good information and awareness were more likely to protect their adolescent children from drug abuse [ 26 ]. El Kazdouh et al. noted that support and advice could be some of the protective factors in this area [ 46 ].

DOMAIN: community factors

• Risk factor

A study in 2017 showed a positive association between adolescent drug abuse and peers who abuse drugs [ 32 , 39 ]. It was estimated that the odds of becoming a lifetime marijuana user was significantly increased by a factor of 2.5 ( p  < 0.001) among peer groups who were taking synthetic drugs. This factor served as peer pressure for youth, who subconsciously had desire to be like the others [ 38 ]. The impact of availability and engagement in structured and unstructured activities also play a role in marijuana use. The findings from Spillane (2000) found that the availability of unstructured activities was associated with increased likelihood of marijuana use [ 42 ].

• Protective factor

Strong religious beliefs integrated into society serve as a crucial protective factor that can prevent adolescents from engaging in drug abuse [ 38 , 45 ]. In addition, the school connectedness and adult support also play a major contribution in the drug use [ 40 ].

The goal of this review was to identify and classify the risks and protective factors that lead adolescents to drug abuse across the three important domains of the individual, family, and community. No findings conflicted with each other, as each of them had their own arguments and justifications. The findings from our review showed that individual factors were the most commonly highlighted. These factors include individual traits, significant negative growth exposure, personal psychiatric diagnosis, previous substance and addiction history, and an individual’s attitude and perception as risk factors.

Within the individual factor domain, nine articles were found to contribute to the subdomain of personal/ individual traits [ 27 , 28 , 29 , 37 , 38 , 39 , 40 , 43 , 44 ]. Despite the heterogeneity of the study designs and the substances under investigation, all of the papers found statistically significant results for the possible risk factors of adolescent drug abuse. The traits of high impulsivity, rebelliousness, difficulty in regulating emotions, and alexithymia can be considered negative characteristic traits. These adolescents suffer from the inability to self-regulate their emotions, so they tend to externalize their behaviors as a way to avoid or suppress the negative feelings that they are experiencing [ 41 , 47 , 48 ]. On the other hand, engaging in such behaviors could plausibly provide a greater sense of positive emotions and make them feel good [ 49 ]. Apart from that, evidence from a neurophysiological point of view also suggests that the compulsive drive toward drug use is complemented by deficits in impulse control and decision making (impulsive trait) [ 50 ]. A person’s ability in self-control will seriously impaired with continuous drug use and will lead to the hallmark of addiction [ 51 ].

On the other hand, there are articles that reported some individual traits to be protective for adolescents from engaging in drug abuse. Youth with the optimistic trait, a high level of mindfulness, and social phobia were less likely to become drug dependent [ 31 , 33 , 37 ]. All of these articles used different psychometric instruments to classify each individual trait and were mutually exclusive. Therefore, each trait measured the chance of engaging in drug abuse on its own and did not reflect the chance at the end of the spectrum. These findings show that individual traits can be either protective or risk factors for the drugs used among adolescents. Therefore, any adolescent with negative personality traits should be monitored closely by providing health education, motivation, counselling, and emotional support since it can be concluded that negative personality traits are correlated with high risk behaviours such as drug abuse [ 52 ].

Our study also found that a history of maltreatment has a positive association with adolescent drug abuse. Those adolescents with episodes of maltreatment were considered to have negative growth exposure, as their childhoods were negatively affected by traumatic events. Some significant associations were found between maltreatment and adolescent drug abuse, although the former factor was limited to the female gender [ 25 , 30 , 36 ]. One possible reason for the contrasting results between genders is the different sample populations, which only covered child welfare centers [ 36 ] and foster care [ 30 ]. Regardless of the place, maltreatment can happen anywhere depending on the presence of the perpetrators. To date, evidence that concretely links maltreatment and substance abuse remains limited. However, a plausible explanation for this link could be the indirect effects of posttraumatic stress (i.e., a history of maltreatment) leading to substance use [ 53 , 54 ]. These findings highlight the importance of continuous monitoring and follow-ups with adolescents who have a history of maltreatment and who have ever attended a welfare center.

Addiction sometimes leads to another addiction, as described by the findings of several studies [ 29 , 34 ]. An initial study focused on the effects of e-cigarettes in the development of other substance abuse disorders, particularly those related to marijuana, alcohol, and commonly prescribed medications [ 34 ]. The authors found that the use of e-cigarettes can lead to more severe substance addiction [ 55 ], possibly through normalization of the behavior. On the other hand, Chuang et al.’s extensive study in 2017 analyzed the combined effects of either multiple addictions alone or a combination of multiple addictions together with the impulsivity trait [ 29 ]. The outcomes reported were intriguing and provide the opportunity for targeted intervention. The synergistic effects of impulsiveness and three other substance addictions (marijuana, tobacco, and alcohol) substantially increased the likelihood for drug abuse from 3.46 (95%CI 1.25, 9.58) to 10.13 (95% CI 3.95, 25.95). Therefore, proper rehabilitation is an important strategy to ensure that one addiction will not lead to another addiction.

The likelihood for drug abuse increases as the population perceives little or no harmful risks associated with the drugs. On the opposite side of the coin, a greater perceived risk remains a protective factor for marijuana abuse [ 56 ]. However, another study noted that a stronger determinant for adolescent drug abuse was the perceived availability of the drug [ 35 , 57 ]. Looking at the bigger picture, both perceptions corroborate each other and may inform drug use. Another study, on the other hand, reported that there was a decreasing trend of perceived drug risk in conjunction with the increasing usage of drugs [ 58 ]. As more people do drugs, youth may inevitably perceive those drugs as an acceptable norm without any harmful consequences [ 59 ].

In addition, the total spent for screen time also contribute to drug abuse among adolescent [ 43 ]. This scenario has been proven by many researchers on the effect of screen time on the mental health [ 60 ] that leads to the substance use among the adolescent due to the ubiquity of pro-substance use content on the internet. Adolescent with comorbidity who needs medical pain management by opioids also tend to misuse in future. A qualitative exploration on the perspectives among general practitioners concerning the risk of opioid misuse in people with pain, showed pain management by opioids is a default treatment and misuse is not a main problem for the them [ 61 ]. A careful decision on the use of opioids as a pain management should be consider among the adolescents and their understanding is needed.

Within the family factor domain, family structures were found to have both positive and negative associations with drug abuse among adolescents. As described in one study, paternal knowledge was consistently found to be a protective factor against substance abuse [ 26 ]. With sufficient knowledge, the father can serve as the guardian of his family to monitor and protect his children from negative influences [ 62 ]. The work by Luk et al. also reported a positive association of maternal psychological association towards drug abuse (IRR 2.41, p  < 0.05) [ 26 ]. The authors also observed the same effect of paternal psychological control, although it was statistically insignificant. This construct relates to parenting style, and the authors argued that parenting style might have a profound effect on the outcomes under study. While an earlier literature review [ 63 ] also reported such a relationship, a recent study showed a lesser impact [ 64 ] with regards to neglectful parenting styles leading to poorer substance abuse outcomes. Nevertheless, it was highlighted in another study that the adolescents’ perception of a neglectful parenting style increased their odds (OR 2.14, p  = 0.012) of developing alcohol abuse, not the parenting style itself [ 65 ]. Altogether, families play vital roles in adolescents’ risk for engaging in substance abuse [ 66 ]. Therefore, any intervention to impede the initiation of substance use or curb existing substance use among adolescents needs to include parents—especially improving parent–child communication and ensuring that parents monitor their children’s activities.

Finally, the community also contributes to drug abuse among adolescents. As shown by Li et al. [ 32 ] and El Kazdouh et al. [ 46 ], peers exert a certain influence on other teenagers by making them subconsciously want to fit into the group. Peer selection and peer socialization processes might explain why peer pressure serves as a risk factor for drug-abuse among adolescents [ 67 ]. Another study reported that strong religious beliefs integrated into society play a crucial role in preventing adolescents from engaging in drug abuse [ 46 ]. Most religions devalue any actions that can cause harmful health effects, such as substance abuse [ 68 ]. Hence, spiritual beliefs may help protect adolescents. This theme has been well established in many studies [ 60 , 69 , 70 , 71 , 72 ] and, therefore, could be implemented by religious societies as part of interventions to curb the issue of adolescent drug abuse. The connection with school and structured activity did reduce the risk as a study in USA found exposure to media anti-drug messages had an indirect negative effect on substances abuse through school-related activity and social activity [ 73 ]. The school activity should highlight on the importance of developmental perspective when designing and offering school-based prevention programs [75].

Limitations

We adopted a review approach that synthesized existing evidence on the risk and protective factors of adolescents engaging in drug abuse. Although this systematic review builds on the conclusion of a rigorous review of studies in different settings, there are some potential limitations to this work. We may have missed some other important factors, as we only included English articles, and article extraction was only done from the three search engines mentioned. Nonetheless, this review focused on worldwide drug abuse studies, rather than the broader context of substance abuse including alcohol and cigarettes, thereby making this paper more focused.

Conclusions

This review has addressed some recent knowledge related to the individual, familial, and community risk and preventive factors for adolescent drug use. We suggest that more attention should be given to individual factors since most findings were discussed in relation to such factors. With the increasing trend of drug abuse, it will be critical to focus research specifically on this area. Localized studies, especially those related to demographic factors, may be more effective in generating results that are specific to particular areas and thus may be more useful in generating and assessing local control and prevention efforts. Interventions using different theory-based psychotherapies and a recognition of the unique developmental milestones specific to adolescents are among examples that can be used. Relevant holistic approaches should be strengthened not only by relevant government agencies but also by the private sector and non-governmental organizations by promoting protective factors while reducing risk factors in programs involving adolescents from primary school up to adulthood to prevent and control drug abuse. Finally, legal legislation and enforcement against drug abuse should be engaged with regularly as part of our commitment to combat this public health burden.

Data availability and materials

All data generated or analysed during this study are included in this published article.

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Acknowledgements

The authors acknowledge The Ministry of Higher Education Malaysia and The Universiti Kebangsaan Malaysia, (UKM) for funding this study under the Long-Term Research Grant Scheme-(LGRS/1/2019/UKM-UKM/2/1). We also thank the team for their commitment and tireless efforts in ensuring that manuscript was well executed.

Financial support for this study was obtained from the Ministry of Higher Education, Malaysia through the Long-Term Research Grant Scheme-(LGRS/1/2019/UKM-UKM/2/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Nawi, A.M., Ismail, R., Ibrahim, F. et al. Risk and protective factors of drug abuse among adolescents: a systematic review. BMC Public Health 21 , 2088 (2021). https://doi.org/10.1186/s12889-021-11906-2

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• Volume 10, Issue 9
• Impact evaluations of drug decriminalisation and legal regulation on drug use, health and social harms: a systematic review
• Article Text
• Article info
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• http://orcid.org/0000-0001-8498-9829 Ayden I Scheim 1 , 2 ,
• Nazlee Maghsoudi 2 , 3 ,
• Zack Marshall 4 ,
• Siobhan Churchill 5 ,
• Carolyn Ziegler 6 ,
• Dan Werb 2 , 7
• 1 Epidemiology and Biostatistics , Dornsife School of Public Health, Drexel University , Philadelphia , Pennsylvania , USA
• 2 Centre on Drug Policy Evaluation , St Michael's Hospital , Toronto , Ontario , Canada
• 3 Institute of Health Policy, Management and Evaluation , University of Toronto , Toronto , Ontario , Canada
• 4 Social Work , McGill University , Montreal , Quebec , Canada
• 5 Epidemiology and Biostatistics , Western University , London , Ontario , Canada
• 6 Library Services , Unity Health Toronto , Toronto , Ontario , Canada
• 7 Medicine , University of California San Diego , La Jolla , California , USA
• Correspondence to Dr Dan Werb; dwerb{at}ucsd.edu

Objectives To review the metrics and findings of studies evaluating effects of drug decriminalisation or legal regulation on drug availability, use or related health and social harms globally.

Design Systematic review with narrative synthesis.

Data sources We searched MEDLINE, Embase, PsycINFO, Web of Science and six additional databases for publications from 1 January 1970 through 4 October 2018.

Inclusion criteria Peer-reviewed articles or published abstracts in any language with quantitative data on drug availability, use or related health and social harms collected before and after implementation of de jure drug decriminalisation or legal regulation.

Data extraction and synthesis Two independent reviewers screened titles, abstracts and articles for inclusion. Extraction and quality appraisal (modified Downs and Black checklist) were performed by one reviewer and checked by a second, with discrepancies resolved by a third. We coded study-level outcome measures into metric groupings and categorised the estimated direction of association between the legal change and outcomes of interest.

Results We screened 4860 titles and 221 full-texts and included 114 articles. Most (n=104, 91.2%) were from the USA, evaluated cannabis reform (n=109, 95.6%) and focussed on legal regulation (n=96, 84.2%). 224 study outcome measures were categorised into 32 metrics, most commonly prevalence (39.5% of studies), frequency (14.0%) or perceived harmfulness (10.5%) of use of the decriminalised or regulated drug; or use of tobacco, alcohol or other drugs (12.3%). Across all substance use metrics, legal reform was most often not associated with changes in use.

Conclusions Studies evaluating drug decriminalisation and legal regulation are concentrated in the USA and on cannabis legalisation. Despite the range of outcomes potentially impacted by drug law reform, extant research is narrowly focussed, with a particular emphasis on the prevalence of use. Metrics in drug law reform evaluations require improved alignment with relevant health and social outcomes.

• substance misuse
• public health
• law (see medical law)

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https://doi.org/10.1136/bmjopen-2019-035148

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Strengths and limitations of this study

This is the first study to review all literature on the health and social impacts of decriminalisation or legal regulation of drugs.

We systematically searched 10 databases over a 38-year period, without language restrictions.

The review was limited to study designs appropriate for evaluating interventions, nevertheless, most included studies used relatively weak evaluation designs.

Included outcomes were heterogeneous and not quantitatively synthesised.

Heterogeneity in the details and implementation of decriminalisation or legal regulation policies was not considered in this review.

Introduction

An estimated 271 million people used an internationally scheduled (‘illicit’) drug in 2017, corresponding to 5.5% of the global population aged 15 to 64. 1 Despite decades of investment, policies aimed at reducing supply and demand have demonstrated limited effectiveness. 2 3 Moreover, prohibitive and punitive drug policies have had counterproductive effects by contributing to HIV and hepatitis C transmission, 4 5 fatal overdose, 6 mass incarceration and other human rights violations 7 8 and drug market violence. 9 As a result, there have been growing calls for drug law reform 10–12 and in 2019, the United Nations Chief Executives Board endorsed decriminalisation of drug use and possession. 13 Against this backdrop, as of 2017 approximately 23 countries had implemented de jure decriminalisation or legal regulation of one or more previously illegal drugs. 14–16

A wide range of health and social outcomes are affected by psychoactive drug production, sales and use, and thus are potentially impacted by drug law reform. Nutt and colleagues have categorised these as physical harms (eg, drug-related morbidity and mortality to users, injury to non-users), psychological harms (eg, dependence) and social harms (eg, loss of tangibles, environmental damage). 17 18 Concomitantly, a diverse and sometimes competing set of goals motivate drug policy development, including ameliorating the poor health and social marginalisation experienced by people who use drugs problematically, shifting patterns of use to less harmful products or modes of administration, curtailing illegal markets and drug-related crime and reducing the economic burden of drug-related harms. 19

Given ongoing interest by states in drug law reform, as well as the recent position statement by the United Nations Chief Executives Board endorsing drug decriminalisation, 13 a comprehensive understanding of their impacts to date is required. However, the scientific literature has not been well-characterised, and thus the state of the evidence related to these heterogeneous policy targets remains largely unclear. Systematic reviews, including two meta-analyses, are narrowly focussed on adolescent cannabis use. Dirisu et al found no conclusive evidence that cannabis legalisation for medical or recreational purposes increases cannabis use by young people. 20 In the two meta-analyses, Sarvet et al found that the implementation of medical cannabis policies in the USA did not lead to increases in the prevalence of past-month cannabis use among adolescents 21 and Melchior et al found a small increase in use following recreational legalisation that was reported only among lower-quality studies. 22

Given increasing interest in quantifying the impact of drug law reform, as well as a lack of systematic assessment of outcomes beyond adolescent cannabis use to date, we conducted a systematic review of original peer-reviewed research evaluating the impacts of (a) legal regulation and (b) drug decriminalisation on drug availability, use or related health and social harms. Our primary aim is to characterise studies with respect to metrics and indicators used. The secondary aim is to summarise the findings and methodological quality of studies to date.

Consistent with our aim of synthesising evidence on the impacts of decriminalisation and legal regulation across the spectrum of potential health and social effects, we conducted a systematic review using narrative synthesis 23 without meta-analysis. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed in preparing this manuscript. 24 The review protocol was registered in PROSPERO (CRD42017079681) and can be found online at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=79681 .

Search strategy and selection criteria

The review team developed, piloted and refined the search strategy in consultation with a research librarian and content experts. We searched MEDLINE, Embase, PsycINFO, Web of Science, Criminal Justice Abstracts, Applied Social Sciences Index & Abstracts, International Bibliography of the Social Sciences, PAIS Index, Policy File Index and Sociological Abstracts for publications from 1 January 1970 through 4 October 2018. We used MeSH (Medical Subject Headings) terms and keywords related to (a) scheduled psychoactive drugs, (b) legal regulation or decriminalisation policies and (c) quantitative study designs. Search terms specific to health and social outcomes were not employed so that the search would capture the broad range of outcomes of interest. See online supplemental appendix A for the final MEDLINE search strategy. For conference abstracts, we contacted authors for additional information on study methods and to identify subsequent relevant publications.

Supplemental material

We included peer-reviewed journal articles or conference abstracts reporting on original quantitative studies that collected data both before and after the implementation of drug decriminalisation or legal regulation. We did not consider as original research studies that reproduced secondary data without conducting original statistical analyses of the data. We defined decriminalisation as the removal of criminal penalties for drug use and/or possession (allowing for civil or administrative sanctions) and legal regulation as the development of a legal regulatory framework for the use, production and sale of formerly illegal psychoactive drugs. Studies were excluded if they evaluated de facto (eg, changes in enforcement practices) rather than de jure decriminalisation or legal regulation (changes to the law). This exclusion applied to studies analysing changes in outcomes following the US Justice Department 2009 memo deprioritising prosecution of cannabis-related offences legal under state medical cannabis laws. Eligible studies included outcome measures pertaining to drug availability, use or related health and social harms. We used the schema developed by Nutt and colleagues to conceptualise health and social harms, including those to users (physical, psychological and social) and to others (injury or social harm). 18

Both observational studies and randomised controlled trials were eligible in principle, but no trials were identified. There were no geographical or language restrictions; titles, abstracts and full-texts were translated on an as-needed basis for screening and data extraction. We excluded cross-sectional studies (unless they were repeated) and studies lacking pre-implementation and post-implementation data collection because such designs are inappropriate for evaluating intervention effects.

Data analysis

Screening and data extraction were conducted in DistillerSR (Evidence Partners, Ottawa, Ontario). We began with title-only screening to identify potentially relevant titles. Two reviewers screened each title. Unless both reviewers independently decided a title should be excluded, it was advanced to the next stage. Next, two reviewers independently screened each potentially eligible abstract. Inter-rater reliability was good (weighted Kappa at the question level=0.75). At this stage, we retrieved full-text copies of all remaining references, which were screened independently by two reviewers. Disagreements on inclusion were resolved through discussion with the first author. Finally, one reviewer extracted data from each included publication using a standardised, pre-piloted form and performed quality appraisal. A second reviewer double-checked data extraction and quality appraisal for every publication, and the first author resolved any discrepancies.

The data extraction form included information on study characteristics (author, title, year, geographical location), type of legal change studied and drug(s) impacted, details and timing of the legal change (eg, medical vs recreational cannabis regulation), study design, sampling approach, sample characteristics (size, age range, proportion female) and quantitative estimates of association. We coded each study-level outcome measure into one metric grouping, using 24 pre-specified categories and a free-text field (see figure 1 for full list). Examples of metrics include: prevalence of use of the decriminalised or regulated drug, overdose or poisoning and non-drug crime.

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Metrics examined by included studies. excl., excluding.

We also categorised the estimated direction of association of the legal change on outcome measure(s) of interest (beneficial, harmful, mixed or null). These associations were coded at the outcome (not study) level and classified as beneficial if a statistically significant increase in a positive outcome (eg, educational attainment) or decrease in a negative outcome (eg, substance use disorder) was attributed to implementation of decriminalisation or legal regulation, and vice versa for harmful associations. The association was categorised as mixed if associations were both harmful and beneficial across participant subgroups, exposure definitions (eg, loosely vs tightly regulated medical cannabis access) or timeframes. Although any use of cannabis and other psychoactive drugs need not be problematic at the individual level, we categorised drug use as a negative outcome given that population-level increases in use may correspond to increases in negative consequences; we thought that this cautious approach to categorisation was appropriate given that such increases are generally conceptualised as negative within the scientific literature. For outcomes that are not unambiguously negative or positive, the coding approach was predetermined taking a societal perspective. For example, increased healthcare utilisation (eg, hospital visits due to cannabis use) was coded as negative because of the increased burden placed on healthcare systems. The association was categorised as null if no statistically significant changes following implementation of drug decriminalisation or legal regulation were detected. We set statistical significance at a= 0.05, including in cases where authors used more liberal criteria.

Quality assessment at the study level was conducted for each full-length article using a modified version of the Downs and Black checklist 25 for observational studies ( online supplemental appendix B ), which assesses internal validity (bias), external validity and reporting. Each study could receive up to 18 points, with higher scores indicating more methodologically rigorous studies. Conference abstracts were not subjected to quality assessment due to limited methodological details.

Patient and public involvement

This systematic review of existing studies did not include patient or public involvement.

Study characteristics

As shown in the PRISMA flow diagram ( figure 2 ), we screened 4860 titles and abstracts and 213 full-texts, with 114 articles meeting inclusion criteria ( online supplemental appendix C ). Key reasons for exclusion at the full-text screening stage were that the article did not report on original quantitative research (n=59) or did not evaluate decriminalisation or legal regulation as defined herein (n=23). Details of each included study are presented in online supplemental table 1 . Included studies had final publication dates from 1976 to 2019; 44.7% (n=51) were first published in 2017 to 2018, 43.9% (n=50) were published in 2014 to 2016 and 11.4% (n=13) were published before 2014.

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram.

Characteristics of included studies are described in table 1 , both overall and stratified by whether they evaluated decriminalisation (n=19) or legalisation (n=96) policies (one study evaluated both policies). Most studies (n=104, 91.2%) were from the USA and examined impacts of liberalising cannabis laws (n=109, 95.6%). Countries represented in non-US studies included Australia, Belgium, China, Czech Republic, Mexico and Portugal. The most common study designs were repeated cross-sectional (n=74, 64.9%) or controlled before-and-after (n=26, 22.8%) studies and the majority of studies (n=87, 76.3%) used population-based sampling methods. Figure 3 illustrates the geographical distribution of studies among countries where national or subnational governments had decriminalised or legally regulated one or more drugs by 2017.

• View inline

Characteristics of studies evaluating drug decriminalisation or legal regulation, 1970 to 2018

Number of included studies from countries that implemented decriminalisation or legal regulation by 2017. Note: Policy changes were classified, following the review inclusion criteria, based on the implementation of a change to national or subnational law to decriminalise drug use and/or possession or to legalise at least one class of drugs. We did not evaluate the extent to which legal changes were reflected in policing and criminal justice practice. Implementation of cannabis legalisation for medical purposes only is not reflected in this map.

Study quality

Quality assessment was performed for the 93 full-length articles included in the review, excluding 21 conference abstracts ( online supplemental table 1 ). Scores ranged from 7 to 18 of 18 possible points, with a mean of 14.4 (SD=2.56). Quality scores were similar comparing US to non-US-based studies ( X =14.4 and 13.7, respectively, p=0.386) but higher for studies evaluating legal regulation ( X =14.8) versus decriminalisation ( X =12.8) (p=0.003). Study quality differed significantly (p<0.001) by the direction of the association with the outcome of interest, with higher quality scores among studies estimating mixed ( X =15.4) or beneficial ( X =15.2) versus null ( X =14.2) or harmful ( X =13.1) effects of legal change on the outcome of interest. Study quality did not appear to increase over time (eg, X =14.0 in 2014 and 14.4 in 2018).

Study outcome measures and metrics

Across 114 studies we extracted 224 outcome measures, which were coded into 32 metrics ( figure 1 ). The most common metric employed by studies was the prevalence of use of the decriminalised or legally regulated drug, which was examined in 39.5% of studies (n=45) and represented 22.3% of outcome measures (n=50). Of these studies, 13 (28.9%; 8 full-length articles and 5 abstracts) did not report any other metric 26–38 and an additional 6 studies (13.3%) reported on the prevalence of use in addition to a single drug-related perception metric (either harmfulness or availability). 39–44 The second most common metric was the frequency of use of the decriminalised or legally regulated drug (14.0% of studies, n=16) and the third was the prevalence or frequency of use of tobacco, alcohol or drugs that remained illegal (12.3% of studies, n=14). The fourth most commonly employed metric was any change in the perceived health harmfulness of using the decriminalised or regulated drug (10.5% of studies, n=12), which was assessed among adolescents or young adults in all studies except for one that assessed this metric among parents. 45

All other metrics were assessed in <10% of included studies. Health service utilisation was evaluated in 7.9% of studies (n=9) using 12 outcome measures, primarily related to emergency department visits and/or hospitalisations. Prescribed (primarily opioid) drug use and perceived availability of the decriminalised or legally regulated drug were reported in 7.0% of studies each (n=8). Overdose or poisoning by the decriminalised or regulated drug, and by other drugs (predominantly opioids), were examined in 5.3% (n=6) and 6.1% of studies (n=7), respectively. Driving while under the influence or with detectable concentrations of the decriminalised or regulated drug (cannabis) was examined in seven studies (6.1%) inclusive of eight outcome measures. Notably, one study assessed self-reported impaired driving, 46 while others assessed the proportion of fatally injured drivers screening cannabis-positive or the overall prevalence of driving with detectable tetrahydrocannabinol (THC) concentrations in blood. Remaining metrics were measured in less than 5% of studies ( figure 1 ). Some pre-specified metrics were not represented in any of the articles, including infectious disease incidence (eg, HIV, hepatitis C), environmental impacts (eg, drug production waste, discarded needles) and labour market participation.

Studies outside the US

Of the 10 studies conducted outside the USA, 6 focussed on cannabis decriminalisation. All three studies from Australia examined the prevalence of cannabis use post-decriminalisation, 31 34 47 while one also measured perceived cannabis availability. 47 Following cannabis decriminalisation, one European multi-country study including Belgium and Portugal examined the prevalence of cannabis use and uptake of cannabis-related addictions treatment 48 and one Czech study considered the age of first cannabis use. 49 An international study using United Nations Office on Drugs and Crime data from 102 countries compared availability, as reflected by cannabis seizures and plant eradication, in countries that had decriminalised cannabis versus those that had not. 50 Three non-US studies evaluated decriminalisation of all psychoactive drugs. Two studies from Portugal examined healthcare and non-healthcare costs and psychoactive drug prices, respectively. 51 52 One study from Mexico examined drug-related criminal justice involvement (arrests) and (violent) crimes. 53 Finally, a study of historic opium legalisation in China (1801 to 1902) measured the price and availability (quantity of exports) of opium before and after legalisation. 54

Impacts of decriminalisation and legal regulation

Results of individual studies are provided in online supplemental table 1 . Online supplemental table 2 tallies findings and average quality scores for each of the metrics; here we summarise findings for metrics examined in more than 5% of studies, in descending order based on the number of datapoints. Across all three substance use metrics (prevalence of use, frequency of use and use of other alcohol or drugs), drug law reform was most often not associated with use (with null findings for 48.0% to 52.4% of outcome measures falling under these metrics). With respect to change in perceived harmfulness of the decriminalised or regulated drug, mixed results were found in half of cases, with heterogeneity detected on the basis of age, gender and state. 39 43 55–57 For example, legal regulation of cannabis for medical use was associated with greater perceived harmfulness of cannabis among eighth graders but not older students in an analysis of US Monitoring the Future data 39 while a study employing US National Survey on Drug Use and Health data found greater perceived harmfulness of cannabis among young adults aged 18 to 25 but not adolescents aged 12 to 17. 57

Among nine studies that employed health service utilisation metrics, harmful effects were reported for 6 of 12 outcome measures, with increases in emergency department visits and/or hospitalisations attributed to decriminalisation or legal regulation. 58–63 However, all but one of those studies 58 assessed change over time in one jurisdiction, without a control group. Further, two studies that also examined changes in acute care use for non-cannabis drugs found reductions in those visits or admissions following cannabis decriminalisation or legal regulation. 60 64 In contrast, six of nine prescription drug use associations were beneficial, with reductions observed in rates of opioid 65–69 and other drug prescribing 70 71 attributed to legal regulation of cannabis for medical use; outcomes in this category came from studies of higher average quality ( X =16.3). Perceived availability of the decriminalised or regulated drug appeared largely unaffected by decriminalisation (null associations for five of nine outcome measures) but two studies indicated increased perceived availability of cannabis among Colorado, US, adolescents following legal regulation for adult use 72 and among adults in US states with legal regulation for medical use. 44 Across the subset of seven outcome measures for overdose or poisoning by the decriminalised or regulated drug (cannabis), in all cases an increase in calls to poison control centres or unintentional paediatric exposures was reported. 59 73–77 However, studies assessing the impacts of cannabis regulation on overdose or poisoning by drugs other than cannabis concluded that the effects were either beneficial (four outcome measures 64 76 78 79 ) or mixed/null (three outcome measures 80–82 ). Driving with detectable concentrations of THC was most often found to increase following decriminalisation or legal regulation (five of eight outcome measures; 83–87 ), but these studies were of lower average quality ( X =12.0).

Impacts of decriminalisation

Of the 19 studies evaluating impacts of decriminalisation, six measured the prevalence of use of the decriminalised drug with eight unique outcome measures. No association was detected for all but three outcomes; following cannabis decriminalisation lifetime use increased among adults in South Australia, 31 while past-month use increased among 12 th graders but not younger students in California, 56 relative to the rest of the country in both cases. After peyote use for ceremonial purposes was decriminalised in the USA in 1994, self-reported use increased among American Indians. 88 Three studies evaluated relationships between decriminalisation and drug-related criminal justice involvement in Mexico and the USA. One high-quality study found that decriminalisation positively influenced criminal justice involvement: in five US states, arrests for cannabis possession decreased among youth and adults. 89 When possession of small amounts of cannabis was decriminalised in the 1970s in Nebraska, however, the mean monthly number of arrests did not change, while cannabis-related prosecutions increased among youth. 90 In Tijuana, Mexico, decriminalisation of all drugs had no apparent impact on the number of drug possession arrests. 53 Two historical and one recent study measured healthcare utilisation. US states that decriminalised cannabis in the 1970s saw greater emergency department visits related to cannabis, but decreased visits related to other drugs. 60 In Colorado, US, decriminalisation was associated with increased emergency department visits for cyclic vomiting. 62 Addiction treatment utilisation, healthcare and non-healthcare costs, driving after use, price of drugs, availability of drugs, frequency of use, attitudes towards use and perceived harmfulness were each evaluated in only one or two studies of decriminalisation.

This systematic review identified 114 peer-reviewed publications and conference abstracts evaluating the impacts of drug decriminalisation or legal regulation from 1970 to 2018. Within this search period, 88.6% were published in 2014 or later. This rapid growth in scholarship was driven by the implementation and subsequent evaluation of cannabis legalisation in a number of US states beginning in 2012, and knowledge production will surely continue to accelerate as longer-term data become available and as other jurisdictions (eg, Canada and Uruguay) analyse the effects of recently implemented cannabis legalisation. Indeed, a first study on the impacts of cannabis legalisation on adolescent use in Uruguay was published in May 2020 (finding no impact on risk of use 91 ). The present study provides an overview of the emerging literature based on our systematic review and suggests three key patterns.

First, peer-reviewed longitudinal evaluations of drug decriminalisation and legal regulation are overwhelmingly geographically concentrated in the US and focussed on cannabis legalisation. Importantly, the lack of non-US studies evaluating legal regulation of cannabis for medical use may reflect the more tightly controlled nature of medical cannabis regulation in other countries, and thus the more limited potential for population-level effects. It is notable that decriminalisation in the absence of legal regulation was evaluated in only 18 studies (15.8%), despite being far more common globally than legal regulation. These gaps may hamper evidence-based drug law reform in countries that are less well-developed, that play a substantial role in drug production and transit or that have different baseline levels of substance (mis)use as compared with the US.

Second, prevalence of use was the predominant metric used to assess the impact of drug law reform, despite its limited clinical significance (eg, much cannabis use is non-problematic) and limited responsiveness to drug policy. This is because ecological analyses have indicated little relationship between drug policies and prevalence of use, 52 as have studies assessing within-state change in use related to legal regulation. 21 These findings are supported by the preponderance of evidence synthesised in this review, although some variation is evident in relation to the specific provisions of legal reforms (eg, liberal vs tightly regulated medical markets 92 ). Impacts of legal cannabis regulation on prevalence and frequency of use continue to be evaluated, with recent data suggesting small increases among adults, but not youth. 93 Drug policies may be more able to influence the types of drugs that people use, drug-related risk behaviours and modes of drug consumption. 94 Metrics to assess these outcomes, however, were lacking in the reviewed literature. For example, only one study (0.8%) investigated whether legal regulation of cannabis was associated with changes in the mode of cannabis consumption. 72 Although the prevalence of use was often measured alongside more clinically or socially significant metrics (eg, prevalence of substance use disorders, educational outcomes among young adults), 42.2% of studies assessing substance use prevalence included that metric alone or in combination with a single drug-related attitude metric.

Third, there was a lack of alignment between the stated policy objectives of drug law reform and the metrics used to assess its impact in the scientific literature. For instance, removal of criminal sanctions to prevent their negative sequelae is a key rationale for decriminalisation and legal regulation, 12 13 95 but only four studies (3.5%) evaluated changes in drug-related criminal justice involvement following drug law reform. Similarly. improving the physical and mental health of people who (already) use drugs is a motivation for drug policy reform but no included studies examined mental or physical health outcomes (aside from substance use disorders) in this population. As a result, there is a risk that decisions on drug policy may be informed by inappropriate metrics. Promisingly, in recent months, additional studies assessing legal regulation that employ a range of criminal justice metrics have been published. 96–98 Finally, despite ample evidence of the impact of criminalisation on infectious disease transmission and acquisition risks, 5 we found no studies evaluating the impact of decriminalisation on these outcomes.

Both the included studies and our systematic review have important strengths and limitations. To our knowledge, we conducted the first review of all global literature on decriminalisation and legal regulation and applied no language restrictions. All eligible articles identified were published in English; this may reflect a paucity of evaluation research published in other languages and/or limitations of our search strategy (eg, some non-English journals may not be indexed in the 10 databases searched). In addition, we excluded grey literature, non-original research and study designs that are not suited to evaluating policy effects (eg, cross-sectional studies), but these restrictions narrowed the geographical scope of included studies. For example, two articles on Portugal were excluded as non-original research, but nevertheless provide important insight on impacts of decriminalisation. 99 100 Despite restricting eligibility to more rigorous study designs, most included studies used relatively weaker eligible designs that are known to be vulnerable to pre-existing trends and confounding; only 22.8% and 5.3%, respectively, used controlled before-and-after or interrupted time series designs to address these threats to validity. The use of these study designs may be related to limited resources for prospective drug policy evaluations, with many studies relying on publicly available, routinely collected data. That the US is unique in the extent to which data on drug use and related harms are routinely collected helps to explain its over-representation in our review. Scoping reviews inclusive of grey literature and cross-sectional designs would be valuable for describing the full range of evaluations that have been conducted globally.

While beyond the scope of our high-level synthesis, the implementation and specific provisions of drug policies vary widely. Decriminalisation policies vary in their definitions of quantities for personal use, application of administrative penalties and the extent to which the law ‘on the books’ is reflected in policing and criminal justice practice. Indeed, in some jurisdictions with nominal decriminalisation, arrests for possession of small quantities of the decriminalised drugs remain routine. 53 Legal regulation models for cannabis are also heterogeneous. For example, policies legally regulating cannabis for medical use may or may not allow for legal dispensaries, and this provision has been shown to substantially modify the impact of legal regulation on cannabis use. 101 To the extent that individual studies employed crude exposure measures (eg, presence vs absence of a law), they may have obscured context-dependent effects of drug law liberalisation. Further, the impact of drug laws on drug use and related outcomes may be limited by a lack of public awareness of the details of local laws. 102

Our use of vote-counting in this synthesis (ie, categorising individual outcome measures as indicating beneficial, harmful, mixed/subgroup-specific or no statistically significant associations) is subject to the same limitation. Vote-counting should also be interpreted with caution in light of the heterogeneity of outcome definitions, the inherent arbitrariness of statistical significance thresholds and the key distinction between statistical and clinical significance. In addition, many included studies are evaluating the same policies (eg, cannabis legalisation in western US states), sometimes using overlapping data but drawing different conclusions based on analytical choices and timeframes. The existence of multiple datapoints for a particular outcome does not imply that the outcome has been well-studied across diverse contexts such that scientific consensus on its effects has been reached. Moreover, as illustrated by a recently published extension of the included article by Bachhuber et al , 79 multiple high-quality studies may generate results that are later revealed to be spurious as additional follow-up data become availability. Specifically, Shover et al demonstrated that the positive association reported between medical cannabis legalisation and opioid overdose mortality in 1999 to 2010 reversed direction in later years, suggesting that earlier findings of a protective effect should not be given causal interpretations. 103 This was foreshadowed in the included article by Powell et al , which found that the purportedly positive effect of medical cannabis legalisation was attenuated in 2010 to 2013. 82 This scientific back-and-forth can be expected given that most included articles are evaluating legal changes introduced rather recently, and thus are examining early impacts with limited years of follow-up. Longer-term impacts of non-medical cannabis legalisation, and how they might be influenced by increased commercialisation, are yet to be seen. 104

Conclusions

The findings of this review indicate a need for a broadening of the metrics used to assess the impacts of drug decriminalisation and legal regulation. Given the growing number of jurisdictions considering decriminalisation or legal regulation of psychoactive drugs, 14–16 the disproportionate emphasis on metrics assessing drug use prevalence, as well as the limited geo-cultural diversity in evaluations, are concerning. Experts have called for a more fulsome approach to evaluating drug policies in line with public health and the United Nations Sustainable Development Goals, with attention to the full breath of health and social domains potentially impacted, including human rights and social inclusion (eg, stigma), peace and security (eg, drug market violence), development (eg, labour market participation), drug market regulation (eg, safety of the drug supply) and clinically-significant health metrics (eg, drug-related morbidity). 105 Drawing on methods such as multi-criterion decision analysis, 19 the engagement of both scientists and policymakers in priority-setting may help to produce evidence that provides a more comprehensive understanding of the breadth of impacts that should be anticipated with drug law reform efforts. Funding will also be required to support rigorous prospective evaluations of legal reforms.

Acknowledgments

The authors would like to thank Gelareh Ghaderi for assistance with screening and data extraction.

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Twitter @aydenisaac

Presented at Presented at the International Society for the Study of Drug Policy (May 22, 2019) and the International Harm Reduction Conference (April 29, 2019).

Contributors DW and AIS conceptualised and supervised the review. CZ designed and conducted the literature searches. AIS drafted the manuscript. SC, ZM and AIS conducted screening and data extraction. NM contributed to drafting the manuscript and developing figures. All authors contributed to interpretation of findings and revising the manuscript for important intellectual content.

Funding This review was supported by the Canadian Institutes of Health Research (CIHR) via the Canadian Research Initiative on Substance Misuse (SMN-139150), the MAC AIDS Foundation, and the Open Society Foundations. Ayden Scheim was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship. Nazlee Maghsoudi is supported by a CIHR Vanier Canada Graduate Scholarship. Dan Werb is supported by a US National Institute on Drug Abuse Avenir Award (DP2- DA040256), a CIHR New Investigator Award, an Early Researcher Award from the Ontario Ministry of Research, Innovation and Science and the St Michael’s Hospital Foundation.

Map disclaimer The depiction of boundaries on the map(s) in this article does not imply the expression of any opinion whatsoever on the part of BMJ (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. The map(s) are provided without any warranty of any kind, either express or implied.

Competing interests None declared.

Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

Patient consent for publication Not required.

Provenance and peer review Not commissioned; externally peer reviewed.

Data availability statement All relevant data are contained within the article and supplementary materials.

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Co-developing a drug with a diagnostic to create a stratified medicine — a therapy that is targeted to a specific patient population on the basis of a clinical biomarker — presents challenges for product developers, regulators, payers and physicians. With the aim of developing a shared framework and tools for addressing these challenges, this article presents an analysis using data from case studies in oncology and Alzheimer's disease, coupled with integrated computational modelling of clinical outcomes and economic value, to quantify the effects of decisions on key issues such as the design of clinical trials.

• Mark R. Trusheim
• Breon Burgess
• Michael C. Palmer

The influence of the 'organizational factor' on compound quality in drug discovery

In the past 15 years, it has become clear that physicochemical properties of drug candidates, such as lipophilicity and molecular mass, have an important influence on the likelihood of compound-related attrition during development. By analysing the properties of compounds described in patents from leading pharmaceutical companies between 2000 and 2010, this article indicates that a substantial part of the industry has not modified its drug design practices accordingly and is still producing compounds with suboptimal physicochemical profiles.

• Paul D. Leeson
• Stephen A. St-Gallay

Trends in the exploitation of novel drug targets

Schiöth and colleagues examine the drugs approved by the US Food and Drug Administration over the past 30 years and analyse the interactions of these drugs with therapeutic targets encoded by the human genome, identifying 435 effect-mediating drug targets. They also analyse trends in the introduction of drugs that modulate previously unexploited targets, and discuss the network pharmacology of the drugs in the data set.

• Mathias Rask-Andersen
• Markus Sällman Almén
• Helgi B. Schiöth

How were new medicines discovered?

To investigate whether some strategies have been more successful than others in the discovery of new drugs, this article analyses the discovery strategies and the molecular mechanism of action for 259 new drugs that were approved by the US Food and Drug Administration between 1999 and 2008. Observations from this analysis — such as the fact that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches in an era in which the major focus was on target-based approaches — could have important implications for efforts to increase the productivity of drug research and development.

• David C. Swinney
• Jason Anthony

The productivity crisis in pharmaceutical R&D

Although investment in pharmaceutical research and development (R&D) has increased substantially in recent decades, the lack of a corresponding increase in the output in terms of new drugs being approved indicates that therapeutic innovation has become more challenging. Here, using a large database that contains information on R&D projects for more than 28,000 compounds investigated since 1990, Riccaboni and colleagues examine the factors underlying the decline in R&D productivity, which include an increasing concentration of R&D investments in areas in which the risk of failure is high.

• Fabio Pammolli
• Laura Magazzini
• Massimo Riccaboni

Probing the links between in vitro potency, ADMET and physicochemical parameters

A common assumption in current drug discovery strategies is that compounds with high in vitro potency at their target(s) have a greater potential to translate into successful, low-dose therapeutics, which is reflected in screening cascades with in vitro potency embedded as an early filter. This analysis of the publicly available ChEMBL database, which includes more than 500,000 drug discovery and marketed oral drug compounds, suggests that the perceived benefit of high in vitro potency may be negated by poorer absorption, distribution, metabolism, elimination and toxicity (ADMET) properties.

• M. Paul Gleeson
• Anne Hersey
• John Overington

The importance of new companies for drug discovery: origins of a decade of new drugs

Understanding the factors that promote drug innovation is important both for improvements in health care and the future of organizations engaged in the field. To investigate these factors, Kneller identifies the inventors of 252 new drugs approved by the US Food and Drug Administration from 1998 to 2007 and their places of work, and classifies these drugs according to innovativeness. This article presents a comprehensive analysis of these data, which highlight the strong contribution of biotechnology companies, particularly in the United States, to innovative drug discovery, and discusses potential contributing factors to the trends observed.

• Robert Kneller

How to improve R&D productivity: the pharmaceutical industry's grand challenge

Improving R&D productivity is crucial to ensuring the future viability of the pharmaceutical industry and advances in health care. This article presents a detailed analysis, based on comprehensive, recent, industry-wide data, to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity, and proposes strategies that could have the most substantial impact in enhancing R&D productivity.

• Steven M. Paul
• Daniel S. Mytelka
• Aaron L. Schacht

Lessons from 60 years of pharmaceutical innovation

This article investigates pharmaceutical innovation by analysing data on the companies that introduced the ∼1,200 new drugs that have been approved by the US FDA since 1950. Implications of this analysis — which shows that the rate of new drug output in this period has essentially been constant despite the huge increases in R&D investment — are discussed, as well as options to achieve sustainability for the pharmaceutical industry.

• Bernard Munos

Can literature analysis identify innovation drivers in drug discovery?

Here, the authors use bibliometrics and related data-mining methods to analyse PubMed abstracts, literature citation data and patent filings. The analyses are used to identify trends in disease-related scientific activity that are likely to give new therapeutic opportunities.

• Pankaj Agarwal
• David B. Searls

Community-wide assessment of GPCR structure modelling and ligand docking: GPCR Dock 2008

The recent determination of several crystal structures of G protein-coupled receptors (GPCRs) is providing new opportunities for structure-based drug design. This article analyses the state of the art in the prediction of GPCR structure and the docking of potential ligands on the basis of a community-wide, blind prediction assessment — GPCR Dock 2008 — that was carried out in coordination with the publication of the human adenosine A 2A receptor structure in 2008 and public release of the three-dimensional coordinates.

• Mayako Michino
• Enrique Abola
• Raymond C. Stevens

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Times Insider

A Psychedelics Reporter With a Changing Perspective

Can an experimental drug cure opioid addiction? Andrew Jacobs, who writes about psychedelic medicine for The Times, explored the “promise and peril” of ibogaine.

By Andrew Jacobs

Times Insider explains who we are and what we do and delivers behind-the-scenes insights into how our journalism comes together.

As a reporter covering psychedelic medicine for the Health and Science desk at The New York Times, the drugs that often command my attention are familiar to any veteran psychonaut: ketamine ; LSD ; psilocybin, or “magic mushrooms” ; and MDMA, also known as Molly or Ecstasy.

Many of these psychoactive substances have been the subjects of research for years, if not decades. And a growing tranche of scientific evidence suggests these drugs have the potential to treat some mental health issues, among them depression, substance abuse and eating disorders.

But research on psychedelics has largely ignored ibogaine, a drug that’s derived from a plant native to the rainforests of Central Africa.

Over the past three years on this beat, I have interviewed researchers who have occasionally mentioned ibogaine, often in tones that hinted at both promise and peril. The handful of experts who have worked directly with the drug cast it as a powerful addiction interrupter — one that can quell the excruciating symptoms of opioid withdrawal and tame the cravings to use again. According to a number of small studies, many patients report being able to achieve long-term sobriety after a single therapeutic session. (In the United States, the drug remains illegal; many patients will travel abroad for ibogaine therapy.)

But there are downsides. An ibogaine journey can be grueling. Some patients can feel the effects for up to 24 hours.

From 1990 to 2020, more than 30 ibogaine-related deaths have also been reported — some of them ascribed to severe arrhythmia, or an irregular heartbeat, that in rare cases can lead to fatal cardiac arrest. Those risks were enough to prompt the Food and Drug Administration in the 1990s to end further study on ibogaine’s potential to treat crack cocaine addiction.

Many psychedelic researchers just left ibogaine alone.

But then came an initiative in Kentucky that electrified the close-knit world of psychedelic research. In 2023, a committee convened by the state’s Republican attorney general was considering a proposal to spend $42 million on ibogaine research and drug development. The money would come from the funds the state was expected to receive in opioid settlements from pharmaceutical companies.

A friend of a friend, Adriana Kertzer, a lawyer in New York whose firm specializes in psychedelic medicine, invited me for coffee to talk about the proposal. In November, Ms. Kertzer put me in touch with W. Bryan Hubbard, the commission’s chair. Mr. Hubbard had little experience with psychedelics, but he became fascinated with ibogaine after reading accounts about its potential to treat opioid addiction.

“I was desperate, and felt that I needed to explore all options that might show promise,” said Mr. Hubbard, who grew up in Appalachia near the West Virginia-Kentucky border, a region of the United States that has been devastated by the opioid epidemic. “I’ve seen the carnage first hand.”

With the number of fatal drug overdoses in the United States topping more than 112,000 between May 2022 and May 2023 — and opioids like fentanyl contributing to the record high — it felt like the right time to take a closer look at ibogaine.

In late November, I traveled to Louisville, Ky., to meet with harm reduction workers, recovering opioid users and those still in the throes of addiction. Among those I met was Jessica Blackburn, 37, who started using Oxycodone in high school and later turned to heroin. Ms. Blackburn spent time in five different inpatient treatment clinics and tried medical interventions, like Suboxone , to treat her addiction. Nothing helped her remain sober until she tried ibogaine eight years ago. She has not touched opioids since.

Given the limitations of existing treatment options, many people I spoke with in Louisville agreed that any treatment with promise should be considered.

But what about ibogaine’s cardiac risks?

Mr. Hubbard was confident that the dangers could be mitigated. He connected me with scientists working on the issue. They included Dr. Deborah Mash, a veteran ibogaine researcher at the University of Miami who has used ibogaine to treat more than 300 patients with opioid use disorder; Dr. Martín Polanco, the medical director of the Mission Within , a program that has used ibogaine to treat over 1,000 veterans with traumatic brain injury and addiction issues; and Dr. Nolan Williams, a Stanford University neuroscientist who was preparing to publish a study that highlighted measures to reduce ibogaine’s heart risks.

All were adamant that ibogaine-related fatalities could be effectively managed by screening out individuals with cardiovascular problems and ensuring ibogaine was administered in a medical setting.

Covering psychedelic medicine can be nerve-racking, given the field’s relatively nascent state, the paucity of large studies and the occasionally breathless boosterism of its advocates.

Journalists on The Times’s Health and Science team are cautious about allowing hope to get ahead of science. When writing the article, my editors and I took care to balance the seeming promise of ibogaine against the clear risks.

The article, which was published this month , elicited a largely positive reaction from experts. In the comments section, more than 100 readers, among them people who had undergone ibogaine therapy, expressed hope that federal regulators might one day approve study of the drug.

Kentucky’s newly elected attorney general, Russell Coleman, doesn’t share their optimism. On March 13, Mr. Coleman effectively killed the commission’s ibogaine initiative.

Mr. Hubbard remains undaunted. Last month, he began working for the Ohio state treasurer’s office on a similar initiative to use opioid settlement money to fund research of ibogaine. A half-dozen other states, he said, have expressed interest in doing the same.

I, too, will be keeping a close eye on this fascinating psychedelic in the months and years to come.

Andrew Jacobs is a Times reporter focused on how healthcare policy, politics and corporate interests affect people’s lives. More about Andrew Jacobs

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The Changing Opioid Crisis: development, challenges and opportunities

Nora d. volkow.

1 National Institute on Drug Abuse, Bethesda, MD 20892

Carlos Blanco

The current opioid epidemic is one of the most severe public health crisis in US history. Responding to it has been difficult due to its rapidly changing nature and the severity of its associated outcomes. This review examines the origin and evolution of the crisis, the pharmacological properties of opioids, the neurobiology of opioid use and opioid use disorder (OUD), medications for opioid use disorder (MOUD), and existing and promising approaches to prevention. The results of the review indicate that the opioid epidemic is a complex, evolving phenomenon that involves neurobiological vulnerabilities and social determinants of health. Successfully addressing the epidemic will require advances in basic science, development of more acceptable and effective treatments, and implementation of public health approaches, including prevention. The advances achieved in addressing the current crisis should also serve to advance the science and treatment of other substance use disorders.

Origins and Evolution of the Crisis

The current opioid epidemic is one of the most severe public health crisis in US history. Providing an effective response has been difficult because of its changing nature, geographic and demographic diversity, multiplicity of its causes, and the severity of adverse outcomes associated with opioid use and opioid use disorder (OUD). Furthermore, opioid analgesics, which fueled the origins of the opioid epidemic, are therapeutically beneficial when used properly. This, compounds the difficulties of regulating their availability because they cannot be banned, in contrast with illicit drugs. While earlier phases (i.e., first wave) of the crisis were predominantly driven by non-medical use and addiction to prescription opioid analgesics, heroin (second wave) and subsequently illicit synthetic opioids (third wave) have become progressively important as the crisis progressed and more recently there is emerging evidence of increasing fatalities associated with the combination of psychostimulant drugs with opioids (fourth wave). These changes explain why despite the decreases in the number of opioid prescription dispensed, the number of opioid fatalities has continued to rise unabated. 1 Although the opioid crisis is often seen through the prism of fatal overdoses, its most dramatic manifestation, the misuse of opioids and OUD also lead to death, disease and suffering from many other causes with devastating medical, social and economic consequences. 2 - 5

Like most complex problems, the opioid crisis has multiple roots, 5 including changing social and economic conditions, limited availability of safe and effective analgesics, insufficient treatment capacity for OUD and legal approaches that criminalize OUD rather than fostering treatment. The two major driving factors of the crisis, however, were the steady increase in the rate of opioid prescriptions, particularly in the early stages of the crisis, and the decrease in price and the increase in availability of heroin and synthetic opioids.

Increases in the rate of opioid prescribing followed the identification of undertreatment of pain in the 1990s as an important clinical problem 6 and the mistaken belief, based on anecdotal evidence, that patients in pain were not at risk for OUD. 7 Although less than 10% of individuals to whom opioids are prescribed develop OUD, 8 large increases in the rates of opioid prescriptions inevitably led to more individuals being exposed to opioids and subsequent increases in OUD prevalence. More importantly, increased availability of opioids generated an enormous surplus of medication that was diverted for non-medical use. 9 From 1991 to 2013, the prevalence of non-medical use of prescription opioids in the US more than doubled, from 1.5% to 4.1%, and the prevalence of prescription OUD tripled, from 0.3% to 0.9%. 10 , 11 At the same time, the severity of nonmedical use, as measured by the frequency of use, also increased among nonmedical users. 12

A second major factor in the crisis was the increased accessibility and purity of heroin coupled with reduced price partly due to increases in the efficiency of its distribution channels, which led to increases in heroin use and heroin use disorder. From 2001-2002 and 2012-2013 the prevalence of lifetime heroin use in the US increased from 0.33% to 1.6% and the lifetime prevalence of heroin use disorder increased from 0.21% to 0.69%. 13 , 14 There is controversy regarding whether efforts to decrease use of prescription opioids led to increases in heroin use and use disorder. Although individuals who use prescription opioids are more likely than those who don’t to use heroin, only 3%-5% of individuals who used prescription drugs non-medically in the previous year also reported using heroin during the same year. 15 Furthermore, increases in heroin use among nonmedical prescription opioids users preceded the development of policies to address misuse of prescription opioids. Thus, it may be the case that efforts to improve prescription of opioids have played a more limited role in the increases in heroin use than that ascribed to them. 16

A more recent entrant has been fentanyl and other very potent synthetic fentanyl analogues. From 2010 to 2017, deaths from fentanyl and other synthetic opioids increased nearly ten -fold, from around 3,000 (14.3% of opioid-related deaths) to over 28,466 (59.8%). 17 , 18 Synthetic opioids are now almost twice as commonly involved in overdose deaths as prescription opioids or heroin. 17 The low production costs of fentanyl and its potency (50- fold compared to heroin) make it an attractive option to mix (“lace”) with heroin and illicit manufactured prescription opioids. 19 At present, it is not known how many users actively seek fentanyl, but regardless of intent, heroin users are being exposed to fentanyl or other analogues without realizing it, increasing their risk of overdosing. Overdoses from fentanyl by itself or combined with heroin appear to be harder to reverse with naloxone than overdoses due to prescription opioids or pure heroin, contributing to the lethality of fentanyl or drugs laced with it. The reasons for the decreased efficacy of naloxone for reversing fentanyl overdoses are unclear and might reflect, its very high potency at the mu opioid receptor (MOR), its very fast pharmacokinetics (entering the brain very rapidly minimizing time for intervention), longer duration of its respiratory depressing effects (that might explain re-narcotization after a temporary reversal of an overdose by naloxone) and/or an additive effects when fentanyl is combined with other drugs including heroin. 20

Pharmacological properties of opioids

In addition to their effect on MOR, opioid drugs also bind to kappa- (KOR) and delta-opioid (DOR) receptors, although their affinity, intrinsic efficacy, pharmacokinetics and bioavailability vary by drug. In particular opioid drugs with fast uptake into the brain and full agonist effects at MOR such as heroin and fentanyl are particularly rewarding. 20 A strategy for developing opioid medications with lower abuse liability entails opioids formulations with slower entry into the brain and/or formulations that cannot be injected, since this is the route of administration that results in the faster rate of drug uptake in brain. The intrinsic efficacy of full agonist drugs such as heroin and fentanyl leads to greater rewarding effects than for partial agonists such as buprenorphine. Additionally, the rate of clearance of opioid drugs from the brain determines their duration of action and the severity of withdrawal symptoms upon their discontinuation. For that reason, heroin is associated with a much more severe withdrawal than a drug such as buprenorphine, which clears the brain more slowly. Opioids drugs with longer half-lives, slower clearance rates and slower brain uptake are favored for the treatment of OUD. By binding to MOR they decrease craving and prevent the emergence of withdrawal symptoms. Methadone enters the brain rapidly, which is why it is given orally when used for OUD treatment, for this will slow its entry into the brain. Also while it is a full MOR agonist, it has agonist effects at galanin receptors, which are co-expressed with MOR in brain reward regions antagonizing them, and thus reducing methadone’s rewarding effects. 31

The positive (increase reward) and negative (avoid pain) reinforcing effects of opioids, trigger learned associations between the receipt of the drug and these experiences resulting in conditioning. In parallel, the repeated administration of opioids triggers physiological adaptations that result in tolerance and in physical dependence. Tolerance necessitates increasing opioid doses in order to achieve the same levels of analgesia and when misusing them increasing the doses or shifting to more potent opioids such as fentanyl in order to experience their rewarding effects. The development of tolerance does not occur at the same rate for the various pharmacological effects of opioids. In general, tolerance to the analgesic and hedonic effects develops faster than to respiratory depression, whereas tolerance to constipation might never develop. 32 This explains why increases in dose to maintain analgesia (or reward) or doses injected to get high can markedly increase the risk of overdose.

Physical dependence to opioids also occurs rapidly and is responsible for the emergence of withdrawal symptoms when opioids are abruptly discontinued, which creates a negative reinforcement mechanism that can contribute to the maintenance of opioid use. The severity of withdrawal symptoms varies as a function of the opioid drug used; greater for higher potency short acting opioids than for longer lasting opioids as well as the chronicity of exposure. The symptoms from acute withdrawal usually resolve within days and are rarely lethal, but are extremely uncomfortable and are a powerful trigger for relapse in those with an OUD and for continued opioid use among those being treated with opioid analgesics. The risk of withdrawal is minimized or prevented by tapering opioids gradually.

Repeated use of opioids often results in physical dependence as a result of multiple neuroadaptations including desensitization and internalization of the MOR, impaired MOR signaling with intracellular effectors, and adaptations in glial signaling and in neuropeptide systems that interact with MOR-sensitive neurons, among others 33 , 34 . In contrast to physical dependence, OUD develops only in a minority of individuals exposed to opioids. It is characterized by a pattern of maladaptive opioid use that leads to clinically significant impairment or distress and is manifested as intense craving for opioids, erosion of inhibitory control over efforts to refrain from using them, persistent thinking about procuring the drug, and impaired control over opioid use. Because of their repeated opioid use, those with OUD also suffer from physical dependence and tolerance, unless they have undergone supervised medical withdrawal (formerly known as detoxification) in which case they can have OUD without having physical dependence or tolerance. This is clinically relevant in that patients undergoing medically supervised withdrawal without subsequent treatment for OUD are at an extremely high risk of relapse and of overdosing since they crave the drug as intensely as prior to their withdrawal but have lost their tolerance to the opioids. The behavioral manifestations of OUD are associated with structural and functional changes in the brain’s reward, executive control, emotion and interoceptive circuits. 58 , 59

Biological factors contributing to OUD

In addition to the environmental contributions to the crisis, multiple biological factors modulate an individuals’ vulnerability for opioid use, non-medical use and OUD, including genetic predisposition, brain development, mental illness and social factors.

Studies of genetic epidemiology indicate that genes contribute about 50% of the vulnerability to SUD, including OUD. Yet identifying specific genetic variants for increased OUD risk has been difficult, which is likely to reflect in part the fact that OUD, like other psychiatric disorders is a polygenic disease. Genes influence brain development and function of brain circuits and neurotransmitter systems that mediate the reactivity to the environment including drug responses. Furthermore, genes can intervene at different stages of OUD development, including propensity to use (i.e. genes that modulate personality traits) risk of transition from use to OUD (i.e. gene involved in conditioning and neuroplasticity), and vulnerability to relapse (i.e. genes that modulate severity of withdrawal symptoms, sensitivity to stress or other potential triggers). Because OUD often co-occurs with other psychiatric disorders, genes that increase the risk for those co-occurring disorders can also indirectly increase OUD risk. The effects of genes are also moderated by environmental influences.

Despite these complexities, studies have been able to identify genes that appear to contribute to OUD risk ( Table 1 ). For example, OPRM1 the gene that encodes for MOR has been implicated in increased vulnerability to OUD. 35 Similarly, converging evidence of genome-wide association, neuroimaging and rodent studies support a role in OUD for CNIH3, a gene that encodes for the Cornichon Family AMPA Receptor Auxiliary Protein that regulates trafficking and gating properties of AMPA receptors. 36 Preliminary results also suggest that the BDNF Val(66) Met genotype, which has been associated with neurobehavioral deficits, may promote drug-seeking in individuals with OUD. 37

Genes associated with increased vulnerability to opioid use disorder

Other genes, though not directly linked to OUD, relate to risk factors, such as personality traits, or brain regions implicated in the circuitry of addiction. For example, polymorphisms associated with low activity in MAOA , the gene for monoamine oxidase A, have been linked to a predisposition to externalizing behaviors and disorders that is moderated by environmental exposures. 38 , 39 Similarly, the catecholamine-O-methyltransferase (COMT) gene variant V(108/158)M, leads to greater dopamine degradation and impaired modulation of prefrontal cortex 40 , and has been associated with increased amygdalar reactivity 41 and with disrupted modulation of cortical and striatal activation during anticipation or receipt of a reward. 42 , 43 Numerous animal and human studies have also demonstrated the role of dopamine receptors in reward related behaviors, 44 - 46 but to date, no study has directly linked any dopamine-related gene to the risk of OUD.

Genes whose product influence synaptic plasticity can also contribute to OUD risk, such as Homer proteins, which regulate the level and activity of glutamate receptors, 47 and matrix metalloproteinase 9 (MMP-9), which in animal models increases motivation for drug-seeking. 48 , 49 Genes that influence response to stress by modulating the glucocorticoid receptor’s affinity for cortisol such as the FKBP5 chaperone protein 50 may also increase risk of OUD.

Brain Development

Drug experimentation is commonly initiated during adolescence and the risk to addiction is increased with early drug use. The greater vulnerability of adolescents to drug use and experimentation is driven by multiple factors including genetics that are associated with the developmental trajectories of the human brain. At the same time the social environments during childhood will influence brain development in ways that can increase its vulnerability to drugs or provide with resilience. Notably, the development of the human brain has a greater sensitivity to environmental factor during the first than second decades of life whereas genes influence brain development throughout the first and second decades. 51 This explain why social stressors are particularly harmful during early childhood. However while it is heuristically useful to distinguish environmental from genetic factors, it is likely that it is their interactions that ultimately determine how the brain will develop.

A better characterization of human neurodevelopment has allowed us to start to understand the role of the environment at critical moments of brain development and how differences in the rate of development of neuronal circuits influence vulnerability for drug use. For example, during adolescence reward and emotion circuits develop faster than those related to executive function, creating an imbalance between systems that favor experimentation, reward-seeking and drug use and systems underpinning self-regulation. Early exposure to drugs of abuse may further impair the development of the prefrontal cortex, decreasing self-regulating capabilities and increasing the long-term risk for SUD. 52

Several brain imaging studies have started or will soon start to generate data to inform the development of the brain and the influence of substance use in this development. The Adolescent Brain Cognitive Development Study (ABCD) is a longitudinal study of children 9-10 years old who will be assessed with brain imaging, genotyping, and deep phenotyping and followed for 10 years. It recently completed the baseline assessment of 11,875 children and has started to provide valuable data on normal variability in brain development and its influence by environmental factors. 53 The Baby Connectome Project is a four-year study of children from birth through five years of age, intended to provide a better understanding of how the brain develops from infancy through early childhood and the factors that contribute to healthy brain development. 54 It will help characterize human brain connectivity and map patterns of structural and functional connectivity to important behavioral skills. Additional biological (e.g., genetic markers) and environmental measures (e.g., family demographics) will be collected and examined to provide a more comprehensive picture of the factors that affect brain development. Finally, the planned HEALthy Brain and Child Development (HBCD) study aims to prospectively follow 7,500 infants through childhood (e.g., age 9-10) to assess structural and functional brain development as well as cognitive, behavioral, social, and emotional development and the long-term impacts of pre/postnatal drug (expected oversampling for opioid prenatal exposures) and adverse environmental exposures on brain and behavioral health and risk for substance use and mental disorders.

Social determinants

Epigenetics are implicated in the persistent neuroplastic changes associated with exposure to environmental factors that increase vulnerability to addiction such as social stressors or drug exposures. 55 For example, the environment’s ability to shape the circuits of emotion, particularly those impacted during critical periods of prenatal, postnatal, and adolescent brain development, 56 taps heavily on epigenetic mechanisms. 46 , 57 Studies have also started to assess the effects of social stressors on the development of the human brain, and these studies are relevant for understanding why social stressors increase the risk for SUD and other psychiatric disorders. Studies evaluating the effects of social deprivation during infancy and early childhood have reported delayed maturation that results in impaired brain connectivity, which could underlie increased impulsivity in these children. 58 Fortunately, preliminary studies suggest that interventions that provide social support may help reverse some of these impairments. 59 Nevertheless, stressful events at any age can increase vulnerability to opioid use and OUD.

Though the developing brain is the most sensitive to adverse social environments, these can also negatively influence the adult brain in ways that increase the vulnerability to drugs use and addiction. This is apparent in the current opioid epidemic and the other “deaths of despair” (overdoses, suicide and alcohol-driven cirrhosis) that have prominently affected adult white Americans from economically impoverished environments. There is a scarcity of research on the effects of adverse social environments on adult brain function. 60 , 61

Neurocircuitry of addiction

Reward circuitry.

Although much remains to be learned, our growing knowledge of the brain’s reward circuitry (originating in the dopamine neurons in the ventral tegmental area projecting to the nucleus accumbens, ventral prefrontal cortex and amygdala) and its changes have been fundamental for understanding drug taking and addiction. Reward (more precisely, reinforcement) can be defined as any event that increases the probability of repeating the action. Animal 62 , 63 and human studies consistently indicate that drugs release dopamine (DA) in the nucleus accumbens (NAc), which is fundamental to their rewarding effects. Additionally, increases in endogenous opioids and cannabinoids are also associated with the rewarding effects of various drugs. 64 , 65 It is thought that the rapid release of DA and its binding to D 1 receptors (D1R) in the ventral (location of NAc) and dorsal striatum, which stimulates cyclic AMP (cAMP) signaling is associated with euphoria and pleasure (so-called “high”) and triggers conditioning (learned association between the drug effects and situation where it occurred). By contrast, stimulation of D 2 receptors (D2R), which inhibit cAMP signaling, does not appear to be associated with rewarding effects per se but blocks the aversive effects when D2R-expressing medium spiny neurons (D2R-MSN) are not inhibited by DA. 66 Individuals with SUD often have decreased baseline DA release in the striatum (including in nucleus accumbens) and experience an attenuated DA increase and less intense reward from drug use (i.e., tolerance), which is interpreted to reflect a hypofunction of their reward circuit. It is unknown to what extent this hypofunction reflects a predisposition of the individual versus consequences from chronic drug exposures.

With repeated drug use, conditioning strengthens and drives the motivation to procure the drug reinforcers. Exposure to conditioned stimuli (referred to as cues) by themselves triggers firing of DA neurons and DA release, energizing the motivation to obtain the drug. When previously neutral stimuli become conditioned to the drug they acquire incentive salience, becoming desirable 67 . Conditioning and the associated DA increases in the striatum are hypothesized to underlie the intense desire for drugs that addicted individuals experience upon exposure to environments or situations where they have taken drugs that frequently leads them to relapse.

The drug-induced stimulation of D1R signaling involved with conditioning triggers synaptic changes in N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors that enhance glutamatergic signaling in the affected synapses. 68 , 69 At the circuit levels these neuroplastic changes strengthen striatal- pallidal-thalamo-cortical loops that include the ventral and the dorsal striatum, resulting in habit formation 70 and compulsive response for drugs. As SUD progresses, a prominent hypothesis is that these circuits become increasingly sensitized to drug-cues, environmental stressors or negative emotional states, which can then more readily trigger compulsive drug consumption. In more advanced stages, substance use behaviors are more driven by a growing importance of dorsal striatum and habits and a decreasing role of positive drug reward. In parallel, as drug-procuring and taking becomes increasingly salient in the addicted individual, non-drug related activities become less motivating and rewarding. 71 , 72

Although DA and glutamate remain central to our understanding of the reward circuits, these circuits are also modulated by γ-aminobutyric acid (GABA), serotonin, acetylcholine, and the endogenous opioid and cannabinoid systems. Similarly, it is important to realize that, like any other, the reward circuit (as well as the executive control circuit) interact and overlap with circuitry involved in the perception of internal bodily states or interoception (including primary sensory cortex, insula, anterior cingulate cortex and precuneus), homeostasis (hypothalamus), stress (amygdala, hypothalamus, and habenula), salience attribution (orbitofrontal cortex) and learning and memory (amygdala, hippocampus and dorsal striatum) and that the interplay with these circuits modulates the responses to rewards and to conditioned cues ( Figure 1 ). 73

The circuitry of opioid use disorder (reprinted with permission from: George O, Koob GF. Control of craving by the prefrontal cortex. Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4165-4166

Emotion Circuitry

Although positive reinforcers play a major role in the initial phases of drug taking and the development of OUD, in more advance stages negative emotional experiences such as withdrawal symptoms, craving and enhanced sensitivity to stress become increasingly important and drive drug taking. The increased role of negative reinforcement in drug taking (as a means to escape the negative emotional state) is a considerable barrier to abstinence and a formidable obstacle to successful treatment.

The negative emotional state can be understood as enhancement of processes that are the inverse of those involved in reward (i.e., “anti-reward processes”) 74 that are derived from neuroadaptions to drug-induced stimulation. 62 In the case of opioids most of the physical manifestations of withdrawal, which emerge with drug discontinuation are caused by decreased MOR-triggered intracellular signaling and by enhanced autonomic reactivity. 75 Early signs of withdrawal, appearing generally in the first 8-36 hours of heroin discontinuation include mydriasis, piloerection, muscle twitching, lacrimation, rhinorrhea, diaphoresis, yawning, restlessness, myalgia, abdominal pain, nausea/vomiting, tremor and insomnia. Individuals with fully developed opioid withdrawal can also experience tachycardia, tachypnea, hypertension or hypotension, dehydration, hyperglycemia, fever, anorexia and diarrhea.

In addition to these physiological manifestations, opioid withdrawal is often associated with neuropsychological symptoms that include, irritability, emotional pain, dysphoria, insomnia and subjective distress that can last several months. The subjective aspects of the negative emotional state are associated with disrupted dopaminergic, serotonergic, noradrenergic, glutamatergic, GABAergic neurotransmission in reward and emotion networks (including NAc). 67 Stress-related neurotransmitters, such as CRF, norepinephrine, and dynorphin, are also recruited in the extended amygdala and contribute to the distress and increased irritability often present in withdrawal and protracted abstinence. 76 The lateral habenula, which decreases DA neuronal firing in VTA when expected rewards do not materialize 77 - 79 and is a target of serotonin neurons from the dorsal raphe that modulate mood, also plays a crucial role in triggering and maintaining negative emotional states. 80 Similarly, the insula, which is reciprocally connected to several limbic regions and to the default mode network (DMN) has an interoceptive function that integrates autonomic and visceral information with emotion and motivation 81 , plays a key role in the self-awareness of negative emotional states and of craving. 82 - 84

Executive Control Circuitry

Impairments in executive function (including self-regulation), which can precede as a vulnerability factor for SUD or develop secondary to chronic drug exposures, are important contributors to impulsive and compulsive drug taking. 67

During withdrawal the emergence of the preoccupation/anticipation phase along with mounting craving for the drug results from the interplay of two opposing systems: a Go and a Stop system. The Go system includes most of the circuitry described in the two previous sections, which underlies the hedonic, habitual and emotional aversive aspects that leads to continued drug taking. 85 , 86 The Stop system seeks to control the incentive value of choices, regulate habitual behavior, maintain goal-directed behavior and suppress affective responses to negative emotional signals. 87 - 89 In this framework, the Stop system seeks to inhibit signals generated by the Go system.

The Stop system involves a widely distributed and complex prefrontal cortex–subcortical circuitry. It is mediated through glutamatergic projections from prefrontal cortex to the caudate and ventral striatum to modulate the striatal-pallidal-thalamocortical direct (D 1 receptor-mediated) and indirect (D 2 receptor-mediated) pathways, and to modulate the mesocortical dopamine neurons in the ventral tegmental area, which exert control over DA release in the prefrontal cortex. 73 Deficits in prefrontal cortex in individuals with SUD are associated in impairments in executive function that can interfere with decision making, self-regulation, inhibitory control, and working memory. 90 Reduced activity in the prefrontal cortex (including dorsolateral prefrontal cortex, anterior cingulate gyrus, and medial orbitofrontal cortex) is also associated with downregulation of D2R in the striatum, 91 - 93 and disrupted GABAergic activity in striatum and prefrontal cortex. 94 , 95

The orbital frontal cortex, anterior cingulate cortex and dorsolateral prefrontal cortex are involved with incentive salience, emotional regulation, and decision making, respectively. Deficits in striatal D2R-mediated DA signaling, which modulates them, may underlie the enhanced motivational value of drugs and the loss of control over drug intake in SUD. 96 Furthermore, because dysfunction of the orbital frontal cortex and the anterior cingulate cortex are associated with compulsive behaviors and impulsivity, 97 DA’s impaired modulation of these regions may contribute to compulsive and impulsive drug taking in SUD. 96

Several pathways can encode signals that increase the risk of relapse with exposure to cues, which can activate the ventral prefrontal cortex, including ventral anterior cingulate, and medial and lateral orbitofrontal cortices. 98 - 101 Cue-induced reinstatement involves glutamatergic projections from the prefrontal cortex, basolateral amygdala, and ventral subiculum to the NAc, and DA projections to the basolateral amygdala and dorsal striatum. 102 - 104

In contrast to cue-induced relapse, stress-induced reinstatement depends on the activation of both CRF and norepinephrine in parts of the extended amygdala (i.e., central nucleus of the amygdala and bed nucleus of the stria terminalis) and the VTA. 105 Protracted abstinence, mostly described for alcohol, appears to involve overactive glutamatergic and CRF systems. 106 , 107 A third pathway to relapse is through interoceptive stimuli related to the insula 82 - 84 and its activation during craving has been associated with relapse. 108

Pharmacological treatment of opioids

A range of pharmacological treatments exists to treat different components of OUD. Information on these medications was recently reviewed by the U.S. Substance Abuse and Mental Health Administration 109 and by the National Academy of Medicine. 110

Medically supervised withdrawal (formerly referred to as detoxification) is the gradual taper of opioid agonist medications (methadone or buprenorphine) guided by a clinician to alleviate withdrawal symptoms. The use of α 2 -agonists such as lofexidine (recently approved by the FDA for the treatment of opioid withdrawal) or clonidine can also help attenuate symptoms of withdrawal, 111 though subsequent initiation of medications for OUD (MOUD) is required to prevent relapse into drug taking. Indeed, medically supervised withdrawal is not recommended as an isolated strategy, as most patients without subsequent MOUD initiation relapse shortly thereafter 112 - 114 and are at increased risk for overdosing due to the loss of tolerance. 115 Medically supervised withdrawal is required, though, for patients starting naltrexone, as described in the next section.

Maintenance

Ongoing outpatient treatment with MOUD leads to better retention and outcomes for OUD 116 and reduced risk of HIV and HCV infection and overdose death. 117 - 121 At present, MOUD constitutes the standard of care for most patients with OUD. There are three FDA-approved MOUD: methadone, buprenorphine and naltrexone. In deciding on a specific medication the clinician should evaluate the patient’s responses to prior MOUD treatment, tolerance to opioids and patient preferences. Patients, in turn, should be informed of the efficacy, risks, benefits and relative advantages of each of these medications.

Methadone has been available the longest and has the largest evidence of efficacy. 119 , 121 Higher doses of methadone are associated with better retention in treatment, less heroin use during treatment and lower withdrawal symptoms, until around 100 mg/day, after which the reliability of evidence is lower. 122 Because methadone is a full MOR agonist, it has no ceiling effect. It can lead to overdoses if it is used at doses above the patient’s tolerance or combined with other central nervous depressants such as alcohol, benzodiazepines or other opioids. To minimize the risk of intoxication or overdose, methadone should be started at low doses and increased gradually with daily monitoring over several weeks. An important barrier to the use of methadone, particularly in rural settings is that, with a few exceptions, in the US methadone has to be administered in a licensed opioid treatment programs (methadone clinics) and cannot be prescribed by office-based clinicians.

The use of buprenorphine 123 , 124 has certain advantages over methadone, which explains its growing use for OUD treatment. First, although it can still be lethal when combined with other central nervous depressant substances, as a partial agonist, buprenorphine has lower lethality than methadone. 124 Second, its antagonist effects at the KOR may contribute to its efficacy for OUD. 125 , 126 Its KOR antagonist properties may also have antidepressant effects, which could help improve the depressive symptoms that are common in OUD. Buprenorphine is also an agonist at the nociceptin receptor, which is also implicated on its therapeutic benefits. To deter the injection of buprenorphine, which would enhance its rewarding effects, it is often prescribed in a formulation that includes naloxone, a short-acting opioid antagonist that has poor bioavailability when sublingually administered, but blocks buprenorphine effects if injected. Currently, in the US, prescribers of buprenorphine for the treatment of OUD need to obtain a waiver from the Drug Enforcement Administration (DEA) after completing an 8-hour training.

Extended-release (XR) formulations of buprenorphine have been developed to improve patient adherence. Although, 6-months buprenorphine implants were shown to be as effective as low-dose sublingual buprenorphine, 127 its benefits are restricted to patients who respond to low doses of buprenorphine (8mg). In 2017, the FDA approved a 1-month XR buprenorphine injection for patients with OUD who have been treated with sublingual buprenorphine for at least one week. Another 1-month and a 1-week XR buprenorphine are currently under FDA review. It would be important to know whether those new formulations can increase treatment retention.

The third FDA-approved MOUD is naltrexone, which is a MOR antagonist that can be prescribed by clinicians in outpatient practice. The efficacy of its immediate release formulation was limited by poor adherence, but the development of a monthly extended release formulation (XR-NTX) significantly improved outcomes. 128 - 131 It has been particularly useful in justice system settings reluctant to use agonist therapies, 130 although there is need to assess whether it would be superior to XR-buprenorphine in those settings. Naltrexone is also a KOR antagonist, and while its affinity is lower than that for MOR, a recent brain imaging study reported KOR occupancies > 80% in patients with alcohol use disorder treated with naltrexone. 132 Antagonism of KOR by naltrexone could contribute to the mood improvements reported in OUD patients treated with naltrexone. 133 A potential barrier for the use of XR-NTX is the need for medically supervised withdrawal. Patients cannot use short-acting opioids for at least 7 days and long-acting opioids for 10-14 days preceding induction onto naltrexone to avoid triggering a withdrawal syndrome. A rapid taper consisting of a single day of buprenorphine followed by ascending doses of oral naltrexone along with clonidine and other adjunctive medications (e.g., clonazepam and prochlorperazine) may allow for faster induction protocols for XR-NTX, 131 but requires further study before it can be recommended as standard strategy.

At present, limited data are available regarding the comparative effectiveness of MOUD or about which patients will respond better to each medication. 109 A Cochrane review concluded that flexible-dose methadone leads to greater retention than sublingual buprenorphine, 119 but whether the same results would hold when compared with XR-buprenorphine is unknown. There are currently no published Cochrane reviews of XR-NTX versus buprenorphine, but two studies 134 , 135 have suggested that patients who can be inducted onto XR-NTX have similar outcomes to those treated with sublingual buprenorphine. However, in one of those studies 134 a substantial proportion of patients were unable to complete XR-NTX induction, mostly due to early relapse, leading to superior outcomes for the buprenorphine group in the intent-to-treat analysis.

As knowledge about MOUDs continues to grow, three priority areas need to be addressed. First, studies suggest that longer time in treatment is associated with better outcomes and that the risk of relapse greatly increases after medication discontinuation, yet rates of MOUD discontinuation in the first 6 months of treatment remain very high. Thus, there is a need to improve retention in MOUD treatment. It is also important to know which patients, when and under what circumstances can safely discontinue MOUD.

Second, current evidence indicates that counseling or psychotherapy do not increase retention in buprenorphine treatment or improve abstinence rates 116 , 136 - 139 and that methadone treatment 140 and buprenorphine without concomitant counseling is vastly superior to no treatment. 141 It is important to determine whether the potential benefits of concurrent psychotherapy outweigh the barrier to treatment created by requiring provision of psychotherapy when delivering buprenorphine treatment (such counseling is at present not required for XR-NTX). This was highlighted in the recent report of the National Academy of Medicine , which emphasized that lack of behavioral treatment support is not a reason for withholding MOUD. 110 Nevertheless, evidence-based behavioral interventions can be useful in engaging some patients with OUD in treatment, retaining them in treatment, improving outcomes, and helping them achieve recovery . 142 More research is needed to determine which behavioral interventions provided in conjunction with MOUD are most helpful for which patients, including evidence on the effectiveness peer support. There is also a need to develop models of care that better attract and retain patients in care and can overcome the barriers posed by the limited availability of well-trained clinicians. The use of technology-based approaches (i.e Telehealth, mHealth) may be a promising avenue to achieve these goals.

Third, research is needed to evaluate whether residential or inpatient treatment is superior to outpatient treatment for initiating MOUD. This question is important to evaluate the optimal allocation of resources for the treatment of OUD.

Preventing Opioid-Related Overdoses

Despite national and local efforts, the number of opioid-related overdoses continue to increase, highlighting the need of clinicians to educate patients and their families about the risk of overdose and how to respond to it. Several medication- and patient-related factors increase the risk of overdose. 143 Patient-related factors include: 1) Age above 65 years; 2) respiratory problems; 3) long-term opioid use; 4) substance use disorder (including alcohol use disorder); 5) comorbid mood disorders and/or suicidality; 6) use after a period of abstinence (e.g. following medically supervised withdrawal or incarceration); 7) prior overdose. Medication-related factors include: 1) Daily dose above 100 morphine milligram equivalents; 2) use of higher doses than prescribed (or than usually consumed, in the case of illicit opioids); 3) combination with fentanyl, other high-potency opioids or other substances, such as alcohol or benzodiazepines.

The acute treatment of overdose is administration of naloxone. For many years naloxone, which required injection, could only be administered by health care providers, but the availability of an auto-injectable naloxone device and a naloxone spray now allow laypersons to administer naloxone to revert overdoses. 144 , 145 Nevertheless, increasing the availability of naloxone to ensure that it can reach those who need it on short notice remains a challenge, as there is considerable variability in the availability of naloxone by locality. 146 A 2019 analysis concluded that making naloxone available without prescription (“over the counter”) would substantially increase its availability. 147

In most cases a single dose of naloxone is sufficient to reverse the overdose. However, when high doses or high potency opioids such as fentanyl are used more than one dose is necessary to restore or maintain spontaneous breathing. 148 Furthermore, the fast pharmacokinetics of fentanyl can result in abrupt respiratory depression, which in some instances does not provide sufficient time to administer naloxone. It is believed that the duration of the respiratory depression from fentanyl or other analogues is longer than the duration of its reversal from naloxone. Moreover, thoracic rigidity associated with serotonergic effects from some of the opioids drugs might also interfere with overdose reversals. Naloxone can also fail to reverse overdoses in which opioids are combined with other CNS depressants, such as alcohol or benzodiazepines. First-responders to an overdose should stay with patients until emergency medical services arrive and transport them to an emergency room for a more systematic evaluation. Reversal of the overdose generally triggers an acute withdrawal syndrome, 111 which can lead patients to leave medical supervision to seek opioids for relieving withdrawal. Upon reversal of an overdose OUD patients should be linked to OUD treatment otherwise their risk of overdosing again is very high. The emergency room offers unique opportunities to start patients on MOUD if they can be linked with ongoing services. 149 Nevertheless, more research is needed to improve the management of patients immediately after reversal of an overdose, to retain them under care and to initiate effective MOUD.

Because of the urgency of the crisis, most efforts to date have emphasized treatment approaches. There is growing recognition, however, of the need to develop effective preventive interventions for OUD. 1 , 5 , 150 Initial preventive approaches in the US focused on improving prescription practices for opioid analgesics and increasing the availability of naloxone to prevent overdoses. The growing role of heroin, fentanyl and other synthetic opioids in the opioid crisis, 1 , 16 , 151 has required broadening the scope of preventive interventions. There are no evidence-based primary and secondary prevention for OUD for adults or for youth transitioning into adulthood, but several approaches appear as promising directions.

One approach would be to adapt existing interventions that have been successful for youth. Evidence-supported prevention interventions delivered in community or school settings have shown effectiveness at reducing substance use and other related problem behaviors, including middle-school interventions that have specifically demonstrated an impact on reducing prescription opioid misuse. 152 However, whether those interventions would work in adults is unknown. An obvious difficulty in adapting these interventions is the lack of a setting similar to school where adults could be easily reached.

A second direction would be the development of conceptual frameworks that articulate the relationship among risk factors for OUD to help guide which interventions might be most effective given the prevalence of the risk factors, how they relate to other relevant risk factors and how modifiable the risk factors are. These models could help examine how risk factors present at birth (e.g., family history of substance use disorders) or childhood (e.g., adverse childhood events) can increase the likelihood of risk factors in adolescence (e.g., early onset of psychiatric disorders, low educational achievement), which in turn increase the risk of OUD in adulthood. 153 Simulations could help identify which interventions might be most promising at the full population level or for subgroups with specific constellations of risk factors, as well as to identify potential unintended consequences of those interventions.

A third approach would be to increase the focus on populations at risk that can be accessed for screening and treatment. Those include, for example, individuals who receive regular health care and those in the justice system. Improved management of opioid prescriptions and of treatment of OUD for pregnant women is also a high priority, as it could benefit the mother and simultaneously decrease the risk of neonatal abstinence syndrome (NAS) in newborns by decreasing their in-utero exposure to opioids.

Even with wider use of non-opioid analgesics or use of non-pharmacological approaches, opioids will continue to be necessary for the treatment of many patients with severe pain. Efforts to prevent the development of opioid misuse and OUD can be started in clinical settings. This includes assessment of risk of OUD before opioids are prescribed, periodic assessment of the need for opioid use, and use of urine testing to rule out illicit use of other substances. There is evidence that prescribing lower doses/fewer pills in the emergency room/post-surgery is associated with lower rates of long-term use and possibly OUD. There is also a need to assess each patient for licit and illicit use of other substances, particularly benzodiazepines and alcohol, which can increase the lethality of opioids by potentiating their depressing respiratory effects. Individuals who misuse opioids or develop OUD should be treated by their primary physicians if they have the necessary expertise and support or otherwise be referred to an addiction specialist.

Prevention approaches should also consider supply approaches. The most common sources of diverted opioid analgesics are friends or relatives who were legitimately prescribed opioids. 154 As with any other medication, it is important to educate patients who receive legitimate prescriptions about the health hazards they create for others when they give them their medications. Similarly, it is important to educate patients about the health risks they incur when they take medications (including opioids) that were not prescribed to them. Use of Prescription Drug Monitoring Programs (PDMPs) can help reduce doctor shopping and overdoses, but their use to date is inconsistent. This may be due in part to the voluntary nature of the programs in many states, delays in updating the information, restrictions in data sharing across jurisdictions and the need to access them through a separate computer from the one used to access electronic health records. 150 Approaches that could help decreased the availability of heroin and fentanyl, traditionally in the purview of law enforcement primarily, would also advance prevention, but their development and implementation are challenging in the face of the evolving nature of the epidemic.

Research Gaps and Translational Opportunities

Basic science.

In addition to making progress in clinical and public health approaches, there is a need to advance fundamental science that can provide the foundations of more effective interventions for the current crisis and provide the basis to combat future ones. For example, there is a need to better understand the genes implicated in individual differences in vulnerability to the stages and sequelae along the OUD trajectory, including the development of tolerance, physical dependence, addiction, hyperalgesia, and respiratory depression for they could help identify new medication targets and in the future could serve as biomarkers to predict risk for side effects. Animal models could be used to identify the functions of the relevant genetic variants, epigenetic modifications, and gene networks.

Similarly, technological advances, such as those emerging from the BRAIN initiative could be leveraged to gain a deeper knowledge of endogenous opioids and to identify the consequences of exogenous opioid administration on the endogenous opioid systems and the cells and circuits they modulate across a trajectory of opioid use, ranging from acute administration, tolerance, physical dependence, addiction, and recovery to relapse. This could include studying profile changes in the transcriptome and methylome of opioid-synthesizing neurons, imaging the intracellular signaling cascades following opioid receptor activation (and how those cascades change across the trajectory of opioid use) and using quantitative brain-wide optical imaging combined with computational pipelines for cellular registration to provide unbiased documentation of the stereotyped distributions of cellular activity and cell-types engaged by opioids under different conditions. Post-mortem brains could be used to identify human-specific genes and their proteins, as has been done in the study of other psychiatric disorders. Use of post-mortem brains would enable the discovery and integration of genomic, epigenomic, proteomic, metabolomic, and non-coding RNA features across many brain regions and cell types that distinguish individuals with vulnerabilities to OUD and opioid-induced respiratory depression. This knowledge could be combined to validate findings in animal models (i.e., does the animal model recapitulate the human brain biology?) and to reverse translate from human to test a hypothesis in rodents.

A systematic investigation of developmental trajectories of the human brain is relevant for our understanding of the mechanism through which adverse child experiences as well as drug exposures during fetal development increase risk for drug use and other mental illnesses. To address this question, the HEALthy Brain and Child Development (HBCD) Study, which is part of the HEAL Initiative from the National Institutes of Health, 155 will establish a large cohort of pregnant women from regions of the country significantly affected by the opioid crisis, and follow them and their children for at least 10 years. The study will help better understand typical brain development, beginning in the prenatal period through early childhood, including variability in development and how it contributes to cognitive, behavioral, social, and emotional function.

New Medications

Despite the existence of effective medications for the treatment of OUD, current rates of engagement and retention in treatment suggest that new medications and devices are needed. The introduction of more acceptable and effective medications is crucial to improve the outcomes of individuals with OUD. In turn, improved outcomes could lead to changes in societal attitudes towards OUD, with broader acceptance of OUD as a treatable brain disorder and lower stigmatization of those suffering from it. Because the circuitry and neurotransmitters of the different phases of OUD only partially overlap, several complementary approaches may be necessary to treat the whole spectrum of severity from sporadic to chronic use, withdrawal and relapse.

To help speed the development of novel pharmacotherapies (i.e., excluding already known mechanisms) NIDA recently created a list of medication development priorities based on data from published literature and internal studies with the most direct relevance to OUD. 156 This list, which is not exclusive did not prioritize any of the 10 proposed mechanisms and included: 1) orexin-1 or 1/2 antagonists; 2) Kappa opioid antagonists; 3) GABA-B agonists; 4) Muscarinic M 5 antagonists; 5) AMPA antagonists; 6) nociception opioid peptide receptors/opioid receptor like agonists or antagonists; 7) mGluR2/3 agonists; 8) Ghrelin antagonists; 9) Dopamine D 3 partial agonists; and, 10) Cannabinoid CB-1 antagonists.

In addition to medications that target specific receptors, the development of allosteric modulators of those receptors is also a high priority. Negative allosteric modulators (NAMs) and positive allosteric modulators (PAMs) may provide more physiologically relevant effects compared with agonists and antagonists acting on the same receptor, which may ultimately result in improved clinical outcomes. 157 The development of opioids that selectively activate MOR G-protein intracellular pathways (“biased agonists”) may lead to medication with potent analgesic properties but with lower risk of respiratory depression and addictive liability, which would contribute to decrease the incidence and prevalence of OUD. 158 Other potential directions could include epigenetic, micro RNA and neuroimmune targets.

Better training of health professionals

Despite the severity of the dual crises of chronic pain and OUD, very few medical schools offer adequate training in pain management, and still fewer offer even one course in addiction. Furthermore, surprisingly little is known about how best to train physicians and other health professionals on the management of OUD including the use of medications. 159 There is also evidence that many individuals trained to provide MOUD do not provide that treatment. Some national organizations offer a combination of didactics, supervision and mentoring to provide training beyond residency, 159 and the new subspecialty of addiction medicine is likely to further increase the availability of well-trained professionals that can treat individuals with OUD. However, broader changes, including combating stigma, enhancing institutional support and increasing reimbursement rates may be necessary to increase rates of treatment among those trained to provide it. Increasing the number of addiction treatment and prevention programs, particularly in low-resource communities is also essential.

The opioid crisis is a complex, evolving phenomenon. It involves neurobiological vulnerabilities and social determinants of health. Successfully addressing the crisis will require advances in basic science, development of more effective treatments, and public health approaches to implement current and emerging knowledge. We hope that this review will alert clinicians and researchers about the current approaches to the crisis and suggest opportunities for future research and for practice improvement. The advances achieved in addressing the current crisis should also serve to expand the science and treatment of other substance use disorders.

Acknowledgments:

The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies or the US government.

Conflict of Interest : The authors have no competing financial interests in relation to the work described in this manuscript.

Drug Abuse Research Paper

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Drug abuse, also referred to as substance or chemical abuse, is the recurrent use of a drug despite the experience of problems caused by the drug use. Difficulties arising in certain areas of a user’s life are of more importance to researchers and treatment professionals than other areas for identification of a drug abuse problem. The following are types of problems that signify drug abuse: impairment meeting major responsibilities in life, such as those regarding school, work, or home; difficulties with the law and social behavior; and aggravation of physical/medical conditions due to drug use. Drug abuse is to be contrasted with drug (chemical/substance) dependence. With drug dependence, use is considered compulsive and beyond the willful control of the user. That is, someone who is drug dependent is addicted; this is thought to be a more severe condition than drug abuse. Treatment of drug abuse is accomplished primarily using a variety of counseling and psychotherapeutic techniques employed to assist the abuser to stop using the drug, to develop new behavioral and mental coping skills, and to rehabilitate his or her life from the damage caused by the substance abuse.

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• Introduction
• Risk Factors and Causes of Drug Abuse
• Course of Drug Abuse
• Assessment of Drug Abuse
• Treatment of Drug Abuse
• Relapse Prevention

1. Introduction

In the discussion of drug abuse, it would be easy but inaccurate to label any regular use of a substance as abusive. Drug use in the United States is commonplace. Many people are capable of consuming drugs without developing problems. Drugs such as caffeine and alcohol, as well as prescription pharmaceutical products such as pain killing agents or antianxiety medication, are routinely and openly consumed every day in the United States (and in other countries as well). The various drugs affect the body differently and are used for specific purposes. For example, caffeine is used to remain alert and to enhance concentration, and tranquilizers are used to quell anxiety and for relaxation. However, drugs of abuse all have in common the property that they are psychoactive. For the sake of discussion, drugs may be classified with respect to different properties; one commonly employed system is in terms of the effect of the drug on the central nervous system (CNS). The following is one such classification system, with examples of drugs in each category:

• CNS stimulants: Cocaine, amphetamine, and caffeine
• CNS depressants: Alcohol, barbiturates, benzodiazepines, and solvent inhalants
• Psychotomimetics (also known as psychedelics or hallucinogens): Marijuana, LSD, and mescaline
• Narcotics/Opioids: Opium, heroin, codeine, morphine, and methadone

Substance use typically begins in adolescence. Adolescent substance use does not appear to be random; that is, it follows a fairly predictable pattern. Adolescents tend to start using substances that are legal and widely available to adults: alcohol and tobacco. Due to the fact that these drugs are the starting point for substance use, they are referred to as ‘‘gateway drugs.’’ In 1975, Kandel developed a stage model of progression of drug use that has since been revised:

• Beer or wine use
• Hard liquor or cigarette use
• Marijuana experimentation
• Alcohol abuse
• Prescription drug use
• Opiates and other illegal drugs

The vast majority of adolescents experiment with the gateway drugs at least one time. However, although most individuals try alcohol and tobacco, only for a minority of adolescents does use advance to abusive levels. As the stages advance, progressively fewer adolescents are found in each category. For example, alcohol will be tried by approximately 9 out of 10 students by their senior year in high school and cigarettes by approximately 6 out of 10 students by senior year. Opiates, at the last stage of the model, will be tried by only 1 out of 100 students by senior year.

Due to the high prevalence of substance use in the United States, it should be no surprise that substance-related problems are often encountered by mental health clinicians. The relatively high frequency with which substance-related problems are encountered by mental health professionals reflects the influence of the following factors: (i) Drug abuse has the potential to create or worsen all psychological symptoms, such as anxiety, depression, impulsive behavior, and antisocial behavior; and (ii) people seeking mental health services also tend to be at elevated risk for substance abuse problems. In other words, drug abuse harms people and contributes to psychiatric symptoms, and people experiencing psychological problems are apt to use drugs abusively.

2. Risk Factors And Causes Of Drug Abuse

With any medical or mental health condition, it is desirable to determine the cause or causes of the affliction. Identifying the cause(s) helps to develop prevention strategies to limit or eliminate future cases and treatment strategies for those already affected by the condition. For example, after the discovery that an absence of insulin was responsible for type 1 diabetes, effective treatment of diabetes with externally supplied insulin became possible. In addition, research is under way to develop early identification tests for intervention strategies to prevent later development of diabetes. This research has led to the isolation of faulty antibodies believed to attack the insulin-producing cells of the pancreas. The antibodies can be detected before the person is symptomatic for diabetes; experimental treatments are being used in an attempt to prevent the development of diabetes in these high-risk individuals.

Human behavior is complex and defies easy explanation. Unlike certain physical characteristics (e.g., eye color) or physical disorders that can be traced to single genes, a disorder such as drug abuse likely represents the interaction of multiple genetic and environmental influences. Complicating things further, ethics prevents us from conducting experimental studies (involving environmental or genetic manipulation) that might help us to tease apart various possible influences. One way to attempt to identify possible causes of substance abuse is to study risk factors. Risk factors are those variables associated with increased likelihood of developing a substance use disorder. Classes of risk factors are listed here with examples in each class:

• Peer: Peer substance use, strong attachment to peers, and positive peer attitudes about substance use
• Parent/family: Parent substance use, positive attitude about substance use, parent tolerance of adolescent substance use, and family disruption (e.g., divorce)
• Personal: Early (childhood) behavior problems, poor academic performance, anxiety/depression, and low self-esteem
• Biological: Genetic predisposition to substance use (e.g., a parent is a substance abuser)
• Community/social: Low socioeconomic status, high availability of substances, and deviant norms that encourage use of substances

Risk factors help us to understand influences to use substances, but we know many more people use them than become abusers. Therefore, the question as to who will progress beyond experimentation and casual use to the level of abuse is not answered by risk factors alone. It appears that use of substances is more a function of external risk factors, such as peer, social, and family factors; abuse of substances appears to be more a function of personal factors, such as psychiatric, behavioral, and emotional problems.

The biopsychosocial disease model is the most widely accepted model of substance abuse and addiction. It should be clear after reviewing the list of risk factors that biological, psychological, and social factors contribute to substance abuse. The biopsychosocial model is sufficiently comprehensive to include all known contributants to substance abuse.

3. Course Of Drug Abuse

Disease conditions are defined by several common factors, such as having identifiable causes, characteristic symptoms, and established treatments. In addition, diseases have an observable course. It is important to describe the course of an illness in part so that the condition can be identified (i.e., for diagnostic purposes). Also, if the untreated progression of an illness was not known, there would be no way to judge the effectiveness of treatment. Treatment interventions endeavor, essentially, to change the course of a disease. Initial attempts to describe and classify the course of alcohol abuse depicted an ever-worsening condition that eventuated in death, unless the drinking was stopped altogether. As it turns out, the long-term outcome of regular alcohol use is not certain death. Some people who use alcohol never develop problems, some who develop problems (alcohol abusers) never become addicted, and a minority of alcohol abusers (approximately one-third) exhibit the progressive deteriorative pattern of drinking. The same overall trends may be expected with other substances of abuse as with alcohol. In 1995, Shaffer and Robbins developed a general model to describe the typical course of an addiction, consisting of the following stages:

• Initiation: Experimentation with a drug is begun.
• Positive consequences: At this point in the use process, only the pleasurable pharmacological and social effects of the substance are experienced.
• Negative consequences: For those individuals who continue to regularly use the substance, eventually negative consequences are experienced in terms of health, relationships, work, school, finances, or the law.
• Turning point: For abusers who continue despite negative consequences, there is some recognition of the damage the substance is causing in their lives and ambivalence ensues.
• Active quitting: For some abusers, ambivalence is resolved in the direction of stopping use.
• Relapse prevention: For those who have quit, behavior changes are maintained over time to prevent resumption of drug use.

4. Assessment Of Drug Abuse

In order to treat a condition, it must first be determined that a given individual has the condition; in other words, the diagnosis of drug abuse must be made. In medicine, objective tests via technologically advanced equipment (e.g., x-ray and magnetic resonance imagery) are often used to assist the doctor in the diagnostic process. In the evaluation of drug abuse, modern technology is hardly relevant. Biological testing, in the forms of urinalysis and evaluation of saliva and blood samples, may be used but are not the mainstay of assessment. Biological testing can determine if a specific drug or drug metabolite is present in a sample but cannot indicate anything about patterns of use, withdrawal symptoms, compulsive behavior, or consequences of use, all of which are important aspects to assess. Therefore, biological testing is confined to the role of confirming recent abstinence; this information is especially important in certain settings (e.g., criminal justice system and workplace) but of limited use in a drug abuse assessment. Since we are more interested in determining whether a pattern of abusive drug use is present or not, relevant information needs to be gathered. Therefore, the interview is the primary method by which information is acquired to make the diagnosis of drug abuse. Typically, the diagnostic interview is conducted with the person in question as well as with others in a position to observe relevant behaviors (most often family members and/or close friends). In addition to the interview, information is sometimes acquired via self-report, paper-and-pencil tests. The following information is typically obtained during a drug abuse assessment:

• List all substances ever used
• Age of first use of all substances
• How used each substance (e.g., smoke, drink, snort, etc.)
• Age of peak use, and amount used, for each substance
• Number of days use substance per week, for each substance
• Amount of substance used on a typical day of use
• Date of last use of each substance
• List all negative consequences resulting from use of substances

Diagnosing a drug abuse disorder is only one element of the assessment process. It is also necessary to determine as part of the evaluation the most appropriate setting in which treatment should take place (e.g., outpatient, halfway house, or inpatient); the proper intensity of treatment (e.g., daily treatment or monthly treatment); whether other treatment needs exist (e.g., medical and/or psychological disorders); and specific, individual treatment goals for a given person.

5. Treatment Of Drug Abuse

There is no one treatment for drug abuse. This fact is a reflection of the complexity of the condition and its diverse manifestations, and it highlights the importance of the assessment process, which is critical in helping determine the best treatment for a given individual. The treatment of drug abuse may occur in different settings, with varying degrees of professional assistance (e.g., self-help/12-step and professional help) and different modalities of professional services (e.g., individual therapy, group therapy, family therapy, and pharmacological treatment). Drug abuse treatment may be characterized as specialized treatment with one main goal: to stop the use of the substance. Treatment is primarily talking therapy—counseling and psychotherapy; in addition, medications may be employed to manage detoxification from some drugs and/or to treat coexisting psychological or medical conditions. However, regardless of the setting of treatment, the intensity of the contact schedule, or who renders the treatment, it is ultimately talking therapy that takes place. Especially early in treatment, the focus of discussion is on behavior directly related to drug use and stopping the use of the drug. Most programs and professionals recommend complete abstinence from drugs; some have the goal of harm reduction (allowing use to continue while attempting to reduce drug use to less harmful levels), but they are in the minority. As treatment progresses, and abstinence is achieved and maintained, the emphasis usually broadens to other areas of the person’s life that may need repair, such as their decision-making skills, coping skills, emotional state, and relationships. In other words, the individual suffers psychological and social damage from drug abuse and may even have had significant deficits in these areas prior to his or her drug abuse; treatment is designed to improve the psychosocial functioning of the individual once he or she is drug-free.

6. Relapse Prevention

Drug abuse has been described as a chronic, relapsing disorder. Like all chronic conditions, long-term effort must be applied for the individual to maintain abstinence from drug use. Nobody would expect the blood sugar levels of someone with diabetes to be in a healthy range if the person only complied with the prescribed care regimen for 1 month after a visit to the physician. Likewise, if a drug abuser only applies the principles of treatment for a limited period of time, resumption of abusive habits would be expected. One way to attempt to guard against a backslide into prior behavior is to extend treatment as long as possible. In addition, teaching relapse prevention skills that an abuser may use going forward in time is an integral part of drug abuse treatment. Some common elements of relapse prevention programs include identification of high-risk situations that are likely to lead to relapse, development and practice of skills to effectively cope with risky situations, enhancement of self-confidence to be able to apply coping skills when needed, learning to limit a slip to an isolated incident rather than allow it to be the beginning of a process of abuse, drug/alcohol monitoring for abstinence verification, and developing positive behaviors (e.g., working and physical exercise).

Bibliography:

• Bukstein, O. (1995). Adolescent substance abuse: Assessment, prevention and treatment. New York: Wiley.
• Dodgen, C. E., & Shea, W. M. (2000). Substance use disorders: ssessment and treatment. San Diego: Academic Press.
• Gold, M. S. (1991). The good news about drugs and alcohol: Curing, treating and preventing substance abuse in the new age of biopsychiatry. New York: Villard.
• Kandel, D. (1975). Stages in adolescent involvement in drug use. Science, 190, 912–914.
• Schuckit, M. A. (1995). Educating yourself about alcohol and drugs: A people’s primer. New York: Plenum.
• Shaffer, H. J., & Robbins, M. (1995). Psychotherapy for addictive behavior: A stage-change approach to meaning making. In A. M. Washton (Ed.), Psychotherapy and substance abuse: A practitioner’s handbook (pp. 103–123). New York: Guilford.

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