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  • Int J Prev Med
  • v.5(Suppl 2); 2014 Dec

A Review Study of Substance Abuse Status in High School Students, Isfahan, Iran

Mah monir nahvizadeh.

Provincial Health Center, Isfahan University of Medical Sciences, Isfahan, Iran

Shohreh Akhavan

1 Vice-chancellery for Research, Isfahan University of Medical Sciences, Isfahan, Iran

Leila Qaraat

Nahid geramian, ziba farajzadegan.

2 Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran

Kamal Heidari

3 Social Determinants of Health Research Center, Isfahan University of Medical Sciences, Isfahan, Iran


As the first experience of substance abuse often starts in adolescence, and studies have shown that drug use is mainly related to cigarette and alcohol consumption, an initial exploration of substance abuse prevalence, including cigarette and alcohol, seems to be the first step in preventing and controlling drug consumption. This study aimed to explore studies on drug use among high school students by investigating articles published in the past decade in Iran.

In this study, the databases inside the country were used to access articles related to substance abuse by students during 2001–2011, among which 7 articles on 14–19 years old high school students were studied.

The seven studied articles showed that the highest drug use prevalence pertained to cigarette and hookah, followed by alcohol, opium, ecstasy, hashish and heroin. Opium and heroin use in Kerman city were, respectively, about 4 and 5 times of their use in other studied cities.


Drug use is relatively high in the adolescent and effective group of the society, which requires particular attention and prompt and immediate intervention.


Substance abuse is a common phenomenon in the world and has invaded the human society as the most important social damage.[ 1 , 2 ] Substance abuse is a nonadaptive model of drug use, which results in adverse problems and consequences, and includes a set of cognitive, behavioral, and psychological symptoms.[ 3 ]

Iran also, due to its specific human and geographic features, has a relatively high degree of contamination.[ 4 ] The World Health Organization's report in 2005 shows that there are about 200 million opiate addicts in the world, reporting the highest prevalence in Iran and the most frequency in the 25–35 year-age group.[ 5 ] The onset of drug use is often rooted in adolescence, and studies show that substance abuse is often related to cigarette and alcohol consumption in adolescence.[ 6 ] Results of studies indicate that age, being male, high-risk behavirs, and the existence of a cigarette smoker in the family or among friends, the experience of substance abuse, inclination and positive thoughts about smoking have relationship with adolescent cigarette smoking.[ 7 ] Studies also confirm that the chance of becoming a cigarette smoker among males and females is almost equal (11.2%); however, the prevalence of regular alcohol consumption in males (22.4%) is slightly higher than in females (19.3%).[ 8 ]

Few studies have been conducted in Iran on adolescents’ patterns of substance abuse, producing various data on the prevalence and the type of consumed drugs, but there is currently no known specific pattern of substance abuse in this age group; therefore, this review study has studied drug consumption prevalence in the student population of the country by collecting various data.

This article is a narrative review focusing on studies conducted in Iran. In this research, all articles related to substance abuse and its patterns among high school students, which were conducted in Iran and published in domestic and international journals, were investigated. The articles were acquired from academic medical journals, research periodicals and the Scholar Google, Magiran, Irandoc, and Medlib. The search keywords included prevalence, substance abuse, Iranian student, and addiction.

This study explored articles in the past 10 years (2001–2011) about Iranian high school students. The full texts of the articles were often accessible in the scientific information database and magiran websites, but the full text of the article about Gilan Province was obtained after contacting the journal's office. Correspondence was made with the author of the article about Mahriz city to obtain the article as it was not published in the Toloee Behdasht journal.

These articles provide information about the consumed drug type, its prevalence in terms of the sex and age, and the experience of at-least-once consumption in the adolescent's life. Some articles had only pointed to drug consumption, which was also included in this research. Some had attended to substance abuse in general terms without distinguishing different kinds of drugs, and in some articles only psychoactive drug use, was mentioned.

The cases, in which the sample volume was not sufficient, or were not in the studied age groups, were excluded from the study. Due to different categorizations in these articles regarding the long-term prevalence of substance abuse or the experience of at-least-once consumption, in this study the shared aspect of these articles, that is, the experience of at-least-once use was adopted. Some articles had addressed the students’ predisposing factors for drug abuse, in addition to drug use prevalence, which were not included in this study for being scattered.

An initial search into the data bases yielded 11 articles, two of which were related to years before the study time frame (1997 and 1998). Furthermore, two articles were ignored, one because of its different age group (a lower age) and the other because it had addressed a particular district in Tehran with a small sample size. These results are based on 7 articles. All studies were about the 14–19 years old group, and only three studies had distinguished between the sexes. All 7 studies considered in this article were cross-sectional.

The prevalence of drug consumption in the studied cities

A study was conducted in 2003 on 500 students, from 142 high schools and vocational schools in Zahedan City, using a multi-stage cluster sampling method. In total, from the total of 259 females and 216 males who completed the questionnaire, the following results were obtained. 0.4% of the females and 2.3% of the males would usually smoke cigarette. The first experience of smoking was most often seen at the age of 14 (26.2%). The prevalence of other drugs was not studied in this research.[ 9 ] A study was conducted in 2009 on 610 students of Kerman's Male Pre-university Centers, in which the prevalence of each drug was reported, but the total consumption prevalence was not mentioned.[ 10 ]

A study in Gilan Province in 2004–2009 on 1927 high school students, including 46% females and 54% males, showed that the percentage of at-least-once use, including and excluding cigarette, was 23.7 and 12.8, respectively.[ 11 ]

A study in Karaj city in 2009–2010 on 447 high school students, including 239 females and 208 males, showed that 57% had at-least-once experience of drug use, including cigarette, of this number 56.1% were male and 43.9% were female.[ 12 ]

A study in Nazarabad city in 2007 on 400 3 rd year high school students, including 204 females and 196 males with the mean age of 17.3, showed that drug use prevalence, including and excluding cigarette, was 24.5% and 11.1%, respectively.[ 13 ] A study was performed in Lahijan city in 2004 on 2328 high school students, including 42.2% females and 57.8% males.[ 14 ] A descriptive study was conducted in 2008 on a 285-member sample of male high school students.[ 15 ]

The consumption prevalence for each drug type in different cities

A research on Kerman's Male Pre-university students yielded the following results. The consumption prevalence of hookah was 15.5%, sedatives (without medical prescription) 40.7%, alcohol 37.7%, cigarette 34.6%, strong analgesics 10.2%, nas 9.7%, opium 8.7%, hashish 6.7%, ecstasy 6.6%, and heroin 4.9%.

Consumption prevalence for each drug type in Gilan: The prevalence was 20% for cigarette, 10.5% for alcohol, 2.4% for opium, 1.2% for ecstasy, 2% for hashish, and 0.3% for heroin. In Karaj city, the consumption prevalence was 53% for hookah, 24.8% for cigarette, 13.6% for alcohol, 2% for ecstasy, 2% for opium, 1.1% for hashish, 0.4% for crystal, and 0.2% for heroin.

In Nazarabad City, the consumption prevalence was found to be 23.1% for cigarette, 2% for opium, 1% for amphetamines and ecstasy, 0.5% for heroin, 0.3% for hashish and cocaine. The male and female drug consumption was 69.7% and 36.2%, respectively, representing a significant statistical difference ( P < 0.05).

A study in Lahijan City showed that the consumption prevalence was 14.9% for cigarette, 2.4% for ecstasy, 4.1% for other drug types (with the highest rate of consumption for opium and hashish). In the Mahriz city of Yazd, the consumption prevalence among the male 3 rd year high school students in 2008 was reported 6.8% for alcohol and 3% for psychoactive substances [ Table 1 ].

The comparison of the prevalence of at-least-once drug use for each drug type in each studied region[ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]

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Drug consumption prevalence for each sex

A study in Zahedan also reported that at-least-once drug use prevalence was 1.6% and 8%, respectively, among females and males; and at-least-once cigarette smoking prevalence was 7.8% and 25.2%, respectively, for females with the mean age of 15.8 and males with the mean age of 16.

In Gilan, drug use, excluding cigarette, was reported 19.1% and 5.3%, respectively, for males and females, representing a significant statistical difference ( P < 0.05). Furthermore, cigarette and drug use prevalence was 31.3% and 14.8% in males and females, respectively, showing that this rate was significantly higher in males ( P < 0.05). Cigarette use prevalence was 25.9% and 3%, respectively, for male and female students. Alcohol consumption was 16.6% and 3.4% for males and females, respectively. Opium consumption was 3.3% and 1.5% among males and females, respectively, which was a significant statistical difference (…). Drug consumption, excluding cigarette, was 19.1% and 5.3%, respectively, for males and females, pointing to a statistically significant difference ( P < 0.05). Ecstasy use prevalence was reported 3% and 1.1%, respectively, for males and females, pointing to a statistically significant difference ( P < 0.00081); 0.5% of males and 0.1% of females were heroin consumers, lacking any significant statistical difference ( P > 0.05). In Karaj city, drug consumption prevalence was studied for each sex and drug type [ Table 2 ].

The comparison of the prevalence of at-least-once drug consumption for each sex in each studied region

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Object name is IJPVM-5-77-g002.jpg

Drug consumption prevalence based on the age distribution in the studied populations

As the study conducted on students with the mean age of 16 in Zahedan showed that the highest incidence of the first experience of cigarette smoking belonged to the age of 14. A study in Kerman on students with the mean age of 17.9 about the age at the first experience yielded the following results for each drug type: 14 for cigarette, 14.6 for alcohol, 13.9 for hookah, 13.1 for sedatives, 15.3 for analgesics, 17 for ecstasy, 16.7 for hashish, 16.7 for heroin, 16.7 for opium, and 15.3 for naswar.

A study in Gilan indicated that drug and cigarette consumption had significantly increased in males aged 19 and above (88.9% of males aged 19 and above) ( P < 0.05). According to a study in Nazarabad, the highest drug use onset was at the age of 15–16. The students’ mean age in the Karaj study was 16.9.

Exploring the MFT performed in the USA on the 10 th graders showed that drug use had increased from 11% to 34% during 1992–1996. In 1998, 12.10% of the 8 th year and 12.5% of the 10 th graders and 25.611 th % had experienced illegal drug use in the previous month.[ 16 ] It was shown that hashish, followed by opium and alcohol, is the most commonly used illicit drug.[ 17 ] The immediate necessity of planning for reducing the consumption of these drugs among students, and consequently among university students, has become increasingly important.

Investigating addictive drugs prevalence among university students showed the prevalence in the following order: Hookah (74.5%), cigarette (67.5%), opium (6.1%), alcohol (13.5%), psychoactive pills (5.26%), hashish and heroin. Entertainment constitutes the tendency for drug consumption in most cases (47.4%).[ 18 ] Results of a meta-analysis showed that 7% of Iranian adolescents regularly smoke, and 27% had experienced smoking. The increased cigarette use prevalence among Iranian adolescents is a major public health concern.[ 19 ] Paying attention to healthy recreations for adolescents and the youth has become increasingly important and needs planning for discouraging drug use. The cross-sectional prevalence of drug use in 1997 among American 12–17 years old adolescents was reported 11.4%, which was close to drug use prevalence, excluding cigarette.[ 16 ]

Another study showed that 56% of male and 42% of female university students were drug users, which accords with the present research with regard to the higher number of the males.[ 20 ] Since, the addiction problem is an old problem in other countries, it might be better to use the solutions practiced by them to speed up our reaction in cases which adhere to our culture and customs.

At-least-once alcohol use prevalence among the 8 th year American students in 2005 and 2006 was 27% and 20%, respectively, increasing to 88% among the 12 th year students.[ 20 ] The history of hashish consumption among the 8 th , the 10 th , and the 12 th year students was 10%, 23%, and 36%, respectively, representing a remarkable difference with our country's students.[ 20 ] About 0.5% of the 8 th year and 10% of the 12 th year students consumed cocaine, and the consumption of amphetamines by the 12 th year students was 1.5%,[ 20 ] being almost close to the consumption rate of Iranian students. The open consumption of hashish is common in France by almost one-third of the population (nearly 30%), compared with the average rate of 19% in European countries; also the consumption of ecstasy and cocaine has increased over 2000–2005, although it is 4% but yet remarkable.[ 21 ]

A study on students’ knowledge of narcotics in Rafsanjan and Yazd cities showed that 5.6% of Yazdian and 10% of Rafsanjanian students had at least one addicted person in their families. Also, 2.23% of the Yazdian and 7% of the Rafsanjanian students held that narcotics could also be useful.[ 22 ] The important issue here is the existence of an addicted relative and his or her leadership role in this regard; therefore, this point suggests the further importance of the sensitivity of this age group with regard to their dependence on narcotics.

It is noteworthy that Kerman City, compared to other studied cities, has received higher rates of drug use, such that opium and heroin consumption in this city has been, respectively, almost 4 and 5 times that of other cities. These statistics also hold true clearly with regard to ecstasy and alcohol consumption, each being almost 3 times that of Karaj and Gilan. Hashish consumption in the pre-university stage in this city is also higher than in other cities, which might be related to easier drug access in Kerman.

In the cities, in which sex-distinct studies were conducted, drug consumption by males had been, with no exception, far higher than by the females, which is, almost 4 times except for hookah and then cigarette. Of course, it is not possible to judge firmly about drug use general prevalence as a result of the few studies in this field; however, the important point is the relatively high drug use among the adolescent and effective group of the society, which deserves particular attention for education and intervention in this group. It has been observed that adolescent and young crystal users, compared to nonusers, show clinical symptoms, have less control and affection in their families, with excitable, aggressive and anxious personalities, and low accountability;[ 23 ] on the other hand, behavioral problems and friend influence are among the strongest risk factors of drug consumption among adolescent consumers.

Nevertheless, it is not clear to what extent the adolescent can manage the effect of behavioral problems and peer group interaction for refusing invitations for drug consumption.[ 24 ] It has been stated that using software programs would assist in the prevention and increasing the youth's skills for reducing drug use.[ 25 ] It has been shown that adolescent inclination to and consumption of drugs decrease significantly in the 1 st year of educational intervention.[ 26 ] On the other hand, studies indicate that there is a relationship between the borderline personality disorder and the extent of drug abuse.[ 27 ]

Therefore, prevention programs for harm reduction, treatment and consultation as the main objective of the intervention structure should apply to consumers.[ 28 ] Also, emphasis should be laid upon the relationship between schools and parental care as important protective factors for adolescents’ health.[ 29 ] Adolescence is a growth period which is associated with a relatively high rate of drug use and its related disorders. Accordingly, recent progress in evaluating drug abuse among adolescents would continue for information sharing in the field of clinical and research services.[ 30 ] Therefore, attention to this group through coherent planning for damage prevention would still remain in priority.


Source of Support: Nil

Conflict of Interest: None declared.

  • Open access
  • Published: 13 November 2021

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


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.

figure 1

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 .

figure 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.


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].


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.


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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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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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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Original research article, illegal drug use is associated with poorer life satisfaction and self-rated health (srh) in young people.

research articles on drug use

  • Imperial College London, London, United Kingdom

Illegal drugs can bring negative health and psychological health consequences to people who use them. However, much less is known about illegal drug use and its association with life satisfaction and self-rated health (SRH) in young people in the context of the United Kingdom, which is important because SRH and life satisfaction are associated with important outcomes including morbidity and mortality. By analyzing data from a nationally representative sample with 2,173 people who do not use drugs and 506 people who use illegal drugs aged between 16 and 22 (mean = 18.73 ± 1.61) years old from Understanding Society: the UK Household Longitudinal Study (UKHLS) using a train-and-test approach and one-sample t -tests, the current study found that illegal drug use is negatively associated with life satisfaction (t(505) = −5.95, p < 0.001, 95% CI [−0.58, −0.21], Cohen’s d = −0.26) but not with SRH. Intervention programs and campaigns should be developed to prevent people from using illegal drugs, which may then avoid the negative consequence of poor life satisfaction associated with illegal drug use.


Illegal drug use is one of the main contributors to the global burden of disease ( 1 ) that has adverse health and psychological consequences ( 2 ). The overall prevalence of illegal drug use in 2018–2019 ranges from 5.9 to 12% in the United Kingdom. However, this number was particularly high for young people, which ranges from 21 to 28% ( 3 ). Moreover, according to Allen and Laborde ( 2 ), “Illicit drug use and dependence are associated with an increased risk of mental disorders, road-traffic accidents, fatal overdoses, infections from unsafe injection practices (e.g., contraction of HIV), suicide and violence ( 1 , 4 ), and illicit drug dependence accounted for 20 million (95% UI: 15.3, 25.4 million) disability-adjusted life years (DALYs) worldwide in 2010 ( 4 ).” Given the negative consequences associated with illegal drug use, there has been progress in trying to identify factors that relate to illegal drug use ( 2 ), including individual, interpersonal, community, and policy factors as pointed out by the social-ecological model. For instance, poor mental health, peer pressure, deprived family environment are factors of illegal drug use ( 5 ), which are also related to life satisfaction and SRH.

Self-rated health (SHR) refers to the subjective evaluation of one’s overall health whereas life satisfaction refers to how a person likes his or her life ( 6 ). It has been suggested that drug use is negatively related to life satisfaction ( 7 ). For instance, Zullig et al. ( 7 ) found that drug use is negatively related to SRH in American high school students. Boyas et al. ( 8 ) found that drug use is negatively related to SRH between Latino and non-Hispanic white adolescents aged between 12–17 in the United States. Moschion and Powdthavee ( 9 ) found that cannabis use is negatively associated with life satisfaction and the decrease in life satisfaction following the use of drugs persists 6 months to a year after initial use in homeless or at risk of being homeless participants in Australia. Illegal drug use may relate to life satisfaction and SRH through pathways such as poor physical and mental health ( 5 ), deprived socioeconomic status ( 10 ), and social stigma ( 11 ).

Thus, although there are some studies about how drug use is related to SHR and life satisfaction in young and middle adolescence [aged below 17; e.g., ( 7 , 8 )] and adults [e.g., ( 12 )], much less is known about how drug use is associated with life satisfaction in young people in late adolescence and emerging adulthood, particularly in the United Kingdom. In late adolescence and emerging adulthood, individuals have to achieve autonomy from their guardians and will experience shifts in social roles and some normative expectations for their own behaviors. In this period of time, young people explore various aspects of their life including education, work, leisure interests, romance, and worldviews. The lifestyle factors associated with this period appear conducive to facilitating the development of addictions such as drugs [see ( 13 ) and ( 14 ) for reviews]. Moreover, newly found autonomy can lead to various mental health problems such as stress, anxiety, and depression, which in turn contribute to illegal drug use ( 15 ).

Thus, the aim of the current study is to investigate how illegal drug use is related to life satisfaction and SRH in young adults in the United Kingdom while controlling for demographics and other substance use behavior. The current study hypothesizes that drug use is negatively related to both life satisfaction and SRH.

Materials and methods

Data were used from Understanding Society: the UK Household Longitudinal Study (UKHLS). This data has been shown to be nationally representative when compared with data from population censuses. Members from households recruited at the first round of data collection were interviewed face-to-face by trained interviewers or through a self-completion online survey. The current study used data in Wave 7, which was collected between 2017 and 2018 ( 16 ). All data collections have been approved by the University of Essex Ethics Committee. Participants received informed consent before participating. This dataset is quite representative as shown by comparing it with population censuses ( 17 ). The question that asks about illegal drug use was only administrated to people aged between 15 and 22 and participants with any missing variables of interest were removed. Thus, there were 506 participants who indicated that they have used illegal drugs in the past year with a mean age of 18.73 ± 1.61 years old and 262 (51.78%) males left after removing missing variables and 2,173 participants who indicated that they never used illegal drugs during the past year with a mean age of 18.37 ± 1.71 years old and 928 (42.71%) males. Descriptive statistics can be found in Table 1 .


Table 1. Descriptive statistics of demographic characteristics, other substance use, life satisfaction, and SRH in non-illegal drug use and illegal drug use.

Illegal drug use

Illegal drug use was measured by the question “Since 1/[interview month] / [interview year–1], how many times have you used or taken any illegal drugs?” “[interview month]” represents the actual month that participants completed the questionnaires, which varied across individuals. “[interview year–1]” represents the actual month that participants completed the questionnaires minus 1 year. Together, these dates can effectively ask whether participants have taken illegal drugs the previous year despite they may complete these questionnaires at different time points. Participants who indicated that they have never used illegal drugs in that given year were considered as people who do not use illegal drugs whereas participants who have used illegal drugs during the past year were classified as people who use illegal drugs.

Life satisfaction

Life satisfaction was measured using the question “How dissatisfied or satisfied are you with… your life overall?” using a seven-point scale ranging from 1 (not satisfied at all) to 7 (completely satisfied). The scores of this measurement were treated as continuous. The results of single-item measures and multi-item measures such as the Satisfaction with Life Scale (SWLS) have been shown to be very similar ( 18 ).

Self-rated health was measured by the question “In general, would you say your health is…” using a five-point scale ranging from 1 (excellent) to 5 (very poor). SRH scores were reverse coded, so now one means very poor and five means excellent. The scores of this measurement were treated as continuous. The reliability of this single measurement of subjective health is good ( 19 ).

Control variables

Control variables include age, sex, monthly income, highest educational qualification, whether or not participants live in the urban area, and whether or not participants have drunk alcohol in the past year, whether or not participants consider themselves as smokers, and whether or not participants have smoked e-cigarettes.

A train-and-test approach was used to analyze current data. First, participants were grouped into two groups based on whether they used illegal drugs. Second, two generalized linear models were applied to people who did not use illegal drugs during the past year by taking control variables as predictors and life satisfaction and SRH as the predicted variable, respectively, with “fitlm()” function in MATLAB 2018a. Visually inspecting the residual plots of these models led to the conclusion that residuals are normally distributed, thus linear models are suitable in this case. Third, these models were used to predict scores that are expected if people who used illegal drugs were people who did not use illegal drugs in the past year by taking their control variables including age, sex, monthly income, highest educational qualification, whether or not participants live in the urban area, whether or not participants have drunk alcohol in the past year, whether or not participants consider themselves as smokers, and whether or not participants have smoked e-cigarettes as predictors. Finally, two one-sample t -tests were applied to see if there are significant differences between the scores that were expected to see if they did not use illegal drugs the past year and their actual life satisfaction and SRH scores. All analyses were conducted on a customized script on MATLAB 2018a.

Descriptive statistics can be found in Table 1 . The overall prevalence of illegal drug use was 18.89%. Young people who used illegal drugs during the past year received less college-level education, tended to live in a rural area, were more likely to consume alcohol during the past year, and were more likely to be a smoker and have used e-cigarettes than people who did not use illegal drugs during the past year.

The current study found that there is a main effect of age [ F (1,2164) = 5.09, p < 0.05], sex [ F (1,2164) = 6.10, p < 0.05], and smoking status [ F (1,2164) = 5.05, p < 0.05] on life satisfaction among people who did not use illegal drugs in the past year. However, the main effect of monthly income, highest educational qualification, residence, drinking status, and vaping status was not significant.

Moreover, there was a main effect of sex [ F (1,2164) = 40.66, p < 0.001], residence [ F (1,2164) = 11.05, p < 0.001], smoking status [ F (1,2164) = 19.80, p < 0.001], and vaping status [ F (1, 2164) = 8.86, p < 0.01] on SRH among people who did not use illegal drugs the past year. However, the main effect of age, monthly income, highest educational qualification, and drinking status on SRH was not significant. The parameter estimates of these general linear models can be found in Table 2 .


Table 2. The estimates ( b ) of linear models trained based on demographic and other substance use predictors of people who did not use illegal drugs the past year.

The current study found that illegal drug use is negatively associated with life satisfaction (t(505) = −5.95, p < 0.001, 95% CI [−0.58, −0.21], Cohen’s d = −0.26) but not with SRH. The mean and standard deviation of predicted scores and actual scores for people who used illegal drugs in the past year were plotted in Figure 1 .


Figure 1. The mean and standard deviation of predicted and actual life satisfaction and SRH scores for people who used illegal drugs the past year.

The aim of the current study was to identify the relationship between illegal drug use and life satisfaction and SRH. By using a train-and-test approach and a t -test to analyze data from Understanding Society, the current study found that illegal drug use is negatively associated with life satisfaction but not SRH, which is largely consistent with the established literature regarding the association between substance use and poorer life satisfaction and SRH [e.g., ( 8 , 12 )]. Illegal drug use can bring not only negative consequences to physical but also psychological health. However, the current study did not find a relationship between drug use and SRH in young people, which may be explained by the fact that the current study controlled for other addictive behaviors including smoking, drinking, and vaping, which has been shown to be associated with poorer SRH [e.g., ( 7 , 8 )].

Risky behaviors in young people tend to cluster ( 20 – 23 ). Indeed, newly found autonomy in late adolescence and early adulthood can be a stressful time. In addition, this group of people is known to be less risk-aversive due to the perceptions of invincibility, which then leads to greater experimentation. Additionally, the underlying brain structures are not fully matured yet such as the inhibitory control network [see ( 24 ) for a review], which then leads to a higher chance of risky behavior. In addition, other factors such as uncertainty about the future, trauma, and mental health, may contribute to risky behavior such as illegal drug use, and poor life satisfaction.

It is reasonable to think that dissatisfaction with life among young people can be associated with other behaviors that are at risk such as sexual risk-taking, violence, aggression, suicide ideation, and dieting behaviors ( 7 ). Behavioral health specialists have begun to focus on the promotion of developmental assets in young people, including psychological wellbeing and adaptation ( 25 – 27 ), which broadens the scope of assessment in young people beyond traditionally assessed risk behaviors and psychiatric symptoms ( 23 , 28 , 29 ). Thus, these approaches may be sensitive to subtle, but clinically meaningful, changes in adolescent cognitive wellbeing. Life satisfaction measures can also extend the score of the wellbeing indicators in other large scale national survey in the United Kingdom.

Despite the strength of this study including well-controlled socioeconomic status and co-use of other substances including alcohol, cigarettes, and e-cigarette, there are some limitations. First, the current study is cross-sectional, which does not give support to strong causal inferences. Future studies should employ longitudinal approaches in order to establish causal association between illegal drug use and life satisfaction and SRH. Second, the current study is based on self-report measures, which can cause bias. Future studies should use more objective measurements to avoid these biases. Third, the type of illegal drug that participants used was not assessed. Future studies should investigate the various effects that different drugs may have on life satisfaction and SHR. Finally, illegal drug use is typically accompanied by psychiatric comorbidities and substance use disorders [e.g., ( 30 , 31 )]. However, they were not controlled in the model. Future studies should collect this information and control it to rule out their possible effects on life satisfaction and SRH.

To conclude, the current study investigated how life satisfaction and SRH are affected by illegal drug use status. By using an innovative train-and-test approach, the results showed that only life satisfaction but not SRH is affected by drug use status. There are also some implications that can be drawn from the current study. Interventions that help people quit illegal drug use and campaigns that prevent people from using illegal drugs are largely needed. Findings from the current study should also be utilized as a fact for educational purposes. Moreover, special attention may need to be given to young people who are at the stage of achieving autonomy, and who are at a higher risk of illegal drug use. For instance, providing consulting services at schools may provide a better chance for young people to successfully achieve autonomy and overcome difficulties in this period of time, which may reduce illegal drug use and promote life satisfaction.

Data availability statement

Publicly available datasets were analyzed in this study. This data can be found here: https://www.understandingsociety.ac.uk .

Ethics statement

The studies involving human participants were reviewed and approved by the University of Essex. The patients/participants provided their written informed consent to participate in this study.

Author contributions

WK: conceptualization, data curation, formal analysis, investigation, methodology, resources, software, writing—original draft, and writing—review and editing.

This work was supported by the Imperial Open Access Fund.

Conflict of interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords : illegal drug, self-rated health, life satisfaction, young people, substance use

Citation: Kang W (2023) Illegal drug use is associated with poorer life satisfaction and self-rated health (SRH) in young people. Front. Psychiatry 14:955626. doi: 10.3389/fpsyt.2023.955626

Received: 29 May 2022; Accepted: 03 February 2023; Published: 21 February 2023.

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  • Published: 12 August 2021

Drug addiction: from bench to bedside

  • Julian Cheron 1 &
  • Alban de Kerchove d’Exaerde   ORCID: orcid.org/0000-0002-0682-5877 1  

Translational Psychiatry volume  11 , Article number:  424 ( 2021 ) Cite this article

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  • Molecular neuroscience

Drug addiction is responsible for millions of deaths per year around the world. Still, its management as a chronic disease is shadowed by misconceptions from the general public. Indeed, drug consumers are often labelled as “weak”, “immoral” or “depraved”. Consequently, drug addiction is often perceived as an individual problem and not societal. In technical terms, drug addiction is defined as a chronic, relapsing disease resulting from sustained effects of drugs on the brain. Through a better characterisation of the cerebral circuits involved, and the long-term modifications of the brain induced by addictive drugs administrations, first, we might be able to change the way the general public see the patient who is suffering from drug addiction, and second, we might be able to find new treatments to normalise the altered brain homeostasis. In this review, we synthetise the contribution of fundamental research to the understanding drug addiction and its contribution to potential novel therapeutics. Mostly based on drug-induced modifications of synaptic plasticity and epigenetic mechanisms (and their behavioural correlates) and after demonstration of their reversibility, we tried to highlight promising therapeutics. We also underline the specific temporal dynamics and psychosocial aspects of this complex psychiatric disease adding parameters to be considered in clinical trials and paving the way to test new therapeutic venues.


Drug addiction including smoking, alcohol and illicit drug use is indirectly or directly responsible for 11.8 million deaths each year in the world [ 1 ]. According to the Global Burden of Disease study, this number is higher than deaths from cancer and accounts for a fifth of all deaths around the world [ 1 ].

Drug addiction is defined as a chronic, relapsing disease that results from the prolonged effects of drugs on the brain. Similarly to other neuropsychiatric diseases, drug addiction is intermingled with behavioural and social aspects that are equally important parts of the disease, complicating the overall therapeutic approach. Actually, it is only recently, in the beginning of the 21st century, that we started to see “the drug-addict” as someone suffering from a disease and whose brain has been altered fundamentally by drugs [ 2 ]. Therefore, the most effective treatment approaches include biological, behavioural and social-context components. Based on the latest scientific advances, treatment and management of drug addiction patients point towards a personalised strategy [ 3 ]. However, there are very few objective and effective strategies for treating drug addiction. Without the mandatory mechanistic basic knowledge on drug addiction, the development of new therapeutic strategies is postponed.

The neurobiological circuits and mechanisms that support compulsive seeking and consumption of drugs with addictive potential are partially known. They comprise a progressive shift in the involvement of ventral to dorsal and medial to lateral striatal circuitry [ 4 , 5 ], along with molecular and cellular adaptations to drugs of abuse exposure. They include neuronal and synaptic plasticity and modifications in gene expression, in part through epigenetic mechanisms [ 6 ]. Notably, drug-induced neuronal modifications can also occur in non-pathological processes, underlying the fact that drugs of abuse hijack normal adaptive changes in the brain [ 7 ]. Indeed, laboratory and clinical observations suggest that addiction is driven by the usurpation of neuronal processes that normally serve reward-related learning and memory. Most of the modifications that have been shown to be involved in a state of addiction (modified gene transcription, epigenetics, neuronal plasticity and neurotrophic mechanisms) are also associated with physiological forms of behavioural memory in murine model such as spatial memory, fear conditioning and operant conditioning [ 7 , 8 ].

We know that only a proportion of individuals (depending of the drug type) will develop drug addiction after several exposures [ 9 ]. This individual vulnerability is probably linked to both genetic and environmental factors [ 10 ]. Drug addiction is highly polygenic, as hundreds of genetic variations combined result in variable vulnerability [ 11 , 12 ]. Several types of environmental factors have been characterised and interact with an individual genetic background [ 12 , 13 ]. Psychosocial stress is one of the factors, but the most important one, is by far, the exposure to drugs of abuse. Usually, drug abuse starts with a ‘gateway’ drug (mostly socially driven) catapulting the individual vulnerability to other drugs of abuse [ 14 ].

During the last three decades, combine effort has been dedicated to identify brain regions and molecular pathways involved in the development of addiction to drugs of abuse. Here, we will focus on experimental approaches that helped to provide a clearer picture on the physiopathology of drug addiction guiding therapeutic opportunities.

Converging actions on brain reward pathway elicit its remodelling

The circuit at the centre of the disease is the mesolimbic pathway, also referred as the reward pathway (Fig. 1 ). The mesolimbic pathway includes dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAc), a major component of the ventral striatum. The GABA medium-sized spiny neurons (MSNs, ~95% of striatal neurons), which are targets of glutamatergic and dopaminergic inputs, form two pathways [ 15 ]. The dopamine D1 receptor–positive (D1R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway) and coexpress dopamine D1 receptors and substance P, whereas D2R striatopallidal MSNs project to the lateral globus pallidus (indirect pathway) and coexpress dopamine D2 receptor, adenosine A2A receptor and enkephalin [ 16 , 17 ]. Through different initial mechanisms, drugs of abuse increase the release of dopamine in the NAc from the VTA [ 18 , 19 , 20 ]. This VTA-NAc pathway could be seen as primum movens for the acute rewarding effects of all drugs of abuse. Regardless that drugs of abuse have distinct protein targets and mechanisms of action, in the end, the main addiction-related modifications are common to nearly all drugs of abuse and converge on the VTA and NAc with common acute functional effects [ 21 ]. It is schematically conjectured, that when stimulated by dopamine, cells in the NAc produce feelings of reward and satisfaction [ 22 ]. The physiological function of this response is to facilitate the motivation for basic biological goal-directed behaviours as survival, social interaction and reproduction. By artificially causing a build-up of dopamine in the NAc, drugs of abuse generate an artificial reward effect [ 22 ]. As all drugs of abuse increase dopaminergic transmission to the NAc after acute administration, they also produce shared modifications in the mesolimbic system after chronic exposure. They include (i) hypofunction of the dopamine pathway that is seen as a major contributor to the negative emotional symptoms associated to drug withdrawal, leading to drug craving and relapse, and (ii) drug-induced adaptations in glutamatergic afferents to the NAc [ 23 , 24 ]. Clearly, these modifications in the mesolimbic system after the exposure to drugs of abuse is oversimplified. The hypofunction of dopaminergic system hypothesis is self-fulfilling in that research work has principally focused on dopamine to the exclusion of other neurotransmitters. Actually, some drug of abuse reinforcement appears to be independent of the mesocorticolimbic dopamine system (e.g. opioids [ 25 ], nicotine [ 26 ]), but support self-administration by imitating the effect of dopamine in the nucleus accumbens [ 21 , 27 , 28 ].

figure 1

Addictive drugs of different types have a common effect of increasing levels of dopamine released by neurons projecting from the ventral tegmental area (VTA). This effect is central for initial drug reinforcement. Notably, drug taking with initial reinforcement involves a potentiation of the projection from prefrontal cortex (PFC) to nucleus accumbens (NAc), while other glutamatergic projections are mostly involved in craving, like basolateral amygdala (BLA)-NAc projection, or in withdrawal/negative symptoms, like paraventricular thalamus (PVT)-NAc projection. With increasing administration of drugs of abuse and progressive shift toward compulsive abuse, the dorsal (dorso-lateral) striatum seems more and more implicated, with dopaminergic cells involved shifting progressively from the VTA to the substantia nigra pars compacta (SNc) [ 4 ]. Recently, data acquired through optogenetic dopamine neuron self-stimulation suggested prominent synaptic strengthening of the orbitofrontal cortex (OFC) to dorsal (dorso-medial) striatum projection in compulsive mice [ 31 ].

Drug addiction is conceptually defined as a three-stages cycle: (1) consumption/binge/intoxication, (2) withdrawal with its negative affect and (3) craving stage (Fig. 2 ) [ 27 ]. Animal models and human imaging studies have exposed the different brain areas involved in each of these stages. Briefly, the VTA-NAc (for reinforcement) and dorsal striatum (for stimulus-response habits) are important for the consumption/binge/intoxication stage, the extended amygdala with the hypothalamus and the brainstem in the withdrawal stage and cortical areas, the dorsal striatum, the hippocampus and the basolateral amygdala in the craving stage (Fig. 2 ).

figure 2

Progression to addiction is defined as a transition between three consecutive phases [ 252 ]: (1) Recreational, sporadic drug taking, in which drug of abuse administration is occasional and one activity among many other distractions of the individual. (2) Intensified and sustained drug use, in which drug administration strengthens and becomes the principal recreational activity of the individual; at this phase drug taking becomes a habit. (3) Loss of control of drug use and addiction, in which drug seeking and taking are now the principal activity of the patient. The first phase can occur to every person as drugs of abuse hijack the same brain circuit as natural rewards. The second phase occurs only in vulnerable users. The phase of addiction seems to be due to a second vulnerable trait with loss of control and compulsivity. Three stages of addiction are described [ 27 ]: (1) Binge/intoxication stage: reinforcing effects of drugs may initially use mainly dopamine and opioid peptides in the nucleus accumbens (NAc) and involves the ventral tegmental area (VTA). Subsequently, cue–response habits develop and includes the substantia nigra pars compacta (SNc) and the dorsal striatum. (2) Withdrawal/negative affect stage: the negative emotional state of withdrawal may involve the extended amygdala with corticotropin-releasing factor (CRF), norepinephrine and dynorphin as key neurotransmitters. Main projections of the extended amygdala consist of the hypothalamus and brainstem. (3) Craving stage: this stage includes conditioned reinforcement in the basolateral amygdala (BLA) and contextual processes in the hippocampus. This is controlled by cortical areas (prefrontal cortex (PFC) and orbitofrontal cortex (OFC)). A key neurotransmitter involved in the craving stage is glutamate.

The progression of drug addiction begins with the first exposure, mostly when the drug is taken voluntarily for its recreational and hedonic effect, and progressively consolidates during repeated but still controlled drug use. While administration intensifies along with loss of control over drug intake, drug use becomes habitual and compulsive in vulnerable individuals [ 4 , 29 , 30 ] (Fig. 2 ). This progression from voluntary drug intake to habitual and compulsive use represents a progression from ventromedial to more dorsolateral regions of the striatum and from prefrontal cortex (PFC) to orbitofrontal (OFC) and more global cortical region [ 4 , 31 ] (Fig. 1 ).

Synaptic plasticity

Brain plasticity is a fascinating capacity allowing appropriate modification of the neural activity in response to new experiences and environmental stimuli [ 32 ]. Modifying the synaptic strength between neurons is widely assumed to be the mechanism by which memory is encoded and stored in the brain [ 7 ]. Hence, it is appealing to hypothesise that drugs of abuse cause long-term alterations on behaviour by changing synaptic plasticity in key brain circuits [ 4 , 7 , 32 ].

Drugs of abuse such as cocaine induce specific synaptic plasticity in the mesolimbic circuitry. One single injection of an addictive drug can already modify the excitatory synaptic strengths in the VTA. Indeed, it has been extensively shown that the AMPA/NMDA ratio is increased in VTA dopamine neurons after one dose of cocaine and that some glutamate AMPA receptor 2 (GluA2)-containing AMPA receptors (AMPARs) are exchanged for GluA2-lacking ones [ 33 , 34 ]. At the same time, NMDA receptor (NMDAR) function decreases. All these elements cause an impairment in eliciting long-term potentiation (LTP). Different types of synaptic plasticity in VTA dopamine neurons induced by rewarding and aversive experiences are comprehensively reviewed by Pignatelli and Bonci [ 35 ]. Midbrain dopamine neurons are central in the mesolimbic circuitry for both natural rewards and drugs of abuse [ 18 , 36 ]. The VTA is known to be a central hub integrating numerous inhibitory inputs as GABAergic synapses represents 50–80% of all synapses onto VTA dopamine neurons [ 37 , 38 , 39 ]. GABAergic inhibition of dopamine neurons is mediated by both fast ionotropic GABA A receptors and slow metabotropic GABA B receptors [ 40 ].

In 2017, Edwards et al. [ 41 ] showed that the principal monosynaptic projection to VTA dopamine neurons arising from the NAc [ 42 ] inhibits the firing of dopamine neurons via activation of GABA B receptors, whereas local VTA inhibitory interneurons inhibits dopamine neurons through GABA A receptors. Today, it is well established that pharmacological activation of GABA B receptors (e.g. by baclofen) reduces cue-associated cocaine craving as well as reduce cocaine use in humans [ 43 , 44 , 45 ] and it reduces rewarding and reinforcing effects of cocaine on animal models [ 46 , 47 , 48 , 49 ]. Edwards et al. report [ 41 ] indicates that the therapeutic effects of baclofen might pass through VTA dopamine neurons’ GABA B receptors. Intrathecal Baclofen is an effective and safe long-term treatment used worldwide to treat severe spasticity [ 50 , 51 ]. Oral baclofen is less effective and has significant rates of side effects, like sedation, somnolence, vertigo and headache especially when prescribed off-label for drug addiction (because higher doses are commonly used) [ 51 , 52 ] . . Indeed, contrasting results on the effect of baclofen in reducing alcohol craving [ 53 , 54 , 55 ] and cocaine dependence [ 43 , 56 ] were probably due to different severity of alcohol dependence of the enroled patients. This is way higher dose are tested and often prescribed off-label for drug addiction [ 55 ]. Thus, self-poisoning that could lead to severe toxicity and death represents one the major concern of baclofen use in drug addiction. Therefore, baclofen should be prescribed with caution and close monitoring [ 52 , 57 ].

Together with drug of abuse-induced LTP at excitatory synapses, plasticity of GABAergic inhibitory synapse in the VTA also have an impact on the firing rate of VTA neurons, at least following opioid [ 58 ] and cocaine administration [ 59 ]. Normally, NMDA activation, during excitatory LTP (induced by high-frequency stimulation), leads to the release of NO that will activate guanylate cyclase in adjacent GABAergic terminals, which in turn, leads to increase in GABA release. This presynaptic NMDA receptor-dependent GABAergic LTP heterosynaptic plasticity, is named LTP GABA . Nugent el al. [ 58 ] showed that opioids blocks LTP GABA through a disruption of the coupling between nitric oxide (NO) and guanylate cyclase. The incapability of GABAergic synapses to potentiate after morphine or cocaine administration may promote LTP of glutamatergic synapses [ 58 , 59 ]. The early loss of inhibitory control combined with potentiation of glutamatergic synapses on dopaminergic neurons might represent adaptations that increase vulnerability to addiction [ 58 , 59 ]. Furthermore, GABA A receptor modulators modify the addictive drugs effects [ 60 , 61 ], and targeting these receptors might be seen as an effective therapeutic strategy but precluded by many side effects among which dependence itself [ 62 , 63 , 64 ].

In addition to the discovery of LTP GABA , Nugent’s group showed that morphine is also able to modulate a form of postsynaptic LTD (LTD GABA ) at GABAergic synapses onto VTA dopamine neurons. Remarkably, after a single administration of morphine, LTD GABA was absent in slices from morphine-treated rats while unaffected in slices from saline-treated rats, indicating a bidirectional control of morphine on GABAergic synaptic plasticity in the VTA [ 65 ]. This absence of LTD GABA is suggested to result from an occlusion effect due to prior morphine-induced decrease in GABAergic synaptic strength through potentiation of glutamatergic transmission and mediated by endocannabinoid signalling [ 66 ]. It is also possible that morphine alters the ability of synapses to exhibit evoked LTP or LTD in the VTA. Previous experiences such as exposure to drugs of abuse, stress, visual or sensory deprivation can change the ability of synapses to undergo subsequent plasticity in response to LTP and LTD induction protocols. This concept of modification of plasticity capability is referred as metaplasticity [ 67 ].

In the NAc, chronic exposure to addictive drugs induces specific synaptic changes that are different from those of the VTA, including a decrease of the AMPA/NMDA ratio as some AMPARs are endocytosed. This leads to a depressed synapse (sometimes referred as long-term depression (LTD) like state), where NMDAR-dependent LTD is reduced or, in some experiments, abolished [ 68 , 69 ]. Highlighting the importance of temporal aspects, studies of withdrawal period after chronic administration of cocaine, showed that synaptic AMPAR levels increase during the first week of withdrawal and persist elevated for weeks [ 70 , 71 , 72 ]. It is established that cocaine challenge transiently decreases AMPAR surface expression, while AMPARs recover back to upregulated levels within a week, with a continuous increase during what is known to be the incubation of craving stage [ 73 ].

The abstinence period after withdrawal is of particular interest considering the classical progression of the disease, the chance of relapse and the opportunity for new therapeutic targets. A seemingly counterintuitive concept named ‘incubation of cocaine craving’ was introduced by Grimm et al. [ 74 ] who modelled cocaine-craving behaviour by using rats trained to press a lever to receive an injection of cocaine and were then forced in a withdrawal period where cocaine reward was no longer given. This concept of ‘incubation’ did not originate in drug addiction research but came from a four-stage model of the creative process proposed by Graham Wallas in 1926 [ 75 ]. Consistent with clinical observations in humans [ 76 , 77 , 78 ], they showed that relapse was progressively stronger over 2 months of cocaine withdrawal and suggest that a craving syndrome progresses or ‘incubates’ during the first 2 months of cocaine abstinence, and probably lasts for longer [ 74 ]. Subsequently, it was shown that this increase was due to the addition of new AMPARs lacking GluA2 and that these new receptors mediate the ‘incubation of cocaine craving’ [ 72 ]. Conrad et al. [ 72 ] showed that after extended withdrawal from cocaine, addition of synaptic AMPARs together with the increased conductance of GluA2-lacking AMPARs triggers higher sensitivity of NAc neurons to cocaine-related cues, leading to a strengthening of drug craving syndrome and relapse. In line with these results, it was suggested that as soon as abstinence is reached, the risk of relapse might be reduced if GluA2-lacking AMPARs were inactivated or removed from NAc synapses. It was thus proposed that GluA2-lacking AMPARs could be a new target for drug development for the treatment of cocaine addiction. While these calcium permeable AMPARs are also critical for the pathogenesis of numerous other neurological disorders (including epilepsy [ 79 ], fragile X syndrome [ 80 ], amyotrophic lateral sclerosis [ 81 ], Parkinson’s [ 82 ] and Alzheimer’s [ 83 ] diseases), developing drugs that specifically target them and not calcium-impermeable AMPARs, which are critical for normal CNS function, is challenging [ 84 ] (Fig. 3 ).

figure 3

DNA is packaged inside nuclei with the help of histones. These are positively charged proteins that strongly adhere to negatively charged DNA and form complexes called nucleosomes. Each nucleosome is composed of DNA wound around histone octomers (H2A, H2B, H3 and H4). Nucleosomes fold up to form chromatin fibre, which forms loops compressed and folded to produce fibres, which are coiled into the chromatid of a chromosome. Only by loosening compacted chromatin, the DNA of a specific gene can be made accessible to transcription. Some of these drug-induced modifications at the chromatin level are extremely stable and sustain the drug of abuse-induced long-term behaviours. Among them, histone post-translational modifications (PTMs) are known to be causally involved in drug-induced behaviours [ 194 ]. PTMs include acetylation (Ac), methylation (Me), phosphorylation (P), ADP ribosylation (PolyADP-R) and dopaminylation (DA), among a growing list of newly discovered modifications [ 162 , 172 ]. For example, while ubiquitylation (Ub) of H2A is known to be a key interactor of H3 methylation [ 253 ], its supposed role in drug addiction is still unknown. At this epigenetic level, some drugs were demonstrated to have an influence on drug-induces behaviours such as histone deacetylase (HDAC), bromodomain and DNA methyltransferase inhibitors. Locus-specific epigenome editing is now encouraging as a new field of investigation as it might help to the discovery of new specific and causal drug of abuse targets. Overview of the tetrapartite glutamatergic synapse composed of a medium spiny neuron (MSN), a glutamatergic projection, a glial cell and the extracellular matrix (ECM). Here, we focused on synaptic potentiation after drug of abuse administration with the addition at the post-synaptic membrane of glutamate AMPA receptor 2 (GluA2) lacking AMPA receptors (AMPARs). This mechanism might be reduced by metabotropic glutamate receptor 1 (mGluR1) positive allosteric modulator or more directly by GluA2-lacking AMPARs antagonists. In the same way, it was also shown that presynaptic mGluR2 agonists can potentially abolish drug seeking and impair craving incubation. Optogenetically-inspired 12 Hz deep brain stimulation (DBS) in the nucleus accumbens can also be a promising novel therapeutic for addiction. Finally, ceftriaxone, N-acetylcysteine, and inhibitor of matrix metalloproteases 9 (MMP-9), mainly through their action on glial cell and the ECM, are very interesting molecules that may be added in the addiction therapeutic arsenal.

Inspired by previous work performed in the VTA showing that metabotropic glutamate receptor 1 (mGluR1) LTD induces removal of GluA2-lacking AMPARs from synapses [ 33 , 34 ], Loweth et al. [ 85 ] demonstrated that synaptic GluA2-lacking AMPAR decrease could be accomplished by in vivo evoked mGluR1 LTD in the NAc. More importantly, their group showed that after prolonged cocaine or methamphetamine withdrawal, systemic injection of a mGluR1 positive allosteric modulator attenuated the expression of incubated craving by reducing GluA2-lacking AMPARs in the NAc [ 85 , 86 ]. These results suggest a strategy in which abstinent methamphetamine or cocaine users could use a systemically active compound to protect themselves against cue-induced relapse.

These latter studies were conducted without differentiating between D1 receptor D1R MSNs and D2R MSNs. In 2014, Pascoli et al. [ 87 ] demonstrated that this increase in the strength of excitatory afferents was exclusively related to D1R MSNs. Interestingly, the type of drug-evoked plasticity involved is also dependent on the input. It has been shown that even in the same D1R MSN a synapse connecting the PFC to the NAc increases its strength by inserting GluA2-lacking AMPARs whereas a synapse connecting the ventral hippocampus to the NAc increases the AMPA/NMDA ratio by inserting GluA2-containing AMPARs [ 87 ].

Besides operant self-administration, all these long-term synaptic modifications also underlie behavioural changes associated with drugs of abuse, such as locomotor sensitisation [ 88 , 89 ]. Locomotor sensitisation is a behavioural protocol used to model drug-induced behaviour [ 90 , 91 ]. In rodents, repeated cocaine injection induces gradually increased locomotor activity; after 5 days of consecutive injections, the locomotor response reaches a ceiling level. This state lasts for months after cocaine withdrawal [ 91 ]. As an experimental model, locomotor sensitisation is linked with increased tendency to self-administer psychostimulants [ 92 , 93 ] and with reinstatement of previously extinguished self-administration [ 94 , 95 ]. Whereas the existence of psychomotor sensitisation in humans is discussed [ 96 , 97 ], it is a key aspect of vulnerability to drug addiction and relapse, specifically drug craving or compulsive drug-seeking behaviour [ 91 , 98 , 99 ]. Still, locomotor sensitisation can be dissociated from the rewarding effect of a drug of abuse and conditioned place preference or self-administration are more appropriate experimental paradigms to test this aspect [ 100 , 101 , 102 ]. Even if drug-induced locomotor sensitisation is unclearly present in humans, as an animal model it offers a clear readout to understand the mechanisms by which drugs of abuse induce long-term brain modifications [ 91 ].

Furthermore, it has been elegantly demonstrated that optogenetic stimulation of the excitatory projections to the NAc is able to reverse cocaine and alcohol-evoked plasticity [ 87 , 88 , 89 ]. Briefly, applying a NMDAR or mGluR1-dependent LTD on cortico-accumbal glutamatergic synapses, before a drug of abuse administration, diminishes its effect. In another study, Luscher’s team took advantage of the knowledge, obtained from optogenetic in vivo experiment in rodents, to implement a novel deep brain stimulation (DBS) protocol that abolishes behavioural sensitization to cocaine (and thus that would be efficient during the relapse phase) [ 103 ]. Basically, the idea is to manipulate synaptic plasticity in the NAc to reverse pathological synaptic transmission and its associated behaviours following exposure to drugs of abuse. In this study, as a therapeutic use of optogenetic tools in humans is for now inapplicable [ 104 ], the authors reversed cocaine-evoked plasticity and thus drug-induced behaviours by using DBS instead of optogenetic. Indeed, DBS is routinely used in clinic and a new DBS protocol can easily be translationally implemented to the human therapeutics [ 105 , 106 ]. They refined the classical high-frequency DBS protocol (that has no sustained effect on cocaine sensitization, probably because it does not affect synaptic plasticity) by applying a low frequency stimulation (12 Hz to equal the one used in the optogenetic endocannabinoid- dependent LTD protocol) in the NAc together with the administration of a D1R antagonist necessary to unmask the mGluR-dependent LTD in D1R MSNs as demonstrated previously [ 107 ] (Fig. 3 , see section on clinical treatment for broader discussion on DBS).

Kalivas’ group showed in 2009 [ 108 ] that after extended withdrawal from chronic cocaine self-administration, cocaine-induced metaplasticity at the excitatory synapses in the NAc that impairs the ability of PFC stimulation to produce LTP or LTD in NAc MSNs. They also showed that N-acetylcysteine reverses cocaine-induced metaplasticity, allowing the induction of both LTP and LTD and that N-acetylcysteine decreases cocaine-relapse in a rodent model. We are currently awaiting the results of a randomised and control study that is testing newly detoxified (and therefore abstinent) hospitalised patients who received a 3–4 week course of treatment, in order determine if N-acetylcysteine can be a useful medication candidate to avoid relapse in patients with cocaine dependence (NCT03423667).

GABAergic D1R and D2R MSNs, equally compose and are mosaically intermingled throughout the striatum [ 109 ]. As explained above, D1R and D2R MSNs send axonal projections outside the striatum, forming the two main output pathways, respectively the direct and indirect pathways [ 16 , 17 ]. In a certainly oversimplified model, the activation of the D1R MSNs result in facilitation of locomotion, reward, and reinforcement while the activation of D2R MSNs result in opposing effects [ 110 , 111 , 112 , 113 ]. In addition to the long-range projections, these neurons form short-range synaptic connections with one another within the striatum, and because they consist of inhibitory collaterals, a mechanism known as lateral inhibition [ 114 , 115 , 116 , 117 ]. Interestingly, these connections are not symmetrical, with D2R MSNs forming more synaptic connections on D1R MSNs [ 115 , 117 ]. Through this previously understudied collateral transmission, Dobbs et al. [ 115 ] presented a novel mechanism by which cocaine exerts its stimulant effect: cocaine, by blocking DAT receptors enhance levels of dopamine and subsequently activating D2Rs, causes a suppression of lateral inhibition and thus disinhibition of D1R MSNs in the NAc which in turn promotes locomotion [ 115 ]. Furthermore, Alvarez’ group suggested that constitutive low D2R levels, through imbalanced lateral inhibition, might pre-sensitised D1R MSNs, facilitate behavioural plasticity to repeated cocaine and promotes an addiction vulnerable phenotype [ 116 ].

The characterisation of the role of glia and the extracellular matrix (ECM) in drug-induced synaptic plasticity is an exciting emerging field of drug addiction research as it comes with promising new therapeutic possibilitiess [ 118 , 119 , 120 ]. Mulholland et al. [ 118 ] summarised and emphasised the role of the ECM and of astroglial cells in the regulation of synaptic plasticity. Of great interest, restoring downregulated glutamate transporter 1 (EAAT2) with ceftriaxone reduces drug seeking in animal models [ 121 , 122 ]. Matrix metalloproteases (MMP) are important regulators of the ECM and contribute to synaptic plasticity [ 123 ]. Inhibiting their activity result in suppression of the reinstatement of cocaine conditioned place preference [ 124 ] and selectively inhibiting MMP-9 prevents cue- and cocaine-induced reinstatement of cocaine self-administration [ 119 ]; these results open additional therapeutic possibilities with the use of inhibitors of MMP-9 as an innovative targeted approach [ 119 , 124 , 125 ] (Fig. 3 ). Still, at our knowledge, there are no randomised controlled study currently investigating these ECM-related drugs.

Drugs of abuse-induced modifications in glutamatergic nuclei targeting the NAc, or the VTA and essential part of the reward circuit, are less studied than cortico-striatal synapses despite the fact that they play a crucial role in the development of drug addiction. Indeed, in the OFC and PFC, chronic alcohol exposure significantly increases LTP in pyramidal neurons [ 126 , 127 ]. Kazanetz et al. [ 128 ] showed that repeated cocaine injections impair endocannabinoid-LTD and mGluR2/3-LTD in the PFC. They postulated that this might mechanistically participate in the induction of a postsynaptic, observed LTP-like phenomenon with an enhanced AMPA/NMDA ratio. It was also demonstrated that neurons of the infralimbic cortex present a decrease in mGluR2 [ 129 ]. In addition, alcohol-dependent rats exhibit an escalation of ethanol seeking, which was abolished by restoring mGluR2 expression in the infralimbic cortex via viral-mediated gene transfer [ 129 ]. Notably, mGluR2 agonist was shown to impair the incubation of cocaine craving [ 130 ] and to attenuate reinstatement of cocaine-seeking [ 131 , 132 ](Fig. 3 ). Recently, Caprioli et al. [ 133 ] extensively reviewed preclinical studies on allosteric modulators of mGluRs on animal models of drug addiction and their potential translational implications. The results reviewed [ 133 ] indicate an remarkable effect of allosteric modulators of presynaptic mGluR2 and possibly mGluR7, supporting the idea that these compounds should be tested as potential medications for addiction treatments.

Besides the PFC, other brain regions appear to be key areas in drug addiction as the paraventricular thalamus (PVT) - a central hub for cortical, sensory and limbic information [ 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. In 2016, Zhu et al. [ 141 ] showed that chronic morphine administration potentiates excitatory synapses between the PVT and D2R MSNs via insertion of GluA2-lacking AMPARs. Remarkably, in vivo optogenetic depotentiation at these synapses abolishes morphine withdrawal symptoms. In a recent paper, projections from the PVT to the NAc were shown to be critical for augmentation of heroin seeking in food-restricted rats [ 142 ] (Fig. 1 ). Actually, Otis et al. [ 143 ] demonstrated that the PVT is an integrative hub for reward seeking behaviour and that PVT-NAc neurons integrate different inputs from the PFC and the lateral hypothalamus to precisely guide reward seeking behaviour. In a recent review, De Groote et al. [ 140 ] focused on the new advances in the understanding of the roles of the PVT-NAc connections in motivated behaviours, highlighting their implications in drug addiction.

Drug addiction-related genes and transcriptomic regulation

Modifications in gene expression contribute to the long-lasting effect sustaining drug addiction; thanks to gene-expression arrays, RNA-sequencing and candidate gene approaches, the specific genes and their regulatory transcriptomic mechanisms involved in drug addiction development and maintenance are now better understood.

Drug addiction-related genes

For example, the use of conditional gene knockout in mice emphasises the importance of monoamine membrane transporters (dopamine transporter, and serotonin transporter) [ 144 , 145 ] and of mGluRs [ 146 , 147 ]. As new animal models of drug addiction, these approaches are also useful to better characterise fine-tuning of important pathways involved in addiction. For example, a scaffold protein known as Maged1 has been shown to be involved in cocaine reward and reinforcement [ 148 ]. We demonstrated that Maged1 inactivation impairs drug-evoked dopamine release and glutamatergic synaptic plasticity in the NAc. Inactivation of Maged1 in mice was able to abolish behavioural sensitization to cocaine as well as cocaine conditioned place preference and operant self-administration behaviours [ 148 ]. This sole genetic alteration, causally linked to a strong alteration of drug-induced behaviours, impairs (at least) two core neuronal mechanisms leading to addictive behaviours: (1) cocaine-evoked release of dopamine in the NAc and (2) NAc plasticity, with a reduced AMPA/NMDA ratio and a resistance to LTD. Actually, it seems that, after Maged1 inactivation, the excitatory synapses in the NAc shift to a depressed state. Our hypothesis is that, in line with the previously discussed in vivo optogenetic induced LTD, this impairment could be a key factor for the significant decrease in sensitization to psychostimulants [ 87 , 103 , 148 ]. Actually, it seems that placing neurons in a state of ‘presensitization’ is able to prevent drug-induced sensitization itself [ 148 , 149 ]. Our group is now trying to understand what are the cellular and molecular pathways directly altered by Maged1 inactivation and responsible for this strong anti-addictive drug phenotype. Remarkably, the promoter of Maged1 was found in a list of 213 promoters that co-precipitate with acetylated histones and with the activated form of cAMP response element binding protein (CREB) after chronic drug taking [ 150 ]. In line with this result, preliminary and unpublished results from our laboratory point out a specific epigenetic mechanism, in parallel with an alteration of synaptic plasticity in excitatory projection to the NAc, that would link Maged1 to its major effect on drug-induced behaviours. This selected gene approach is of great interest in refining our knowledge of pathways hijacked by addictive drugs. Using cell sorting of D1R MSNs and D2R MSNs as described previously [ 151 ], our group also identified the G-protein-regulated inducer of neurite outgrowth 3 (GPRIN3) in both MSN populations but strikingly more expressed in D2R MSNs [ 149 ]. The GPRIN family (GPRIN1, GPRIN2 and GPRIN3) are Gαi/o-regulated proteins suggested to intermediate the communication between GPCRs and the sequential intracellular target [ 152 ]. Indeed, GPRIN1 and GPRIN2 have been described as alternative (to adenylyl cyclase) mediators of GPCRs signalling but GPRIN3 had a much less defined role [ 152 , 153 ]. To understand the role of GPRIN3 in the pathophysiology of the D2R-indirect pathway, we induced a D2R-MSNs-specific knockdown (KD) of GPRIN3 using small hairpin RNA and lentiviruses [ 151 , 154 ]. We first observed a significant increase in distal branching, the points of convergence between glutamate and dopamine synapses in MSNs [ 155 ] and also key targets of cocaine, which itself promotes increase in distal branching in the NAc of mice [ 156 , 157 , 158 , 159 ]. Thus, we tested the cocaine acute effect and locomotor sensitization and observed a decrease in cocaine-induced hyperlocomotion after inactivation of GPRIN3 using a CRISP/Cas9 approach. The significant increase in distal branching in GPRIN3 D2R-MSNs KD corroborates our hypothesis that the lack of GPRIN3 induces a ‘presensitization process’, able to change the targets of cocaine and therefore altering its effects [ 149 ]. Finally, we provide the first evidence that GPRIN3 partners with D2R in the striatum and modulates cocaine-induced behaviours [ 149 ].

Transcriptomic and epigenetic regulations

Epigenetics is a broad field and has multiple definitions that comprise several biochemical mechanisms (including DNA methylation and histone modifications) sustaining modifications in gene expression throughout the lifecycle of an organism without mutations of the DNA itself [ 160 , 161 , 162 ]. Epigenetics can be considered as the process through which environment (and normal development) interacts with an individual’s genome to determine all phenotypic traits, in health and disease. Stable modifications in gene expression are also said to be ‘epigenetic’, because they are heritable in the short term (through mitosis) [ 160 ] and in some cases trans-generationally, thus, providing a potential mechanism for environmental influences to be passed from parents to offspring [ 163 , 164 , 165 ]. Handel and Romagopalan [ 163 ] mentioned that “epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution”. Such trans-generational epigenetic inheritance of drug addiction vulnerability remains debatable [ 161 ], but has been increasingly studied for the last 20 years [ 166 , 167 ]. Some epigenetic changes are very stable, an thus mediate both drug addiction susceptibility and drug-induced brain alterations that underlie the development of drug addiction [ 161 ].

As the NAc is seen as the central hub of drug addiction, with the notion that chronic drug use induces long-lasting structural, electrophysiological and transcriptional changes in the NAc, researchers are mostly targeting epigenetic modifications in NAc cells. Still, considering initial reports of cocaine-induced epigenetic modifications [ 168 , 169 ], it might be relevant to study further epigenetic changes in other regions such as glutamatergic inputs to the NAc, and further in the VTA, as they are implicated in the physiopathology of drug addiction [ 170 , 171 ] as mentioned above.

To date, the three main epigenetic mechanisms consist of (1) DNA methylation, (2) action of the non-coding RNAs and (3) histone post-translational modifications (PTMs). As an illustrative example, we will focus here only on histone PTMs. PTMs of histone residues on their N-terminal tails, that protrude from the nucleosome core, control chromatin condensation and the switch between euchromatin and heterochromatin and thus DNA-accessibility and gene expressions. PTMs include acetylation, methylation, phosphorylation, ADP ribosylation, ubiquitylation and sumoylation, among a growing list of newly discovered modifications [ 162 , 172 ].

Among these PTMs, the most studied is the acetylation of H3 and H4, that is increased in the NAc after chronic exposure to drugs of abuse [ 150 , 173 , 174 ]. This increase in global acetylation levels is the result of drug-induced alterations in the balance of histone acetyltransferase and histone deacetylase (HDAC) function and is associated with gene activation. CREB-binding protein, a histone acetyltransferase critical to memory processes [ 175 ], is required for cocaine-induced increases in histone acetylation in the NAc [ 176 ].

Fifteen years ago, Tsankova et al. [ 177 ] showed that imipramine, a monoamine reuptake inhibitor used for decades to treat depression, was effective through histone remodelling in depression and highlight the therapeutic potential for chromatin regulation with histone methylation and deacetylation inhibitors in depression. Nevertheless, like with synaptic plasticity (see above), discovering a drug that would interfere with epigenetic mechanisms and thus decrease drugs of abuse effect faces temporal aspects issues [ 173 , 176 , 178 , 179 , 180 , 181 , 182 ]. Indeed, timing has a strong impact considering conflicting results obtained after experimental manipulations of histone acetylation. An acute administration of HDAC inhibitors systemically or directly into the NAc, promotes behavioural responses to the drugs. However, prolonged administration decreases cocaine behavioural effects. In 2013, adding a new layer of complexity, Kennedy et al. provided comprehension to this time-dependent regulation [ 183 ]. Remarkably, they showed that prolonged intraNAc administration (but not acute administration) of a HDAC inhibitor attenuated cocaine behavioural effects by inducing a form of repressive histone methylation. This study showed, for the first time, cross-talk among different types of histone modifications [ 183 ]. Besides cross-talk between different epigenetic modifications, multiple modifications work in parallel and there is often a decoupling between an observed modification at a specific locus and its final transcription [ 161 ]. Decoding these chromatin marks will be a future challenging field. Like with HDAC inhibitors, there are promising findings based on the use of DNA methyltransferases inhibitor [ 184 , 185 ] (Fig. 3 ). Though, the main issue with these new potential treatments for drug addiction is their lack of specificity. One of the key challenge for the pharmaceutical industry will be to generate small molecules with more specific targets [ 6 ].

While histone acetylation and methylation are increasingly studied, an important field of future investigation will be to understand the other drug-induced histone PTMs. It already seems that chronic cocaine alters levels of histone phosphorylation [ 174 , 186 , 187 ], and poly-ADP ribosylation [ 188 ]. Recently, an unexpected role for the intracellular dopamine in VTA has been revealed, showing that DA interacts with chromatin to initiate a new form of epigenetic regulation called dopaminylation [ 189 ] (see Table 1 for a summary of cocaine-related epigenetic modifications).

Further studies showed that histone PTMs that occur in the NAc after chronic drug administration are locus specific [ 150 , 190 , 191 ]. Even though, drugs of abuse alter global levels of multiple histone PTMs, such as increased histone acetylation or decreased methylation in the NAc, genome-wide studies have confirmed that a greater number of genomic sites show increased acetylation [ 150 ] or decreased methylation [ 190 , 191 ]. Conversely, hundreds of genes show opposite or no changes in these same PTMs after drug exposure. What defines whether, and in which direction, a specific gene is modified in the context of a global histone PTM is an intriguing and unsolved question [ 161 ]. These genome-wide studies (ChIp on chip or ChIpSeq) are nowadays fundamental to understand where PTMs and other epigenetic modifications are deposited. This will be fundamental to guide new therapeutics.

Actually, with new tools such as zinc finger proteins (ZFPs) DNA-binding domains and, more recently, RNA-guided CRISPR/dCas9 (drastically easier to design) [ 192 , 193 ], it is now possible to control epigenetic modifications at a single gene in a specific type of cell in a specific brain region [ 162 ]. Heller et al. demonstrated that gene-targeted epigenetic editing (targeted to the Fosb [ 194 ] and Cdk5 [ 195 ] locus with ZFP technology) can alter drug-related behaviours [ 194 , 195 ]. This represents crucial evidence that gene-specific changes to the epigenome are not simply correlated, but rather causal, in regulating transcriptional responses to drugs of abuse administrations. These new results of “causal epigenomics” are very encouraging as they open the way to precise translational therapeutic approaches for drug addiction and other CNS diseases.

Linking epigenetics and synaptic plasticity

Today, most studies investigate synaptic plasticity and epigenetic as two distinct fields and it is not clear how these research topics are connected to each other. Understanding how epigenetics is connected to synaptic plasticity is an emerging research issue [ 6 ].

Of course, bridging epigenetic mechanisms with synaptic plasticity is not limited to drug addiction field. For example, in 2011, Monsey et al. [ 196 ] elegantly demonstrated that DNA methylation and histone H3 acetylation regulate auditory fear conditioning and its related synaptic plasticity in the amygdala. In 2014, Massart et al. [ 197 ] suggested that sleep deprivation induces epigenetic modification (alteration in DNA methylation and hydroxymethylation) that triggers synaptic plasticity modifications by changing expression of plasticity related genes.

Regarding drug addiction, some epigenetic marks seem fundamental and upstream as illustrated by HDAC inhibitors effect on drug-induced synaptic and behavioural modifications [ 178 , 198 , 199 , 200 ]. Additionally, Maze et al. [ 201 ] demonstrated morphological plasticity induced by cocaine through the histone methyltransferase G9a. Again advocating for causal epigenetic, Authement et al. [ 66 ] demonstrated that HDAC inhibition locally in the VTA is sufficient to reverse epigenetic modifications and synaptic plasticity changes after morphine administration.

Two transcription factors implicated in addiction exemplify this bridging attempt: CREB and ∆FosB (a truncated form of the FosB gene) are both activated by several drugs of abuse [ 202 ]. CREB activation occurs in both subtypes of NAc MSNs (D1R and D2R), while ∆FosB activation is limited to D1R MSNs in response to all drugs of abuse except for opioids, which remarkably induce the protein in both MSNs [ 203 ]. Expression of active CREB in NAc MSNs increases their excitability [ 204 ] and underlies drug-induced long-term synaptic plasticity and associated changes in dendritic spine plasticity [ 205 ]. ∆FosB is also linked to synaptic plasticity but evokes contrasting effects on the two MSN subtypes, with increased AMPA receptor function induced in D1R MSNs and decreased AMPA receptor function induced in D2R MSNs [ 206 ]. Renthal et al. [ 150 ] unravelled CREB and ∆FosB target genes and observed that these genes are mainly involved in neuronal excitability and synaptic function. Moreover, as already briefly discussed above, CREB and ∆FosB action have also been related to multiple epigenetic regulations, including histone acetylation and methylation [ 150 ]. Besides, a novel mechanism for bridging the gap between epigenetic control of transcription and synapse plasticity might be seen in microRNAs [ 207 ]. The most studied miRNA in the context of synaptic plasticity is miR-132 and is known to be CREB-dependent [ 208 ]. In the striatum, miR-212 targets the epigenetic regulator methyl CpG binding protein 2 (MeCP2). MeCP2 acts as a transcriptional repressor through recruitment of histone deacetylases to methylated DNA segments [ 209 , 210 ].

Clinical treatments for drug addiction

Besides psychosocial interventions [ 211 ] such as cognitive behavioural therapy, the most widely used treatment for drug addiction involves agonist-like medication, a solution inadequately called replacement or substitution therapy [ 212 ]. This type of treatment has been successfully implemented in the daily practice for opioid use disorder (e.g.: methadone, buprenorphine) [ 213 ] and tobacco use disorder (e.g.: nicotine patch or gum, varenicline) [ 214 ]. Currently, this agonist-like treatment is also promising for psychostimulant use disorder [ 215 ]. Still, considering the addictive drug-like effect, the risk of abuse, misuse and diversion, replacement therapy should be prescribed with caution [ 215 , 216 ].

Recently, a randomised and control study on a cocaine vaccine failed to show an effectiveness but instead raised an important issue: immunised subjects may have increased their cocaine use to overcome the competitive anti-cocaine antibody inhibition [ 217 ]. Even though significant improvements have been developed for immunopharmacotherapies for psychostimulant addiction over the last decade, very few candidates have been evaluated so far in clinical trials [ 218 ]. These considerations are some of the reasons why other treatments for drug addiction should emerge with the help of neurobiological research [ 219 ].

Following successful subthalamic nucleus DBS for Parkinson’s disease [ 220 , 221 , 222 ], DBS was investigated for diverse psychiatric diseases including depression [ 223 ], obsessive-compulsive disorder [ 224 ] and Tourette syndrome [ 225 ]. Today, indications for DBS are enlarging, with several positive case reports and small cases series that studied NAc DBS for drug addiction. The first studies showing potential positive effects on drug addiction were reports on application of NAc DBS primarily intended for other medication-refractory neuropsychiatric disorder where a comorbid drug addiction was unexpectedly resolved [ 226 , 227 ]. For DBS treatment in drug addiction, it seems that clinical empirical results led to further bench investigations and refinement [ 88 , 103 , 228 , 229 , 230 , 231 ], or at least, clinical and animal studies evolved in parallel with poor connectivity between the two.

Afterwards, many case reports and small cases series studied NAc DBS being used primarily for drug addiction, all showing encouraging decreases in drug use [ 232 , 233 , 234 , 235 , 236 , 237 ]. However, these studies are limited by their descriptive nature, inconstant follow-up, multiple publication bias, small patient numbers and lack of blinded stimulation and standardised outcome measures. At this stage, additional preclinical and clinical research are needed to clarify the role of DBS in the treatment of drug addiction [ 237 ]. Currently, randomised and control clinical studies are conducted (NCT01245075).

In a recent review, Sanna et al. [ 238 ] highlighted how repetitive transcranial magnetic stimulation (rTMS) confirms the hypodopaminergic hypothesis of drug addiction. While enhancing dopaminergic function through direct or indirect pharmacological approaches does not significantly alleviate symptoms, in numerous studies, and has not yielded a single FDA-approved medication [ 239 ], rTMS might indirectly modulate the dopaminergic system. Many rTMS studies stimulate the dorsolateral PFC [ 240 , 241 ] that projects to the VTA and thus induces an increase in dopamine release in the synaptic cleft in the NAc [ 55 , 242 , 243 ]. Nevertheless, considering the heterogeneity of methods used in rTMS studies during the last 10 years [ 238 ], protocols and guidelines, were recently suggested by an international network of experts in neuromodulation and addiction to improve homogeneity of studies [ 244 ]. From this report, it is clear that multiple technical details for optimal stimulation need further investigations that might be achieved through preclinical studies. For example, low frequency (but not high-frequency) rTMS before methamphetamine exposure in rats blocked drug-induced conditioned place preference [ 245 ]. Being non-invasive, with insignificant side effects, rTMS could be seen as a great opportunity for drug addiction treatment. We are currently waiting for the results of a randomised and control study that aims at determine if, in heavy alcohol users, a single session of TMS can lower a patient’s craving and brain response to alcohol cues (NCT02939313).

Interesting views of clinical treatments for drug addiction are discussed in some other reviews [ 212 , 215 , 216 , 219 ]. The clinical impact of new treatments also depends on their translation into clinical practice which is mainly promoted by the pharmaceutical industry [ 219 ]. Indeed, even when an effective treatment is identified through basic research, it is commonly challenging to translate it to clinical practice, as illustrated by naltrexone as a treatment of alcoholism [ 219 ]. Another example of problematic translation to clinic is illustrated by modafinil, a treatment that has been reported to attenuate cocaine euphoria but for which larger clinical randomised and controlled studies showed controversial results [ 246 , 247 ].

Future directions

Drug addiction is a brain disease strongly influenced by environment and psychosocial aspects. The psychosocial conditions in which it has developed are extremely important. Exposure to conditioned cues can be a central issue in causing drug cravings and relapses, even after successful treatment, and thus they have to be minimised [ 2 , 74 , 77 ]. The pathophysiological aspects are particularly unsteady. For instance, as discussed in this review and in other ones [ 73 , 248 ], synaptic plasticity is dynamically altered after psychostimulant administration, so that a treatment could have opposite effects depending on timing aspects of the administration protocol. In addition, a prolonged treatment may involve compensatory mechanisms, giving unexpected results (e.g.: when HDAC inhibitors and psychostimulants are both administered acutely, they have synergistic effects through hyperacetylation and thus transcriptional activation of psychostimulant-regulated target genes. Conversely, when a drug of abuse is given in the context of chronic HDAC inhibitor, compensatory mechanisms may promote acetylated histone to the promoters of genes responsible for inducing histone methylation and thus chromatin condensation and gene repression, all of which, in turn, gave opposite effect [ 183 ]). Thus, the evolution through the different stages of the disease has to be taken into account [ 249 ] and treatment must follow them. These two aspects have to be incorporated in a holistic treatment strategy. Besides, studying combination of different cutting-edge approaches, with animal models of addiction, such as targeted rTMS or DBS with more systemic epigenetic modulation might show a better restoration of altered synaptic transmission and decrease the probability of relapse in drug addiction. Basically, drug addiction is a disease that seems to be difficult to treat preventively but it is more conceivable to help patients that would be in an abstinence stage not to experience relapse of their disease. As addiction is chronic and relapsing, a good treatment outcome is a significant reduction of drug administration and long periods of withdrawal, with only sporadic relapses [ 2 ].

It is clear that the main issues for optimal therapeutic management of this specific psychiatric disease belong to its dynamic complexity, diverse temporal evolution and undeniably psychosocial aspects. In this review, we focused mostly on the effects of drugs of abuse on synaptic plasticity and epigenetic modifications. Nowadays, these two subfields are mostly studied separately and the understanding of how these two main addictive drug-induced brain modifications interact might be fundamental for addiction research [ 6 ]. Indeed, argument for clinical trials for new treatments emerge from fundamental behavioural studies that should be implemented in a global approach to the addicted patient.


Here, we highlight, from a vast fundamental literature (mainly based on rodent models), promising therapeutics that would potentially treat drug addiction. Based on effect, on synaptic plasticity and epigenetic mechanisms, treatments such as GluA2-lacking AMPAR antagonists [ 72 , 84 ], mGluR1 positive allosteric modulator [ 85 ], NAc 12Hz-DBS [ 103 ] (in line with other promising neuromodulation therapeutics such as rTMS or transcranial direct current stimulation [ 250 ]), N-acetylcysteine [ 108 ], HDAC inhibitors [ 183 ] or even (in very early stages of investigation) CRISPR/dCas9 epigenetic editing [ 194 , 195 ] could be potential candidates for human randomised clinical trials (Fig. 3 ).

Finally, it is fundamental to consider the specific clinical aspects of the disease that would help to develop a personalised-treatment strategy. Indeed, after going from the bench to the bedside it will also be essential to assess the reversed route.

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We thank Michele Zoli, Romain Icick and Daniel Rial for helpful comments and corrections on the manuscript. Julian Cheron is supported by a fellowship of the FRS-FNRS (Belgium). Alban de Kerchove d´Exaerde is a Research Director of the FRS-FNRS. FRS-FNRS (Belgium). Fondation Simone et Pierre Clerdent, Fondation ULB, supported this study.

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Cheron, J., Kerchove d’Exaerde, A.d. Drug addiction: from bench to bedside. Transl Psychiatry 11 , 424 (2021). https://doi.org/10.1038/s41398-021-01542-0

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