Evidence-based Treatment Options in Cannabis Dependency

Background: Now that the consumption of natural and synthetic cannabinoids is becoming more widespread, the specific treatment of cannabis-related disturbances is an increasingly important matter. There are many therapeutic options, and it is not always clear which ones are evidence-based and appropriate for use in a given clinical situation.

Methods: This review is based on reports of pertinent randomized and controlled trials (RCTs) that were retrieved by a selective search in the PubMed and Cochrane databases.

Results: Cognitive behavior therapy (CBT) combined with other techniques has been found to have a moderate to large effect (Cohen’s d = 0.53–0.9) on the amount of cannabis consumed as well as on the level of psychosocial functioning or the dependence syndrome. Systemic multidimensional family therapy (MDFT) has been found beneficial for younger adolescents who consume large amounts of cannabis and have psychiatric comorbidities. Short-term interventions with motivational talk therapy have been found effective for patients with or without an initial desire to achieve cannabis abstinence. All of these psychotherapeutic interventions are effective at evidence level Ia. The administration of gabapentin had a weak effect (d = 0.26) on the quantity consumed and on abstinence (evidence level Ib). Withdrawal symptoms can be alleviated with cannabinoid-receptor antagonists (d = 0.223 and 0.481) (evidence level Ib). On the other hand, there is evidence that serotonergic antidepressants can worsen withdrawal manifestations and increase the likelihood of relapse.

Conclusion: Psychotherapeutic techniques remain the foundation of treatment for cannabis dependence. No drug has yet been approved for the treatment of cannabis dependence because of the lack of scientific evidence. The rates of abstinence that are currently achieved, even with psychotherapy, are still only moderate. Further clinical studies are needed for the evaluation of combinations of various treatments that can meet the needs of individual patients.

Cannabinoids are the group of the world’s most commonly used illicit substances (e1). In Germany, no other illicit substance enjoys such a widespread acceptance as cannabis (e2) due to its reputation among users of a not so harmful substance with low dependence potential (e3). The risk of dependence on cannabis (6.2 %) is lower than that of alcohol (11.2%) or nicotine (36.0%) (e4). However, today 36% of all patients which contact the German addiction care system are cannabis users and 56% of the initial contacts made to addiction care facilities are related to problems with the use of cannabis (e5).

While for most of the other substances specific withdrawal syndromes have been defined, the existence of a cannabis withdrawal syndrome has been a controversial issue for years. With the description of a specific cannabis withdrawal syndrome in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (e6), the characteristics of cannabis as an addictive substance were operationalized for the first time (Table 1).

Table 1

DSM-5 Diagnostic Criteria for Cannabis Withdrawal Syndrome

Despite the increasing demand for more effective treatment options (e5, e7), there is as yet no general accepted treatment approach (e8). Therefore, the aim of this study was to present the current evidence-based concepts for the treatment of cannabis dependence and their implementation in Germany.

Methods

A selective literature search was conducted in PubMed and the Cochrane Central Register of Clinical Trials. The current guideline for the treatment of cannabis dependence was published in 2004 (e9); thus, the search period extended from 1 January 2004 to 31 December 2015 to update the available evidence base. PubMed was searched using the MeSH terms “marijuana abuse/therapy“ in combination with the search terms “dependence” or “use disorder”; altogether, 285 pertinent publications were identified. The search of the Cochrane database using the terms “cannabis dependence“ or “cannabis withdrawal“ yielded 67 hits. The literature references of the identified studies were also examined to discover further relevant studies. Initially, all articles with focus on the treatment of cannabis dependence or the cannabis withdrawal syndrome were used. All randomized controlled trials (RCTs) related to the treatment of cannabis withdrawal syndrome and cannabis dependence were included.

Results

The most important endpoints were

• severity of the withdrawal symptoms
• amounts of cannabis consumed and abstinence rates
• severity of the dependence syndrome
• psychopathology
• cannabis-associated problems.

The severity of the withdrawal syndrome is likely associated with an increased probability of relapse; therefore, this condition is relevant to the general treatment prognosis (e10). A reduction of drug use may significantly improve the emotional state and psychosocial functioning of the user (e11). When analyzing the results, it should be taken into account that it is difficult to evaluate the impact of the various treatment options on the amount of substance used and the abstinence rates, because a retrospective quantification of the exact amounts of cannabis consumed is almost impossible. In addition, many studies did not obtain qualitative parameters, such as drug screening in urine (DSU). The use of synthetic cannabinoids creates an additional methodological challenge, since these substances cannot be detected with standard testing methods.

Proven methods of psychotherapy

Cognitive behavioral therapy (CBT) ranks among the best evaluated methods in the treatment of cannabis dependence (1–7). Typically, it is used in combination with other methods, such as motivational interviewing (MI) or motivational enhancement therapy (MET) [e12]). In a study with adult users (N = 450), the combination of CBT, MET and case management showed strong effects with regard to abstinence and reduction of use in the intervention group as compared with the control group (Cohen´s d = 0,98; p<0.001, and d = 1.14; p<0.001, respectively) (1).

In the German CANDIS study, CBT was combined with MET and psychosocial problem solving training (PST) (6). In a sample of 279 patients (7), the intervention group showed significantly more negative urine drug screenings and a significant reduction in the amount of substance consumed (d = –0.9; p<0.001) after end of treatment. This effect was still observed after 3 months. In addition, psychosocial functioning significantly improved (d = –0.7; p<0.001; Cannabis Problems Questionnaire). One study where subjects participated in 4 sessions of a telephone short intervention with elements from CBT and MET (4) showed a reduction in use compared with the control group after 4 months (d = 0.6; p = 0.0003). A combination of CBT and contingency management (CM) was also evaluated in several studies, but contradictory results were obtained (2, 3, 5) (Table 2).

Table 2

Psychotherapeutic and psychosocial approaches to the treatment of cannabis dependence

Multidimensional family therapy (MDFT) (8) was investigated in the European INCANT study (9–13). In a sample population of 450 users, aged 13–18 years, MDFT was compared with standard psychotherapy (10). While both interventions were effective, MDFT proved superior with regard to treatment adherence (p<0.002) and effects on cannabis dependence symptoms (d = 1.27; p = 0.015). In a high-user sub-group, additionally a more marked reduction in the amounts of cannabis consumed (d = 0.6; p = 0.002) was found 12 months after intervention. The efficacy of MDFT had already been proven in earlier comparative studies (e13, e14). MDFT combines one-to-one sessions with adolescents and parents with family group sessions and also includes the non-family social environment (8, 9).

In addition, numerous studies provided evidence of the efficacy of MI-based short interventions in cannabis-using patients. Here, 1–4 sessions over a period of several weeks already resulted in significant, although moderate, effects, even if the patients initially did not ask for treatment (1, 14–22).

In addition, cost effective, low-threshold online interventions are available, such as online CBT as part of the “Reduce your use “program (23). In a sample population of 225 users, this method showed a minor effect on reduction of use, which was still present after 3 months (d = 0.33; p = 0.02). A further example is the “Quit-the-Shit program“ (24), offering a weekly chat with a therapist. A sample of 206 users showed effects on the reduction of use in comparison to the control group (d = 0.75–0.98) and on self-efficacy (d = 0.6) (each p<0.001). In the “Can-reduce“ program, online CBT in combination with a chat achieved significant higher abstinence rates (Odds Ratio [OR] 0.21; p = 0.05) and a more marked reduction in use (d = 0.34; p = 0.02) compared with online CBT alone (25).

Especially challenging is the treatment of cannabis dependence in the presence of comorbid psychiatric disorders. There is a high rate of cannabis users among patients with psychosis or near-psychosis symptoms in specialized early psychosis detection centers (e15). The concomitant medical and psychotherapeutic treatment of addiction and comorbid disorders requires an individualized and disorder-specific differentiated treatment concept incorporating a cross-sector approach (e16, e17).

Pharmacotherapy of cannabis dependence

Whether the concept of replacement therapy can also be applied to cannabis use was studied for cannabinoid receptor-1 (CB1) agonists. Agonists are used because their action on the receptor is similar to that of the addictive substance, allowing them to reduce withdrawal symptoms while ideally not triggering a “high” or craving. In an inpatient treatment setting, a significant effect of nabiximols (N = 52; d = 0.442; p = 0.01) and dronabinol (N = 152; d = 0.282; p = 0.02) on withdrawal symptoms was demonstrated; however, at the follow-ups after 28 weeks and 84 days, respectively, both substances had no impact on abstinence or the amount of substance consumed (26, 27) (Table 3).

Table 3

Medications for the treatment of cannabis dependence

Another—presently experimental—approach, known from the treatment of opioid dependence, is the administration of receptor antagonists, such as rimonabant (e18); however, clinical studies investigating this approach are not yet available.

Furthermore, GABAergic medication (e.g. valproic acid and gabapentin) were evaluated for this indication. A group of 25 adult patients in an outpatient treatment setting showed no significant differences between valproic acid treatment and placebo, neither with regard to withdrawal syndrome nor abstinence (28). Following reports on the efficacy of gabapentin in treating certain alcohol withdrawal symptoms (e19), a favorable effect of gabapentin has now also been demonstrated in patients with cannabis dependence (29). A study with 50 patients treated with gabapentin in an outpatient setting showed a reduction in withdrawal symptoms (p<0.001). Furthermore, in patients receiving gabapentin or placebo over a period of 12 weeks a favorable effect of gabapentin on the amount of substance consumed (verified by urine testing; d = 0.26; p = 0.026) and on cannabis-related mental (p = 0.028) and physical (p = 0.046) symptoms was found. Cognitive functions improved as well (p = 0.029).

As anxiety is also a symptom of cannabis withdrawal, the non-GABAergic anxiolytic agent buspirone was studied for this indication, but no significant results were found (p = 0.55 [30] or p = 0.86 [31]) (Table 3).

Similarly, antidepressants were tested as medications to treat cannabis dependence. In these studies, nefazodone (32) and fluoxetine (33) were not superior to placebo. In fact, an increase in depressive symptoms was observed among patients with cannabis withdrawal syndrome receiving bupropion (e20). A 12-week study with 103 adult users reported an increase in withdrawal symptoms under venlafaxine treatment (risk difference [RD] 0.20; p = 0.014) (34) and a higher abstinence rate in the placebo group (p<0.01) (35). A trend towards lower abstinence rates in the intervention group was found in a study evaluating the serotonergic antidepressant escitalopram (p = 0.077) (36). Lithium showed in a sample population of 38 adult cannabis users in an outpatient setting no effects on withdrawal syndrome and the amount of substance consumed (37, 38) (eTable).

eTable

Antidepressants und lithium for the treatment of cannabis dependence

The effect of N-acetylcysteine, a nutritional supplement and mucolytic agent, is probably due to an increased expression of cysteine glutamate exchangers in the nucleus accumbens. Their levels are typically reduced by drug use (e21). A study (39) involving 116 adolescents in the 13–21 years age group found increased cannabis abstinence rates under treatment with N-acetylcysteine, measured as negative drug screening in urine (OR 2.4; p = 0.029); however, at 4-weeks follow-up, these changes were no longer significant (p = 0.131) (39).

Discussion

Treatment recommendations have to take the significant heterogeneity of patients with cannabis dependence into account; therefore, differentiated and appropriately graded advice and treatment concepts are needed (40). Subject to individual requirements and needs, patients can undergo treatment in a youth care, addiction care, outpatient psychotherapy, or inpatient psychiatric setting.

The combination of CBT, MET and PPS (CANDIS manual [e22]) is currently regarded as the best-evaluated approach for adults with cannabis dependence (evidence level: Ia) (6, 7). However, this combination treatment requires an initial motivation for change and wish for abstinence; therefore, younger adolescents, not yet able to make resolutions of this kind, may not be fully reached with this type of treatment. In addition, on formal grounds this approach is not always directly compatible with addiction rehabilitation. Therefore, combinations of CBT and other methods are usually offered by statutory health insurance-funded outpatient psychotherapists.

The efficacy of MDFT is well backed by evidence (evidence level Ia). Yet, there are data indicating that older adolescents and young adults benefit more from CBT/MET (6, 7), while younger adolescents with heavy use or comorbid psychiatric disorders appear to show a better response to MDFT (10–12). Here, it has to be taken into account that an initial wish for abstinence is no requirement for participation in MDFT. This method is more complex and requires more effort than CBT/MET, resulting in increased costs and difficulties with implementation (40). Nevertheless, more wide-spread use is conceivable, provided that adequate finance models are developed and youth care and addiction care are better integrated into child and adolescent mental healthcare.

Additionally, treatment approaches that are based on motivational interviewing (MI) can be recommended (evidence level Ia). These are effective in combination with CBT and as part of MDFT. On the other hand, MI, as a short intervention, is also effective in the treatment of cannabis dependence, even if not combined with other methods. This method is comparatively easy to learn, economical and effective. MI also plays a special role in early-intervention and consultation programs (40). In addition, some other early-intervention and counselling programs are worth mentioning, in particular FreD (e23), CAN Stop (e24) and Realize-it (e25) which have been initiated in Germany in recent years. These programs were established in numerous German addiction counselling facilities. They are also easy to learn, cost-effective and highly accepted (40). Online programs were evaluated in several studies and to some extent implemented in standard care, due to their low threshold and their cost effectiveness.

No recommendation can presently be made for pharmacological treatment, even though there is evidence in support of the efficacy of gabapentin (29) and CB1 agonists (26, 27) (each evidence level Ib). Here, further studies are needed to evaluate the benefits of the clinical use of these medications. Antidepressants cannot be recommended for the treatment of cannabis dependence. In fact, there is evidence that especially venlafaxine, but also bupropion and possibly escitalopram, have adverse effects on the withdrawal syndrome and may increase relapse probability.

It is striking that, despite treatment, abstinence rates generally are rather moderate and relapse rates rather high (e26, e27). Consequently, there is a high need for the development of evidence-based standards for the treatment of cannabis dependence (e28). A further issue is that no other substance is so controversially discussed with regard to its health risks as cannabis (e29–e32). Besides the establishment of treatment standards, primary and secondary prevention play an important role.

Conflict of interest statement

The authors declare that no conflict of interest exists.

Manuscript received on 10 January 2016, revised version accepted on
3 May 2016

Translated from the original German by Ralf Thoene, MD.

Corresponding author
Dr. med. Tomislav Majić
Psychiatrische Universitätsklinik der Charité
St. Hedwig Krankenhaus
Große Hamburger Str, 5–11
10115 Berlin, Germany

@Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref3916

eTable:
www.aerzteblatt-international.de/16m0653

References

1. The Marijuana Treatment Project Research Group: Brief treatments for cannabisdependence: findings from a randomized multisite trial. J Consult Clin Psychol 2004; 72: 455–66

2. Kadden RM, Litt MD, Kabela-Cormier E, Petry NM: Abstinence rates following behavioral treatments for marijuana dependence. Addict Behav 2007; 32: 1220–36

3. Stanger C, Budney AJ, Kamon JL, Thostensen J: A randomized trial of contingency management for adolescent marijuana abuse and dependence. Drug Alcohol Depend 2009; 105: 240–7

4. Gates PJ, Norberg MM, Copeland J, Digiusto E: Randomized controlled trial of a novel cannabis use intervention delivered by telephone. Addiction 2012; 107: 2149–58

5. Litt MD, Kadden RM, Petry NM: Behavioral treatment for marijuana dependence: randomized trial of contingency management and self-efficacy enhancement. Addict Behav 2013; 38: 1764–75

6. Hoch E, Noack R, Henker J, et al.: Efficacy of a targeted cognitive-behavioral treatment program for cannabis use disorders (CANDIS). Eur Neuropsychopharmacol 2012; 22: 267–80

7. Hoch E, Bühringer G, Pixa A, et al.: CANDIS treatment program for cannabis use disorders: findings from a randomized multi-site translational trial. Drug Alcohol Depend 2014; 134: 185–93

8. Liddle HA: Multidimensional Family Therapy for adolescent cannabis users. Cannabis Youth Treatment (CYT) Series, Volume 5. Rockville, MD: Center for Substance Abuse Treatment, Substance Abuse and Mental Health Services Administration 2002.

9. Tossmann P, Jonas B, Rigter H: Multidimensionale Familientherapie (MDFT) bei cannabisbezogenen Störungen. Sucht 2012; 58: 157–66

10. Rigter H, Henderson CE, Pelc I, et al.: Multidimensional family therapy lowers the rate of cannabis dependence in adolescents: a randomised controlled trial in western European outpatient settings. Drug Alcohol Depend 2013; 130: 85–93

11. Hendriks V, van der Schee E, Blanken P: Treatment of adolescents with a cannabis use disorder: main findings of a randomized controlled trial comparing multidimensional family therapy and cognitive behavioral therapy in The Netherlands. Drug Alcohol Depend 2011; 119: 64–71

12. Hendriks V, van der Schee E, Blanken P: Matching adolescents with a cannabis use disorder to multidimensional family therapy or cognitive behavioral therapy: treatment effect moderators in a randomized controlled trial. Drug Alcohol Depend 2012; 125: 119–26

13. Schaub MP, Henderson CE, Pelc I, et al.: Multidimensional family therapy decreases the rate of externalising behavioural disorder symptoms in cannabis abusing adolescents: outcomes of the INCANT trial. BMC Psychiatry 2014; 14: 26

14. Martin G, Copeland J: The adolescent cannabis check-up: randomized trial of a brief intervention for young cannabis users. J Subst Abuse Treat 2008; 34: 407–14

15. Stephens RS, Roffman RA, Fearer SA, Williams C, Burke RS: The marijuana check-up: promoting change in ambivalent marijuana users. Addiction 2007; 102: 947–57

16. Fernandes S, Ferigolo M, Benchaya MC, et al.: Brief motivational intervention and telemedicine: a new perspective of treatment to marijuana users. Addict Behav 2010; 35: 750–5

17. Walker DD, Stephens R, Roffman R, et al.: Randomized controlled trial of motivational enhancement therapy with nontreatment-seeking adolescent cannabis users: a further test of the teen marijuana check-up. Psychol Addict Behav 2011; 25: 474–84

18. Stein MD, Hagerty CE, Herman DS, Phipps MG, Anderson BJ: A brief marijuana intervention for non-treatment-seeking young adult women. J Subst Abuse Treat 2011; 40: 189–98

19. Fischer B, Jones W, Shuper P, Rehm J: 12-month follow-up of an exploratory ’brief intervention’ for high-frequency cannabis users among Canadian university students. Subst Abuse Treat Prev Policy 2012; 7: 15

20. de Dios MA, Herman DS, Britton WB, Hagerty CE, Anderson BJ, Stein MD: Motivational and mindfulness intervention for young adult female marijuana users. J Subst Abuse Treat 2012; 42: 56–64

21. Lee CM, Kilmer JR, Neighbors C, et al.: Indicated prevention for college student marijuana use: a randomized controlled trial. J Consult Clin Psychol 2013; 81: 702–9

22. de Gee EA, Verdurmen JE, Bransen E, de Jonge JM, Schippers GM: A randomized controlled trial of a brief motivational enhancement for non-treatment-seeking adolescent cannabis users. J Subst Abuse Treat 2014; 47: 181–8

23. Rooke S, Copeland J, Norberg M, Hine D, McCambridge J: Effectiveness of a self-guided web-based cannabis treatment program: randomized controlled trial. J Med Internet Res 2013; 15: e26

24. Tossmann HP, Jonas B, Tensil MD, Lang P, Strüber E: A controlled trial of an internet-based intervention program for cannabis users. Cyberpsychol Behav Soc Netw 2011; 14: 673–9

25. Schaub MP, Haug S, Wenger A, et al.: Can reduce—the effects of chat-counseling and web-based self-help, web-based self-help alone and a waiting list control program on cannabis use in problematic cannabis users: a randomized controlled trial. BMC PsychiatrY 2013; 13: 305

26. Allsop DJ, Copeland J, Lintzeris N, et al.: Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry 2014; 71: 1–11

27. Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes E V: Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 2011; 116: 142–50

28. Levin FR, McDowell D, Evans SM, et al.: Pharmacotherapy for marijuana dependence: a double-blind, placebo-controlled pilot study of divalproex sodium. Am J Addict 2004; 13: 21–32

29. Mason BJ, Crean R, Goodell V, et al.: A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology 2012; 37: 1689–98

30. McRae-Clark AL, Carter RE, Killeen TK, et al.: A placebo-controlled trial of buspirone for the treatment of marijuana dependence. Drug Alcohol Depend 2009; 105: 132–8

31. McRae-Clark AL, Baker NL, Gray KM, et al.: Buspirone treatment of cannabis dependence: a randomized, placebo-controlled trial. Drug Alcohol Depend 2015; 156: 29–37

32. Carpenter KM, Mc Dowell D, Brooks DJ, Levin FR: A preliminary trial: double-blind comparison of nefazodone, bupropion-SR and placebo in the treatment of cannabis dependence. Am J Addict 2009; 18: 53–64

33. Cornelius JR, Bukstein OG, Douaihy AB, et al.: Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults. Drug Alcohol Depend 2010; 112: 39–45

34. Kelly MA, Pavlicova M, Glass A, et al.: Do withdrawal-like symptoms mediate increased marijuana smoking in individuals treated with venlafaxine-XR? Drug Alcohol Depend 2014; 144: 42–6

35. Levin FR, Mariani J, Brooks DJ, et al.: A randomized double-blind, placebo-controlled trial of venlafaxine-extended release for co- occurring cannabis dependence and depressive disorders. Addiction 2013; 108: 1084–94

36. Weinstein A, Miller H, Bluvstein I, et al.: Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: a double-blind placebo-controlled study. Am J Drug Alcohol Abuse 2014; 40: 16–22

37. Johnston J, Lintzeris N, Allsop DJ, et al.: Lithium carbonate in the management of cannabis withdrawal: a randomized placebo-controlled trial in an inpatient setting. Psychopharmacology (Berl) 2014; 231: 4623–36

38. Allsop DJ, Bartlett DJ, Johnston J, et al. : The effects of lithium carbonate supplemented with nitrazepam on sleep disturbance during cannabis abstinence. J Clin Sleep Med 2015; 11: 1153–62

39. Gray KM, Carpenter MJ, Baker NL, et al.: A double-blind randomized controlled trial of n-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry 2012; 169: 805–12

40. Tossmann P, Gantner A: Frühintervention, Beratung und Behandlung bei Cannabisstörungen. Suchttherapie 2016; 17: 1–5

e1. UNODC – United Nations Office on Drugs and Crime: World Drug Report 2015. New York: United Nations Publication 2015. www.unodc.org/documents/wdr2015/World_Drug_Report_2015.pdf (last accessed on 17 June 2016).

e2. Mortler M: Drogen- und Suchtbericht der Deutschen Bundesregierung 2014: 43. Berlin: Die Drogenbeauftragte der Bundesregierung, Bundesministerium für Gesundheit 2015.

e3. Eul J, Stöver H: Gebrauch und vergleichende Bewertung von Cannabis in der deutschen Bevölkerung. Suchttherapie 2012; 13: 177–84

e4. Behrendt S, Wittchen HU, Höfler M, Lieb R, Beesdo K: Transitions from first substance use to substance use disorders in adolescence: is early onset associated with a rapid escalation? Drug Alcohol Depend 2009; 99: 68–78

e5. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA): European drug report. Trends and developments 2015. www.emcdda.europa.eu/edr2015 (last accessed 8 January 2016).

e6. American Psychiatric Association: Diagnostic and statistical manual of mental disorders: DSM-5. 5th edition. Arlington, VA, USA: American Psychiatric Publishing, Inc. 2013.

e7. Braun B, Künzel J, Brand H: Jahresstatistik 2013 der professionellen Suchtkrankenhilfe. In: Deutsche Hauptstelle für Suchtfragen (DHS): Jahrbuch Sucht 2015. Lengerich: Pabst Science Publishers 2015.

e8. Kleber HD, Weiss RD, Anton RF jr., et al.: Treatment of patients with substance use disorders, second edition. Am J Psychiatry 2007; 164 (4 suppl):1–276.

e9. Bonnet U, Harries-Hedder K, Leweke FM, Schneider U, Tossmann P: AWMF-Leitlinie: Cannabisbezogene Störungen. Fortschr Neurol Psychiat; 2004; 72: 318–29

e10. Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursac Z: Comparison of cannabis and tobacco withdrawal: severity and contribution to relapse. J Subst Abuse Treat 2008; 35: 362–8

e11. de Dios MA, Anderson BJ, Herman CE, Caviness CM, Budney AJ, Stein M: Marijuana use subtypes in a community sample of young adult women. Womens Health Issues 2010; 20: 201–10

e12. Miller W, Rollnick S: Motivational interviewing: preparing people to change addictive behaviour. London: Guilford Press 1991.

e13. Liddle HA, Dakof GA, Turner RM, Henderson CE, Greenbaum PE: Treating adolescent drug abuse: a randomized trial comparing multidimensional family therapy and cognitive behavior therapy. Addiction 2008; 103: 1660–70

e14. Dennis M, Godley SH, Diamond G, et al.: The Cannabis Youth Treatment (CYT) study: main findings from two randomized trials. J Subst Abuse Treat 2004; 27: 197–213

e15. Kraan T, Velthorst E, Koenders L, et al.: Cannabis use and transition to psychosis in individuals at ultra-high risk: review and meta-analysis. Psychol Med 2016; 46: 673–81

e16. Gouzoulis-Mayfrank E, König S, Koebke S, Schnell T, Schmitz-Buhl M, Daumann J: Trans-sector integrated treatment in psychosis and addiction. Dtsch Arztebl Int 2015; 112: 683–91

e17. Spohr B, Steffen R, Jockers-Scherübl M: „Double Trouble“: Ein integriertes psychotherapeutisch-psychoedukatives Gruppenprogramm für Patienten mit der Doppeldiagnose Schizophrenie und Cannabismissbrauch. Gemeindenahe Psychiatr 2006; 1/2: 17–30.

e18. Huestis MA, Boyd SJ, Heishman SJ, et al.: Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users. Psychopharmacology (Berl) 2007; 194: 505–15

e19. Mason BJ, Light JM, Williams LD, Drobes DJ: Proof-of-concept human laboratory study for protracted abstinence in alcohol dependence: effects of gabapentin. Addict Biol 2009; 14: 73–83

e20. Haney M, Ward AS, Comer SD, Hart CL, Foltin RW, Fischman MW: Bupropion SR worsens mood during marijuana withdrawal in humans. Psychopharmacology (Berl) 2001; 155: 171–9

e21. Gray KM, Watson NL, Carpenter MJ, Larowe SD: N-Acetylcysteine (NAC) in young marijuana users: an open-label pilot study. Am J Addict 2010; 19: 187–9

e22. Hoch E, Zimmermann P, Henker J, et al.: Modulare Therapie von Cannabisstörungen. Das CANDIS-Programm. Göttingen: Hogrefe, 2011.

e23. Görgen W, Hartmann R, Oliva H: Frühintervention bei erstauffälligen Drogenkonsumenten – FreD, Abschlussbericht der wissenschaftlichen Begleitung. Forschungsbericht 299, Sozialforschung. Bonn: Bundesministerium für Gesundheit und Soziale Sicherung 2003.

e24. Baldus C, Kindermann SS, Stappenbeck J, Reis O, Moré K, Thomasius R: „CAN Stop“ – Entwicklung und Evaluation eines Gruppentrainings für Jugendliche und junge Erwachsene mit problematischem Cannabiskonsum. Suchttherapie 2011; 12: 33.

e25. Tossmann HP, Kasten L: Realize it. Abschlussbericht des Bundestransfers 2010. www.drogenbeauftragte.de/Fileadmin/dateien-dba/DrogenundSucht//Illegale_Drogen/Cannabis/Downloads/Realize-it-Transfer/Abschlussbericht.pdf (last accessed on 28 June 2016).

e26. Moore BA, Budney AJ: Relapse in outpatient treatment for marijuana dependence. J Subst Abuse Treat 2003; 25: 85–9

e27. Flórez-Salamanca L, Secades-Villa R, Budney AJ, García-Rodríguez O, Wang S, Blanco C: Probability and predictors of cannabis use disorders relapse: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2013; 132: 127–33

e28. Plenert M, Werse B: Für eine verantwortungsvolle Regulierung von Cannabis. In: Werse B, Stöver H, Plenert M, Schäffer D (eds.): Alternativer Sucht- und Drogenbericht 2014; 119–23.

e29. Hoch E, Bonnet U, Thomasius R, Ganzer F, Havemann-Reinecke U, Preuss UW: Risks associated with the non-medicinal use of cannabis. Dtsch Arztebl Int 2015; 112: 271–9

e30. Morgan CJ, Muetzelfeldt L, Muetzelfeldt M, Nutt DJ, Curran HV: Harms associated with psychoactive substances: findings of the UK national drug survey. J Psychopharmacol 2010; 24: 147–53

e31. Grotenhermen F: The toxicology of cannabis and cannabis prohibition. Chem Biodivers 2007; 4: 1744–69

e32. Stöver H, Thomasius R: Legalisierung von Cannabis. Sucht 2013; 59: 51–3

e33. McCambridge J, Slym RL, Strang J: Randomized controlled trial of motivational interviewing compared with drug information and advice for early intervention among young cannabis users. Addiction 2008; 103: 1809–18

e34. Jungerman FS, Andreoni S, Laranjeira R: Short term impact of same intensity but different duration interventions for cannabis users. Drug Alcohol Depend 2007; 90: 120–7

e35. Lee CM, Neighbors C, Kilmer JR, Larimer ME: A brief, web-based personalized feedback selective intervention for college student marijuana use: a randomized clinical trial. Psychol Addict Behav 2010; 24: 265–73

e36. Davis ML, Powers MB, Handelsman P, Medina JL, Zvolensky M, Smits JA: Behavioral therapies for treatment-seeking cannabis users: a meta-analysis of randomized controlled trials. Eval Health Prof 2015; 38: 94–114