DÄ internationalArchive16/2015Risks Associated With the Non-Medicinal Use of Cannabis

Review article

Risks Associated With the Non-Medicinal Use of Cannabis

Dtsch Arztebl Int 2015; 112(16): 271-8; DOI: 10.3238/arztebl.2015.0271

Hoch, E; Bonnet, U; Thomasius, R; Ganzer, F; Havemann-Reinecke, U; Preuss, U W

Background: Cannabis is the most commonly consumed illicit drug around the world; in Germany, about 4.5% of all adults use it each year. Intense cannabis use is associated with health risks. Evidence-based treatments are available for health problems caused by cannabis use.

Methods: Selective literature review based on a search of the PubMed database, with special emphasis on systematic reviews, meta-analyses, cohort studies, randomized controlled trials (RCTs), case–control studies, and treatment guidelines.

Results: The delta-9-tetrahydrocannabinol content of cannabis products is rising around the world as a result of plant breeding, while cannabidiol, in contrast, is often no longer detectable. Various medical conditions can arise acutely after cannabis use, depending on the user’s age, dose, frequency, mode and situation of use, and individual disposition; these include panic attacks, psychotic symptoms, deficient attention, impaired concentration, motor incoordination, and nausea. In particular, intense use of high doses of cannabis over many years, and the initiation of cannabis use in adolescence, can be associated with substance dependence (DSM-5; ICD-10), specific withdrawal symptoms, cognitive impairment, affective disorders, psychosis, anxiety disorders, and physical disease outside the brain (mainly respiratory and cardiovascular conditions). At present, the most effective way to treat cannabis dependence involves a combination of motivational encouragement, cognitive behavioral therapy, and contingency management (level 1a evidence). For adolescents, family therapy is also recommended (level 1a evidence). No pharmacological treatments can be recommended to date, as evidence for their efficacy is lacking.

Conclusion: Further research is needed to elucidate the causal relationships between intense cannabis use and potential damage to physical and mental health. Health problems due to cannabis use can be effectively treated.

LNSLNS

Recreational use of cannabis has recently been legalized in several states of the USA. At the same time, scientific research is improving our knowledge of the therapeutic potential of medicinal drugs containing cannabis (1). In this light, it is not surprising that more and more patients are asking their doctors and other healthcare professionals for information about the health risks and medical benefits of cannabis.

Cannabis is the most widely consumed illegal substance across the world (2). According to United Nations estimates, 125 to 227 million people consume cannabis worldwide (2). A recent national epidemiological survey of addiction in Germany showed that 4.5% of the adult population had used cannabis in the previous year (3). Consumption is particularly common among 18- to 20-year-olds (12-month prevalence: 16.2%). An estimated 1% of the population of the European Union (12 million persons) are daily users of cannabis (4). Cannabis is mostly consumed in the form of marijuana (dried flowers and leaves) or hashish (the delta-9-tetrahydrocannabinol [THC]-containing resin of the inflorescences) (4). Oil containing THC is also sometimes ingested in foodstuffs. Police reports indicate that cannabis plants are increasingly being grown in European countries and less cannabis is being imported (4).

The content of THC, the principal psychotropic substance in cannabis, has increased sharply in the past decade (4). Another active ingredient, cannabidiol (CBD), is no longer present in many strains (e1, e2). The anxiolytic, antipsychotic, anti-inflammatory, antiemetic, and neuroprotective actions that are ascribed to CBD (e3) may compensate the adverse effects of THC (5). The consumption of cannabis products high in THC and low in CBD is thought to cause undesired effects in persons with a corresponding predisposition (e4). The total number of addiction treatments owing to cannabis consumption is increasing in Europe and the USA (2, 4, e5).

Goal

The aim of this review is to summarize the current state of knowledge with regard to the potential physical and mental adverse effects of intensive recreational use of cannabis and outline the options for treatment of health impairments resulting from cannabis consumption.

Method

Selective surveys of clinical data were carried out in PubMed. This narrative review included systematic reviews, meta-analyses, narrative reviews, randomized controlled trials (RCTs), cohort studies, case–control studies, guidelines, and reports from public institutions (eTable 1). The evidence was evaluated according to the guidelines of the Oxford Centre for Evidence-Based Medicine (6) (eTable 2).

Somatic consequences of non-medicinal cannabis use
Somatic consequences of non-medicinal cannabis use
Table
Somatic consequences of non-medicinal cannabis use
Literature survey
Literature survey
eTable 1
Literature survey
idence level according to Oxford Centre for Evidence-based Medicine (CEBM)
idence level according to Oxford Centre for Evidence-based Medicine (CEBM)
eTable 2
idence level according to Oxford Centre for Evidence-based Medicine (CEBM)

Disorders associated with cannabinoids

Acute intoxication, harmful and addictive use of cannabis

When cannabis is smoked, THC passes from the lungs into the bloodstream, reaching the internal organs and the brain within minutes. In the brain, THC exerts its effect principally via the CB1 cannabinoid receptors, located mainly in regions of the cerebrum associated with locomotion, learning, memory, and the reward system. The smoking of herbal cannabis can lead to acute intoxication (79) (Box). The effect depends on the composition of the cannabis preparation, the dose, the frequency and form of intake, and the circumstances, as well as the user’s individual disposition and experience of cannabis consumption (7, e6). When the pharmacological effect has worn off, the symptoms disappear (10, 11). The cannabis metabolite THC-COOH can be demonstrated in urine for 2 to 6 weeks after last use (e7).

Acute cannabinoid intoxication
Acute cannabinoid intoxication
Box
Acute cannabinoid intoxication

Further cannabinoid-associated disorders are defined in DSM-5 (e8) and in ICD-10 (e9). While ICD-10 distinguishes between harmful and addictive use of cannabis, in DSM-5 the severity of health impairment can be classified in three segments (mild, moderate, severe) of a continuum. Both classifications also describe a specific cannabis withdrawal syndrome, which can occur within 24 h of consumption (10, 11, e8, e9). For cannabis withdrawal syndrome to be diagnosed, at least two mental symptoms (e.g., irritability, restlessness, anxiety, depression, aggressiveness, loss of appetite, sleep disturbances) and at least one vegetative symptom (e.g., pain, shivering, sweating, elevated body temperature, chills) must be present. The symptoms are at their most intensive in the first week and can persist for as long as a month. Clinically, withdrawal from cannabis is usually uncomplicated (10, 11, e10, e11).

In the German general population, around 1% of adults fulfill the DSM-IV criteria of cannabis abuse (0.5%) or cannabis addiction (0.5%) (3). For comparison, higher rates of prevalence are found for alcohol abuse and dependence (3.1% and 3.4% respectively) and for nicotine addiction (10.8%) (3). Dependence on other illegal substances, e.g., amphetamines (0.2%) or cocaine (0.3%) is less common (3). Overall, around 9% of all cannabis consumers become dependent on cannabis at some time during their lives (e12). This rate rises to 17% for those who started using cannabis in adolescence (e13) and 25 to 50% if cannabinoids are consumed daily (e14). As yet there are no data for Germany on the prevalence of health impairments as a result of cannabis use according to DSM-5.

The amotivational syndrome, characterized by reduced motivation to perform the activities of daily living, disorders of concentration and attention, and blunting of affect (e15), has been insufficiently investigated to date and empirical proof is lacking (e16). In regular consumers of cannabis this pattern of symptoms may be produced by a disturbance of focused attention (e17) or a prolonged intoxication effect (12).

Cognitive consequences

A meta-analysis (13) (evidence level: 1a) reported mild negative effects on learning capacity (effect strength [ES] = –0.24, 99% confidence interval [CI] –0.39 to –0.02) and memory (ES = –0.27, 99% CI –0.49 to –0.04) in non-abstinent habitual consumers of cannabis. These effects were also demonstrable after at least 24 h abstinence. Attentiveness and reaction time were not impaired. A more recent meta-analysis (14) (evidence level: 1a) also shows low-level global cognitive impairments in acute cannabis consumption (global ES = –0.29, 95% CI –0.46 to –0.12). Compared with abstinent persons, non-abstinent cannabis users exhibited mild impairments in the following areas:

  • Abstract thinking or executive performance (ES = –0.21, 95% CI –0.38 to –0.05)
  • Attention (ES = –0.36, 95% CI –0.56 to –0.16)
  • Retentiveness (ES = –0.25, 95% CI –0.47 to –0.07)
  • Learning (ES = –0.35, 95% CI –0.55 to –0.15)
  • Psychomotor functions (ES = –0.34, 95% CI –0.57 to –0.11)

After abstinence for at least a month, these differences were no longer detectable (ES = –0.12, 95% CI –0.32 to 0.07). The effects may be reversible in adults. Other studies show that especially in consumers who began using cannabis in adolescence, cognitive impairments may still be present after 4 weeks’ abstinence. Persisting mild to moderate deficits were found in the following areas:

  • Psychomotor velocity (β = –0.32, ES = 0.09, p<0.05)
  • Attention (β = –0.33, ES = 0.06, p<0.04)
  • Memory (β = –0.34, ES = 0.06, p<0.04)
  • Planning ability (β = –0.53, ES = 0.30, p<0.001) (e18, e19).

A long-term study in New Zealand yields evidence of an unfavorable influence of regular cannabis consumption in adolescence on intelligence in later life (e20) (evidence level: 1b). In persons who had regularly used cannabis before reaching the age of majority, the mean intelligence quotient at the age of 38 years was eight points lower than at the age of 13 years. These effects were not evident in probands whose long-term consumption of cannabis had begun when they were already adult. The study excluded any possibility that the effects were due to acute cannabis intoxication, addiction to other substances, schizophrenia, or a lower level of education. These findings indicate elevated vulnerability to neurocognitive impairments among adolescents who regularly use cannabis, with questionable reversibility (e21) (evidence level: 2a).

These results are complementary to age-dependent structural changes in the gray and white matter of the brain. In a study of young cannabis users (e22), the decrease in volume of the right amygdala and the hippocampus on both sides of the brain correlated with the severity of dependence on cannabis (R2 = 0.54) and the amount of cannabis consumed weekly (R2 = 0.43). There is also evidence of changes in the axonal fiber pathways (e23) (evidence level: 1b): cannabis users showed a loss of axonal integrity (reduction of fiber pathways by up to 84%) in the area of the right fimbria and bilaterally in a region of the corpus callosum, as well as a decrease of 88% in the fiber bundle from the splenium of the corpus callosum to the right precuneus. In both cases the age at which regular cannabis use had begun correlated significantly with radial (t = 2.5, p = 0.02 versus t = 4.0, p = 0.002) and axial (t = 1.9, p = 0.06 versus t = 3.2, p = 0.002) density.

Influence on education

A meta-analysis of three prospective cohort studies with a total of over 6000 participants suggests a connection between early cannabis use (before the age of 15 years) and an increased risk of leaving school early or attaining a lower level of education (15) (evidence level: 1a).

Somatic risks

The Table provides an overview of the possible somatic consequences of acute and chronic use of cannabis.

Mental comorbidity

Affective disorders, suicidality, anxiety disorders: Between 50% and 90% of cannabis-dependent persons are diagnosed with a further mental disorder or health impairment from consumption of alcohol or other substances at some point in their lives (e49). Some studies suggest a positive relationship between cannabis consumption and bipolar disorders (27, 28, e50e52) or between augmented manic symptoms and cannabis use (e52, e53). The relationship of cannabis use with depression is less clear. A few longitudinal studies (29) have found a slightly increased risk for the development of unipolar depression (odds ratio [OR] 1.17–1.62) (evidence level: 2a), particularly in persons with early onset of cannabis use and consumption of large amounts of cannabis, while others have not (e54). Especially in adolescents and young adults who use cannabis, increased occurrence of suicidal thoughts has been described (OR 1.80–4.55) (30, e55) (evidence level: 3a). The data are heterogeneous, so no confident statement can be made with regard to the extent of the risk for suicidality (31), and no consistent causal link has been found (31, 32, e56, e57).

Chronic intoxication, withdrawal symptoms, additional addictions, adaptational or personality disorders, and—particularly in adolescents—disorders of emotional development and social behavior are assumed to be further additional factors in the development of depression and suicidality in cannabis users (30, 33, e54, e58). In bipolar disorders, above all, accompanying cannabis use is associated with a less favorable course, poorer adherence, elevated risk of suicide, and decreased response to lithium (e59). Treatment of the affective disorder may lead to reduction of the accompanying cannabis use (34). Treatment of the cannabis dependency is also probably advantageous for the course of the affective disorder. To date this assumption is based exclusively on clinical observation, with no empirical support. More evidence exists for a connection between cannabis use and anxiety disorders, particularly panic disorders. The risk of an anxiety disorder was significantly elevated in persons who consumed cannabis weekly up to the age of 29 years (OR 3.2, 95% CI 1.1 to 9.2) (e60) (evidence level: 2b). Furthermore, epidemiological investigations have revealed a 2.5– to 6-fold risk of anxiety disorders in those dependent on cannabis (e61).

Psychoses: Early, regular, long-term, and heavy consumption of cannabis, in association with other stressors such as experience of violence and abuse in childhood or psychoses in the original family, has been connected with increased risk of psychotic disorders (30, 35, e62e64). The pooled data in a meta-analysis quantified the increased risk of psychoses after frequent cannabis consumption with an OR of 2.09 (95% CI 1.54 to 2.84) (evidence level: 2a). In the presence of a certain genetic pattern, as shown in an animal experiment, cannabinoids and stress can favor the development of a psychosis (3638).

Consumption of cannabis and other substances: Various studies have demonstrated a link between early, regular cannabis use and continuing consumption of other illegal drugs or alcohol (33). However, there are no empirical data to support the gateway hypothesis, i.e., the notion that use of cannabis leads directly to use of other substances (e65, e66).

Secondary cannabis consumption: Many consumers may use cannabis to alleviate troublesome psychic or physical symptoms (e67). This has been reported for patients with posttraumatic stress syndrome (e68, e69) or chronic pain (e70). Cannabis is also smoked by some persons with schizophrenic psychoses, perhaps because of the antipsychotic action of CBD (e3), and increases the risk of more and longer-lasting paranoid syndromes (e71) and intoxication phenomena (e72, e73) in 40% of user.

Further research is required to clarify the causal nature of the links between cannabis consumption patterns and adverse events. In future studies particular care should be taken to control for confounding variables.

Treatment

In Europe, cannabis consumption is the most common reason for a first drug treatment due to use of an illegal substance (4). The number of first treatments rose from 45 000 to 61 000 between 2006 and 2011 and remained stable at 59 000 in 2012.

In Germany, patients with cannabis-related disorders are usually treated as outpatients, e.g., in dependency outreach services, addiction clinics, or specialist centers. Uncomplicated withdrawal is also treated on an outpatient basis.

Qualified inpatient treatment is indicated in the case of:

  • Complicated course of intoxication
  • Severe withdrawal syndrome and/or severe after-effects
  • High danger of relapse
  • Comorbid mental disorders (39)

The treatment is divided into acute and post-acute phases. The acute phase (duration 2 to 4 weeks; in adolescents, 4 to 12 weeks) can include physical detoxication, diagnosis, and treatment of withdrawal symptoms, as well as detection and possibly treatment of any coexisting disorders. In addition to intensive counseling and structuring of daily activities, accompanied by psychopharmaceutical support if indicated, the patient is encouraged to begin abstinence-stabilizing treatment in cases where treatment motivation is lacking in the presence of impairment of psychosocial function (i.e., difficulties in organizing the daily routine and structuring activities).

More complicated episodes of intoxication may be characterized by panic attacks or by psychotic or delirious symptoms. In these cases it is helpful to talk to the patient and, if applicable, to administer antipsychotics (preferably atypical) and/or sedatives for a limited period of time (39).

Rehabilitational postacute treatment (duration: 6 to 9 months) serves to ensure abstinence, prevent relapse, stabilize the patient’s mental, social, and occupational situation, and treat any comorbidity. In adolescents, attention needs to be paid to educational support, reintegration into school, and the situation regarding family and residence.

Psychotherapeutic interventions

A meta-analysis (40) and several systematic reviews of RCTs (evidence level: 1a) (e74e76) demonstrate that short interventions (6 to 12 sessions) with combinations of measures to promote motivation, cognitive-behavioral therapy, and contingency management (learning via systematic rewards) have the greatest effect. Furthermore, family therapy interventions have proved effective in children and adolescents (evidence level: 1a) (e74). The abstinence rates lie between 10 and 50% (40, e77e81). Around half these patients relapse within a year (40, e77e81).

More successful than the attempt to achieve abstinence from cannabis are measures to reduce the frequency and intensity of consumption and ameliorate the psychosocial problems and other health impairments associated with cannabis use (e75).

Internet- and computer-based interventions are effective in reaching young people at the time when their use of cannabis is becoming problematic and in achieving a reduction in consumption (e82).

Pharmacotherapy

No medications are yet licensed for the treatment of cannabis-related disorders. Drug treatment is necessary only in the presence of severe withdrawal symptoms (e.g., with gabapentin, benzodiazepines, sedative antipsychotics), psychoses (with antipsychotics), or panic attacks (with benzodiazepines, sedative antipsychotics) (39). Two RCTs investigated treatment of cannabis withdrawal with synthetic THC (dronabinol) or cannabis extracts (e.g., nabiximols). These medications were superior to placebo with regard to compliance and amelioration of withdrawal symptoms, but not for reduction of consumption (e83, e84).

Buspirone and the CB1-receptor antagonist rimonabant have also been shown to be effective (e85); however, rimonabant was taken off the market in 2008 because of its depressive action.

Summary

The use of cannabis is widespread, extending from experimental consumption to dependence. Empirical data have now clearly shown that starting early in life and regularly using high amounts of cannabis for a long period of time increases the risk of various mental and physical disorders and endangers age-appropriate development. Because many studies have failed to control properly for confounding variables, it still cannot be stated beyond doubt that there is a causal connection between cannabis consumption patterns and cognitive damage or the development of comorbid psychic or somatic disorders. The worldwide increase in the THC content of cannabis may increase the health risks, particularly for adolescent users. Further research is required to determine why some people are more affected than others by the unfavorable consequences.

Conflict of interest statement

Dr. Hoch has received honoraria from the publisher Hogrefe for authorship or co-authorship of a publication on a subject related to the topic of this article.

Prof. Bonnet has received honoraria for lectures and training courses from Actelion, Bristol-Myers Squibb, Esparma, GlaxoSmithKline, Lilly, Lundbeck, Merz, Otsuka, and Servier. He has received third-party funding for the conduct of a clinical application study from Servier. He has received personal honoraria for writing two CME articles published in the journal Info Neurologie und Psychiatrie—one on the addictive potential of propofol and one on the diagnosis and treatment of cannabis withdrawal syndrome.

Prof. Thomasius, Dr. Ganzer, Prof. Havemann-Reinecke, and Prof. Preuss declare that no conflict of interest exists.

Manuscript received on 24 September 2014, revised version accepted on 27 January 2015.

Translated from the original German by David Roseveare.

Corresponding author:

Dr. rer. nat. Eva Hoch
Klinik für Abhängiges Verhalten und Suchtmedizin
Zentralinstitut für Seelische Gesundheit, J5
68159 Mannheim
eva.hoch@zi-mannheim.de

@For e-references please refer to:
www.aerzteblatt-international.de/ref1615

eTables:
www.aerzteblatt-international..de/15m0271

1.
Grotenhermen F, Müller-Vahl K: The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 2012; 109: 495–501 VOLLTEXT
2.
United Nations Office on Drugs and Crime: World Drug Report 2014 (United Nations publication, Sales No. E.14.XI.7).
3.
Pabst A, Kraus L, Gomes de Matos E, Piontek D: Substanzkonsum und substanzbezogene Störungen in Deutschland im Jahr 2012. Sucht 2013; 59: 321–31 CrossRef
4.
Europäische Beobachtungsstelle für Drogen und Drogensucht: Drogenangebot in Europa (EMCDDA). In: Europäischer Drogenbericht 2014: Trends und Entwicklungen. Luxemburg: Amt für Veröffentlichungen der Europäischen Union 2014.
5.
Niesink R, van Laar MW: Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry 2013; 4: 130 CrossRef MEDLINE PubMed Central
6.
OCEBM Levels of Evidence Working Group: The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. www.cebm.net (last accessed on 16 December 2014).
7.
Bonnet U, Scherbaum N: Cannabisbezogene Störungen. Teil II: Psychiatrische und somatische Folgestörungen und Komorbiditäten. Fortschr Neurol Psychiat 2010; 78: 1–11.
8.
Crippa JA, Derenusson GN, Chagas MH, et al.: Pharmacological interventions in the treatment of the acute effects of cannabis: a systematic review of literature. Harm Reduct J 2012; 9: 7 CrossRef MEDLINE PubMed Central
9.
Hall W, Degenhardt L: Adverse health effects of non-medical cannabis use. Lancet 2009; 374: 1383–91 CrossRef
10.
Bonnet U, Specka M, Stratmann U, Ochwadt R, Scherbaum N: Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification: Cannabis withdrawal syndrome and its correlation with delta-9-tetrahydrocannabinol and -metabolites in serum. Drug Alcohol Depend 2014; 143: 189–97 CrossRef MEDLINE
11.
Preuss UW, Watzke AB, Zimmermann J, Wong JW, Schmidt CO: Cannabis withdrawal severity and short-term course among cannabis-dependent adolescent and young adult inpatients. Drug Alcohol Depend 2010; 106: 133–41 CrossRef MEDLINE
12.
Karila L, Roux P, Rolland B: Acute and long-term effects of cannabis use: A Review. Curr Pharm 2014; 20: 4112–8 CrossRef
13.
Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T: Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc 2003; 9: 679–89 CrossRef MEDLINE
14.
Schreiner AM, Dunn ME: Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol 2012; 20: 420–29 CrossRef MEDLINE
15.
Horwood L, Fergusson D, Hayatbakhsh M, et al.: Cannabis use and educational achievement: Findings from three Australasian cohort studies. Drug and Alcohol Depend 2010; 110: 247 CrossRef MEDLINE
16.
Rawal SY, Tatakis DN, Tipton DA: Periodontal and oral manifestations of marijuana use. J Tenn Dent Assoc 2012; 92: 26–31 MEDLINE
17.
Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 2007; 167: 221–8 CrossRef MEDLINE PubMed Central
18.
Volkow ND, Baler RD, Compton WM, Weiss SRB: Adverse health effects of marijuana use. N Engl J Med 2014; 370: 23 CrossRef MEDLINE
19.
Pratap B, Korniyenko A: Toxic effects of marijuana on the cardiovascular system. Cardiovasc Toxicol 2012; 12: 143–8 CrossRef MEDLINE
20.
Jones RT: Cardiovascular system effects of marijuana. J Clin Pharmacol 2002; 42: 58–63 CrossRef
21.
Sidney S, Beck JE, Tekawa IS, Quesenberry CP, Friedman GD: Marijuana use and mortality. Am J Public Health 1997; 87: 585–90 CrossRef
22.
Singh NN, Pan Y, Muengtaweeponsa S, Geller TJ, Cruz-Flores S: Cannabis-related stroke: case series and review of literature. J Stroke Cerebrovasc Dis 2012; 21: 555–60 CrossRef MEDLINE
23.
Tennstedt D, Saint-Remy A: Cannabis and skin diseases: Eur J Dermatol 2011; 21: 5–11 MEDLINE
24.
Wu CS, Jew CP, Lu HC: Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol 2011; 6: 459–80 CrossRef
25.
Bari M, Battista N, Pirazzi V, Maccarrone M: The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci 2011; 16: 498–516 CrossRef
26.
Tanasescu R, Constantinescu CS: Cannabinoids and the immune system: an overview. Immunobiology 2010; 215: 588–97 CrossRef MEDLINE
27.
Gibbs M, Winsper C, Marwaha S, Gilbert E, Broome M, Singh SP: Cannabis use and mania symptoms: A systematic review and meta-analysis. J Affect Disord 2014; 23: 39–47 MEDLINE
28.
Strakowski SM, DelBello MP, Fleck DE, et al.: Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania. Arch Gen Psychiatry 2007; 64: 57–64 CrossRef MEDLINE
29.
Lev-Ran S, Roerecke M, Le Foll B, George TP, McKenzie K, Rehm J: The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies. Psychol Med 2014; 44: 797–810 CrossRef MEDLINE
30.
Moore TH, Zammit S, Lingford-Hughes A, et al.: Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007; 370: 319–28 CrossRef
31.
Hall W, Degenhardt L: The adverse health effects of chronic cannabis use. Drug Test Anal 2014; 6: 39–45 CrossRef MEDLINE
32.
Horwood L, Fergusson D, Coffey D, et al.: Cannabis and depression: An integrative data analysis of four Australasian cohorts. Drug Alcohol Depend 2012; 126: 369 CrossRef MEDLINE
33.
Petersen KU, Thomasius R (eds.): Auswirkungen von Cannabiskonsum und -missbrauch. Lengerich, Deutschland/Rockledge, USA: Dustri, Pabst Science Publishers 2007; 79–95.
34.
Baker AL, Hides L, Lubman DI: Treatment of cannabis use among people with psychotic or depressive disorders: a systematic review. J Clin Psychiatry 2010; 71: 247–54 CrossRef MEDLINE
35.
Radhakrishnan R, Wilkinson ST, D’Souza DC: Gone to pot—a review of the association between cannabis and psychosis. Front Psychiatry 2014; 5: 54 CrossRef MEDLINE PubMed Central
36.
Brzozka M, Falkai P, Havemann-Reinecke U: Für Schizophrenie braucht man Drei. Suchtmed 2009; 11: 98–110.
37.
Brzozka M, Fischer A, Falkai P, Havemann-Reinecke U: Acute treatment with cannabinoid receptor agonist WIN55212,2 improves prepulse inhibition in psychosocially stressed mice. Behav Brain Res 2011; 218: 280–7 CrossRef MEDLINE
38.
Bossong MG, Niesink RJ: Adolescent brain maturation, the endogenous cannabinoid system, and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol 2010; 92: 370–85. CrossRef MEDLINE
39.
Bonnet U, Harries-Hedder K, Leweke FM, Schneider U, Tossmann P: AWMF-Leitlinie: Cannabis-bezogene Störungen. Fortschr Neurol Psychiatrie 2004; 72: 318–29 CrossRef MEDLINE
40.
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 CrossRef MEDLINE
e1.
Cascini F, Aiello C, Di Tanna G: Increasing delta-9-tetrahydrocannabinol (Delta-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev 2012; 5: 32–40 CrossRef
e2.
Atakan Z: Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol 2012; 2: 241–54 CrossRef MEDLINE PubMed Central
e3.
Englund A, Morrison PD, Nottage J, et al.: Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 2013; 27: 19–27 CrossRef MEDLINE
e4.
Swift W, Wong A, Li KM, Arnold JC, McGregor IS: Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile. PLoS One 2013; 24: 8.
e5.
United States Department of Justice, Drug enforcement administration: National drug threat assessment summary 2013; 12. www.dea.gov (last accessed on 3 March 2015).
e6.
Thomasius R, Weymann N, Stolle M, Petersen KU: Cannabiskonsum und -missbrauch bei Jugendlichen und jungen Erwachsenen. Auswirkungen, Komorbidität und therapeutische Hilfen. Psychotherapeut 2009; 54: 170–8 CrossRef
e7.
Musshoff F, Madea B: Review of biologic matrices (urine, blood, hair) as indicators of recent or ongoing cannabis use. Ther Drug Monit 2006; 28: 155–63 CrossRefMEDLINE
e8.
American Psychiatric Association (APA): Diagnostic and statistical manual of mental disorders (5th edition). Arlington, VA: American Psychiatric Publishing 2013.
e9.
World Health Organisation (WHO): ICD-10 Classifications of mental and behavioural disorder: Clinical descriptions and diagnostic guidelines. Geneva: World Health Organisation 1992.
e10.
Budney AJ, Hughes JR, Moore BA, Vandrey R: Review of the validity and significance of cannabis withdrawal syndrome.
Am J Psychiatry 2004; 161: 1967–77 CrossRef MEDLINE
e11.
Budney AJ, Hughes JR: The cannabis withdrawal syndrome.
Curr Opin Psychiatry 2006; 19: 233–8 CrossRef MEDLINE
e12.
Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, et al.: Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2011; 115: 120–30 CrossRef MEDLINE PubMed Central
e13.
Anthony JC: The epidemiology of cannabis dependence. In: Roffman RA, Stephens RS (eds.): Cannabis dependence: Its nature, consequences and treatment Cambridge, UK: Cambridge University Press 2006; 58–105.
e14.
Hall WD, Pacula RL: Cannabis use and dependence: Public health and public policy. Cambridge, UK: Cambridge University Press 2003.
e15.
Tennant FS, Groesbeck CJ: Psychiatric effects of hashish. Arch Gen Psychiatry 1972; 27: 133–6 CrossRef
e16.
Hall WD, Solowij N: Adverse effects of cannabis. Lancet 1998; 352: 1611–16 CrossRef
e17.
Grover S, Basu D: Cannabis and psychopathology: update 2004. Indian J Psychiatry 2004; 46: 299–309 MEDLINE PubMed Central
e18.
Medina KL, Hanson KL, Schweinsburg AD, et al.: Neuropsychological functioning in adolescent marijuana users: Subtle deficits detectable after a month of abstinence. J Int Neuropsychol Soc 2007; 13: 807–20 CrossRef MEDLINE PubMed Central
e19.
Solowij N, Jones KA, Rozman ME, et al.: Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology 2011; 216: 131–44 CrossRef MEDLINE
e20.
Meier MH, Caspi A, Abler A, et al.: Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci 2012; 109: 15970–1 CrossRef MEDLINE PubMed Central
e21.
Lisdahl KM, Gilbart ER, Wright NE, Shollenbarger S: Dare to delay? The impacts of adolescent alcohol and marijuana use onset on cognition, brain structure, and function. Front Psychiatry 2013; 4: 53 MEDLINE PubMed Central
e22.
Cousijn J, Vingerhoets WAM, Koenders L, et al.: Relationship between working-memory network function and substance use: a 3-year longitudinal fMRI study in heavy cannabis users and controls. Addict Biol 2013; 19: 282–93 CrossRef MEDLINE
e23.
Zalesky A, Solowij N, Yücel M, et al.: Effect of long-term cannabis use on axonal fibre connectivity. Brain 2012; 135: 2245–55 CrossRef MEDLINE
e24.
Lee MH, Hancox RJ: Effects of smoking cannabis on lung function. Expert Rev Respir Med 2011; 5: 537–46 CrossRef MEDLINE
e25.
Hancox RJ, Poulton R, Ely M, et al.: Effects of cannabis on lung function: a population-based cohort study. Eur Respir J 2010; 35: 42–7 CrossRef MEDLINE PubMed Central
e26.
Owen KP, Sutter ME, Albertson TE: Marijuana: respiratory tract effects. Clin Rev Allergy Immunol 2014; 46: 65–81 CrossRef MEDLINE
e27.
Tessmer A, Berlin N, Sussman G, Leader N, Chung EC, Beezhold D: Hypersensitivity reactions to marijuana. Ann Allergy Asthma Immunol 2012; 108: 282–4 CrossRef MEDLINE
e28.
Herkenham M, Lynn AB, Little MD, et al.: Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87: 1932–6 CrossRef MEDLINE PubMed Central
e29.
Joshi M, Joshi A, Bartter T: Marijuana and lung diseases. Curr Opin Pulm Med 2014; 20: 173–9 CrossRef MEDLINE
e30.
Reid PT, Macleod J, Robertson JR: Cannabis and the lung. J R Coll Physicians Edinb 2010; 40: 328–3 CrossRef MEDLINE
e31.
Hezode C, Roudot-Thoraval F, Nguyen S, et al.: Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005; 42: 63–71 CrossRef MEDLINE
e32.
Galli JA, Sawaya RA, Friedenberg FK: Cannabinoid hyperemesis syndrome. Curr Drug Abuse Rev 2011; 4: 241–9 CrossRef
e33.
Gessford AK, John M, Nicholson B, Trout R: Marijuana induced hyperemesis: a case report. W V Med J 2012; 108: 20–2 MEDLINE
e34.
Fisher BA, Ghuran A, Vadamalai V, Antonios TF: Cardiovascular complications induced by cannabis smoking: a case report and review of the literature. Emerg Med J 2005; 22: 679–80 CrossRefMEDLINE PubMed Central
e35.
Reece AS: Chronic toxicology of cannabis. Clin Toxicol (Phila) 2009; 47: 517–24 CrossRef MEDLINE
e36.
Bachs L, Morland H: Acute cardiovascular fatalities following cannabis use. Forensic Sci Int 2001; 124: 200–3 CrossRef
e37.
Mateo I, Infante J, Gomez Beldarrain M, Garcia-Monco JC: Cannabis and cerebrovascular disease. Neurologia 2006; 21: 204–8 MEDLINE
e38.
Mukamal KJ, Maclure M, Muller JE, Mittleman MA: An exploratory prospective study of marijuana use and mortality following acute myocardial infarction. Am Heart J 2008; 155: 465–70 CrossRef MEDLINE PubMed Central
e39.
Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE: Triggering myocardial infarction by marijuana. Circulation 2001; 103: 2805–9 CrossRef
e40.
Muniyappa R, Sable S, Ouwerkerk R, et al.: Metabolic effects of chronic cannabis smoking. Diabetes Care 2013; 36: 2415–22 CrossRef MEDLINE PubMed Central
e41.
Rubio F, Quintero S, Hernandez A, et al.: Flumazenil for coma reversal in children after cannabis. Lancet 1993; 341: 1028–9 CrossRef
e42.
Hayatbakhsh MR, Flenady VJ, Gibbons KS, et al.: Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res 2012; 71: 215–9 CrossRef MEDLINE
e43.
Gray KA, Day NL, Leech S, Richardson GA: Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol Teratol 2005; 27: 439–48 CrossRef MEDLINE
e44.
Gray TR, Eiden RD, Leonard KE, Connors GJ, Shisler S, Huestis MA: Identifying prenatal cannabis exposure and effects of concurrent tobacco exposure on neonatal growth. Clin Chem 2010; 56: 1442–50 CrossRefMEDLINE PubMed Central
e45.
Feng BJ, Khyatti M, Ben-Ayoub W, et al.: Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa. Br J Cancer 2009; 101: 1207–12 CrossRef MEDLINE PubMed Central
e46.
Berthiller J, Straif K, Boniol M, et al.: Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb. J Thorac Oncol 2008; 3: 1398–403 CrossRef MEDLINE
e47.
Aldington S, Harwood M, Cox B, et al.: Cannabis use and risk of lung cancer: a case-control study. Eur Respir J 2008; 31: 280–6 CrossRef MEDLINE PubMed Central
e48.
Aldington S, Harwood M, Cox B, et al.: Cannabis use and cancer of the head and neck: case-control study. Otolaryngol Head Neck Surg 2008; 138: 374–80 CrossRef MEDLINE PubMed Central
e49.
Kessler RC, Berglund P, Chiu WT, et al.: The US National Comorbidity Survey Replication (NCS-R): design and field procedures. Int J Methods Psychiatr Res 2004; 13: 69–92 CrossRef CrossRef MEDLINE
e50.
Lai H, Sitharthan T: Exploration of the comorbidity of cannabis use disorders and mental health disorders among inpatients presenting to all hospitals in New South Wales, Australia. Am J Drug Alcohol Abuse 2012; 38: 567 CrossRef MEDLINE
e51.
Kvitland LR, Melle I, Aminoff SR, Lagerberg TV, Andreassen OA, Ringen PA: Cannabis use in first-treatment bipolar I disorder: relations to clinical characteristics. Early Interv Psychiatry 2014 [Epub ahead of print] CrossRef MEDLINE
e52.
Silberberg C, Castle D, Koethe D: Cannabis, cannabinoids, and bipolar disorder. In: Castle D, Murray R, D’Souza D (eds.): Marijuana and madness. 2nd edition. Cambridge University Press. New York 2012; 129–36.
e53.
Henquet C, Krabbendam L, de Graaf R, ten Have M, van Os J: Cannabis use and expression of mania in the general population. J Affect Disord 2006; 95: 103 CrossRef MEDLINE
e54.
Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Allebeck P: Cannabis use and depression: A longitudinal study of a national cohort of Swedish conscripts. BMC Psychiatry 2012; 12: 112 CrossRef MEDLINE MEDLINE
e55.
Pedersen W: Does cannabis use lead to depression and suicidal behaviours? A population-based longitudinal study. Acta Psychiatr Scand 2008; 118: 395–403 CrossRef MEDLINE
e56.
Fergusson D, Horwood L: Early onset cannabis use and psychosocial adjustment in young adults. Addiction 1997; 92: 279 CrossRef
e57.
Patton G, Harris J, Schwartz M, Bowes G: Adolescent suicidal behaviors: A population-based study of risk. Psychol Med 1997; 27: 715 CrossRef
e58.
Watzke AB, Schmidt CO, Zimmermann J, et al.: Personality disorders in a clinical sample of cannabis dependent young adults. Fortschr Neurol Psychiatr 2008; 76: 600–5 CrossRef MEDLINE
e59.
Lev-Ran S, Le FB, McKenzie K, George TP, Rehm J: Bipolar disorder and co-occurring cannabis use disorders: Characteristics, co-morbidities and clinical correlates. Psychiatry Res 2013; 209: 459–65 CrossRef MEDLINE
e60.
Degenhardt L, Coffey C, Romaniuk H, et al.: The persistence of the association between adolescent cannabis use and common mental disorders into young adulthood. Addiction 2013; 108: 124–33 CrossRef MEDLINE
e61.
Stinson FS, Ruan WJ, Pickering R, Grant BF: Cannabis use disorders in the USA: prevalence, correlates and co-morbidity. Psychol Med 2006; 36: 1447–60 CrossRef MEDLINE
e62.
Galvez-Buccollini JA, Proal AC, Tomaselli V, et al.: Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis. Schizophr Res 2012; 139: 157–60 CrossRef MEDLINE PubMed Central
e63.
Giovanni M, Giuseppe DI, Gianna S, Domenico DB, Luisa DR, Massimo DG: Cannabis use and psychosis: theme introduction. Curr Pharm Des 2012; 18: 4991–8 CrossRef
e64.
Schafer G, Feilding A, Morgan CG, Agathangelou M, Freeman TP, Valerie Curran H: Investigating the interaction between schizotypy, divergent thinking, and cannabis use. Conscious Cogn 2012; 21: 292–8 CrossRef MEDLINE PubMed Central
e65.
Degenhardt L, Dierker L, Chiu WT, et al.: Evaluating the drug use „gateway“ theory using cross-national data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys. Drug Alcohol Depend 2010; 108: 84–97 CrossRef MEDLINE PubMed Central
e66.
van Gundy K, Rebellon CJ: A Life-course perspective on the “gateway hypothesis“. J Health Soc Behav 2010; 51: 244–59 CrossRef MEDLINE
e67.
Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA: Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Ab 2013; 40: 23–30 MEDLINE
e68.
Passie T, Emrich HM, Karst M, Brandt SD, Halpern JH: Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug Test Anal 2012; 4: 649–59 CrossRef MEDLINE
e69.
Greer GR, Grob, CS, Halberstadt: PTSD symptom reports of patients evaluated for the new mexico medical cannabis program. Journal of Psychoactive Drugs 2014; 46: 73–7 CrossRef MEDLINE
e70.
Gourlay D: Addiction and pain medicine. Pain Res Manag 2005; 10 Suppl A: 38A–43A.
e71.
Nazeer A, Calles JL Jr: Schizophrenia in children and adolescents. In: Greydanus DE, Calles JL Jr, Patel DR, Nazeer A, Merrick J (eds.): Clinical aspects of psychopharmacology in childhood and adolescence. New York: Nova Science 2011; 152.
e72.
Semple DM, McIntosh AM, Lawrie SM: Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 2005; 19: 187–94 CrossRef
e73.
Fergusson DM, Horwood LJ, Ridder EM: Tests of causal linkages between cannabis use and psychotic symptoms. Addiction 2005; 100: 354–66 CrossRef MEDLINE
e74.
Bender K, Tripodi S, Sarteschi C, Vaughn M: A meta-analysis of interventions to reduce adolescent cannabis use. Res Soc Work Pract 2011; 21: 153–64 CrossRef
e75.
Denis C, Lavie E, Fatséas M, Auriacombe M: Psychotherapeutic interventions for cannabis abuse and/or dependence in outpatient settings. Cochrane Database Syst Rev 2006; (3): CD005336. Review. Update in: Cochrane Database Syst Rev 2013; 6: CD005336 MEDLINE
e76.
Dutra L, Stathopoulou G, Basden SL, et al.: A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008; 165: 179–87 CrossRef MEDLINE
e77.
Budney AJ, Moore BA, Rocha HL, Higgins ST: Clinical trial of abstinence-based vouchers and cognitive-behavioral therapy for cannabis dependence. J Consult Clin Psychol 2006; 74: 307–16 CrossRef
e78.
Budney AJ, Roffman R, Stephens RS, Walker D: Marijuana dependence and its treatment. Addict Sci Clin Pract 2007; 4: 4–16 CrossRef
e79.
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 CrossRef MEDLINE
e80.
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 CrossRef MEDLINE
e81.
Kadden RM, Litt MD, Kabela-Cormier E, Petry NM: Abstinence rates following behavioral treatments for marijuana dependence. Addict Behav 2007; 32: 1220–36 CrossRef MEDLINE PubMed Central
e82.
Tait RJ, Christensen H: Internet-based interventions for young people with problematic substance use: a systematic review. Med J Aust 2010; 192: 15 MEDLINE
e83.
Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV: Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 2011; 116: 142–50 CrossRef MEDLINE MEDLINE
e84.
Allsop DJ, Copeland J, Lintzeris N: Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry 2014; 71: 281–91 CrossRef MEDLINE
e85.
Benyamina A, Lecacheux M, Blecha L, Reynaud M, Lukasiewcz M: Pharmacotherapy and psychotherapy in cannabis withdrawal and dependence. Expert Rev Neurother 2008; 8: 479–91 CrossRef MEDLINE
Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health, University of Heidelberg: Dr. Hoch
Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Teaching Hospital of the University of Duisburg/Essen: Prof. Bonnet
German Center for Addiction Research in Childhood and Adolescence (DZSKJ), University Hospital Hamburg-Eppendorf: Prof. Thomasius, Dr. Ganzer
Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Göttingen and DFG Research Center and Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) of the University Medical Center Göttingen: Prof. Havemann-Reinecke
Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Kreiskrankenhaus Prignitz, Perleberg; Department of Psychiatry, Psychotherapy, and Psychosomatic Medicine, Martin-Luther-University Halle-Wittenberg, Halle (Saale): Prof. Preuss
Acute cannabinoid intoxication
Acute cannabinoid intoxication
Box
Acute cannabinoid intoxication
Key messages
Somatic consequences of non-medicinal cannabis use
Somatic consequences of non-medicinal cannabis use
Table
Somatic consequences of non-medicinal cannabis use
Literature survey
Literature survey
eTable 1
Literature survey
idence level according to Oxford Centre for Evidence-based Medicine (CEBM)
idence level according to Oxford Centre for Evidence-based Medicine (CEBM)
eTable 2
idence level according to Oxford Centre for Evidence-based Medicine (CEBM)
1.Grotenhermen F, Müller-Vahl K: The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 2012; 109: 495–501 VOLLTEXT
2.United Nations Office on Drugs and Crime: World Drug Report 2014 (United Nations publication, Sales No. E.14.XI.7).
3.Pabst A, Kraus L, Gomes de Matos E, Piontek D: Substanzkonsum und substanzbezogene Störungen in Deutschland im Jahr 2012. Sucht 2013; 59: 321–31 CrossRef
4.Europäische Beobachtungsstelle für Drogen und Drogensucht: Drogenangebot in Europa (EMCDDA). In: Europäischer Drogenbericht 2014: Trends und Entwicklungen. Luxemburg: Amt für Veröffentlichungen der Europäischen Union 2014.
5.Niesink R, van Laar MW: Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry 2013; 4: 130 CrossRef MEDLINE PubMed Central
6.OCEBM Levels of Evidence Working Group: The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. www.cebm.net (last accessed on 16 December 2014).
7.Bonnet U, Scherbaum N: Cannabisbezogene Störungen. Teil II: Psychiatrische und somatische Folgestörungen und Komorbiditäten. Fortschr Neurol Psychiat 2010; 78: 1–11.
8.Crippa JA, Derenusson GN, Chagas MH, et al.: Pharmacological interventions in the treatment of the acute effects of cannabis: a systematic review of literature. Harm Reduct J 2012; 9: 7 CrossRef MEDLINE PubMed Central
9.Hall W, Degenhardt L: Adverse health effects of non-medical cannabis use. Lancet 2009; 374: 1383–91 CrossRef
10.Bonnet U, Specka M, Stratmann U, Ochwadt R, Scherbaum N: Abstinence phenomena of chronic cannabis-addicts prospectively monitored during controlled inpatient detoxification: Cannabis withdrawal syndrome and its correlation with delta-9-tetrahydrocannabinol and -metabolites in serum. Drug Alcohol Depend 2014; 143: 189–97 CrossRef MEDLINE
11.Preuss UW, Watzke AB, Zimmermann J, Wong JW, Schmidt CO: Cannabis withdrawal severity and short-term course among cannabis-dependent adolescent and young adult inpatients. Drug Alcohol Depend 2010; 106: 133–41 CrossRef MEDLINE
12.Karila L, Roux P, Rolland B: Acute and long-term effects of cannabis use: A Review. Curr Pharm 2014; 20: 4112–8 CrossRef
13.Grant I, Gonzalez R, Carey CL, Natarajan L, Wolfson T: Non-acute (residual) neurocognitive effects of cannabis use: a meta-analytic study. J Int Neuropsychol Soc 2003; 9: 679–89 CrossRef MEDLINE
14.Schreiner AM, Dunn ME: Residual effects of cannabis use on neurocognitive performance after prolonged abstinence: a meta-analysis. Exp Clin Psychopharmacol 2012; 20: 420–29 CrossRef MEDLINE
15.Horwood L, Fergusson D, Hayatbakhsh M, et al.: Cannabis use and educational achievement: Findings from three Australasian cohort studies. Drug and Alcohol Depend 2010; 110: 247 CrossRef MEDLINE
16.Rawal SY, Tatakis DN, Tipton DA: Periodontal and oral manifestations of marijuana use. J Tenn Dent Assoc 2012; 92: 26–31 MEDLINE
17.Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA: Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med 2007; 167: 221–8 CrossRef MEDLINE PubMed Central
18.Volkow ND, Baler RD, Compton WM, Weiss SRB: Adverse health effects of marijuana use. N Engl J Med 2014; 370: 23 CrossRef MEDLINE
19.Pratap B, Korniyenko A: Toxic effects of marijuana on the cardiovascular system. Cardiovasc Toxicol 2012; 12: 143–8 CrossRef MEDLINE
20.Jones RT: Cardiovascular system effects of marijuana. J Clin Pharmacol 2002; 42: 58–63 CrossRef
21.Sidney S, Beck JE, Tekawa IS, Quesenberry CP, Friedman GD: Marijuana use and mortality. Am J Public Health 1997; 87: 585–90 CrossRef
22.Singh NN, Pan Y, Muengtaweeponsa S, Geller TJ, Cruz-Flores S: Cannabis-related stroke: case series and review of literature. J Stroke Cerebrovasc Dis 2012; 21: 555–60 CrossRef MEDLINE
23.Tennstedt D, Saint-Remy A: Cannabis and skin diseases: Eur J Dermatol 2011; 21: 5–11 MEDLINE
24.Wu CS, Jew CP, Lu HC: Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain. Future Neurol 2011; 6: 459–80 CrossRef
25.Bari M, Battista N, Pirazzi V, Maccarrone M: The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci 2011; 16: 498–516 CrossRef
26.Tanasescu R, Constantinescu CS: Cannabinoids and the immune system: an overview. Immunobiology 2010; 215: 588–97 CrossRef MEDLINE
27.Gibbs M, Winsper C, Marwaha S, Gilbert E, Broome M, Singh SP: Cannabis use and mania symptoms: A systematic review and meta-analysis. J Affect Disord 2014; 23: 39–47 MEDLINE
28.Strakowski SM, DelBello MP, Fleck DE, et al.: Effects of co-occurring cannabis use disorders on the course of bipolar disorder after a first hospitalization for mania. Arch Gen Psychiatry 2007; 64: 57–64 CrossRef MEDLINE
29.Lev-Ran S, Roerecke M, Le Foll B, George TP, McKenzie K, Rehm J: The association between cannabis use and depression: a systematic review and meta-analysis of longitudinal studies. Psychol Med 2014; 44: 797–810 CrossRef MEDLINE
30.Moore TH, Zammit S, Lingford-Hughes A, et al.: Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007; 370: 319–28 CrossRef
31.Hall W, Degenhardt L: The adverse health effects of chronic cannabis use. Drug Test Anal 2014; 6: 39–45 CrossRef MEDLINE
32.Horwood L, Fergusson D, Coffey D, et al.: Cannabis and depression: An integrative data analysis of four Australasian cohorts. Drug Alcohol Depend 2012; 126: 369 CrossRef MEDLINE
33.Petersen KU, Thomasius R (eds.): Auswirkungen von Cannabiskonsum und -missbrauch. Lengerich, Deutschland/Rockledge, USA: Dustri, Pabst Science Publishers 2007; 79–95.
34.Baker AL, Hides L, Lubman DI: Treatment of cannabis use among people with psychotic or depressive disorders: a systematic review. J Clin Psychiatry 2010; 71: 247–54 CrossRef MEDLINE
35.Radhakrishnan R, Wilkinson ST, D’Souza DC: Gone to pot—a review of the association between cannabis and psychosis. Front Psychiatry 2014; 5: 54 CrossRef MEDLINE PubMed Central
36.Brzozka M, Falkai P, Havemann-Reinecke U: Für Schizophrenie braucht man Drei. Suchtmed 2009; 11: 98–110.
37.Brzozka M, Fischer A, Falkai P, Havemann-Reinecke U: Acute treatment with cannabinoid receptor agonist WIN55212,2 improves prepulse inhibition in psychosocially stressed mice. Behav Brain Res 2011; 218: 280–7 CrossRef MEDLINE
38.Bossong MG, Niesink RJ: Adolescent brain maturation, the endogenous cannabinoid system, and the neurobiology of cannabis-induced schizophrenia. Prog Neurobiol 2010; 92: 370–85. CrossRef MEDLINE
39.Bonnet U, Harries-Hedder K, Leweke FM, Schneider U, Tossmann P: AWMF-Leitlinie: Cannabis-bezogene Störungen. Fortschr Neurol Psychiatrie 2004; 72: 318–29 CrossRef MEDLINE
40.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 CrossRef MEDLINE
e1.Cascini F, Aiello C, Di Tanna G: Increasing delta-9-tetrahydrocannabinol (Delta-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev 2012; 5: 32–40 CrossRef
e2.Atakan Z: Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharmacol 2012; 2: 241–54 CrossRef MEDLINE PubMed Central
e3.Englund A, Morrison PD, Nottage J, et al.: Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 2013; 27: 19–27 CrossRef MEDLINE
e4.Swift W, Wong A, Li KM, Arnold JC, McGregor IS: Analysis of cannabis seizures in NSW, Australia: cannabis potency and cannabinoid profile. PLoS One 2013; 24: 8.
e5.United States Department of Justice, Drug enforcement administration: National drug threat assessment summary 2013; 12. www.dea.gov (last accessed on 3 March 2015).
e6.Thomasius R, Weymann N, Stolle M, Petersen KU: Cannabiskonsum und -missbrauch bei Jugendlichen und jungen Erwachsenen. Auswirkungen, Komorbidität und therapeutische Hilfen. Psychotherapeut 2009; 54: 170–8 CrossRef
e7.Musshoff F, Madea B: Review of biologic matrices (urine, blood, hair) as indicators of recent or ongoing cannabis use. Ther Drug Monit 2006; 28: 155–63 CrossRefMEDLINE
e8.American Psychiatric Association (APA): Diagnostic and statistical manual of mental disorders (5th edition). Arlington, VA: American Psychiatric Publishing 2013.
e9.World Health Organisation (WHO): ICD-10 Classifications of mental and behavioural disorder: Clinical descriptions and diagnostic guidelines. Geneva: World Health Organisation 1992.
e10.Budney AJ, Hughes JR, Moore BA, Vandrey R: Review of the validity and significance of cannabis withdrawal syndrome.
Am J Psychiatry 2004; 161: 1967–77 CrossRef MEDLINE
e11.Budney AJ, Hughes JR: The cannabis withdrawal syndrome.
Curr Opin Psychiatry 2006; 19: 233–8 CrossRef MEDLINE
e12.Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, et al.: Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend 2011; 115: 120–30 CrossRef MEDLINE PubMed Central
e13.Anthony JC: The epidemiology of cannabis dependence. In: Roffman RA, Stephens RS (eds.): Cannabis dependence: Its nature, consequences and treatment Cambridge, UK: Cambridge University Press 2006; 58–105.
e14.Hall WD, Pacula RL: Cannabis use and dependence: Public health and public policy. Cambridge, UK: Cambridge University Press 2003.
e15.Tennant FS, Groesbeck CJ: Psychiatric effects of hashish. Arch Gen Psychiatry 1972; 27: 133–6 CrossRef
e16.Hall WD, Solowij N: Adverse effects of cannabis. Lancet 1998; 352: 1611–16 CrossRef
e17.Grover S, Basu D: Cannabis and psychopathology: update 2004. Indian J Psychiatry 2004; 46: 299–309 MEDLINE PubMed Central
e18.Medina KL, Hanson KL, Schweinsburg AD, et al.: Neuropsychological functioning in adolescent marijuana users: Subtle deficits detectable after a month of abstinence. J Int Neuropsychol Soc 2007; 13: 807–20 CrossRef MEDLINE PubMed Central
e19.Solowij N, Jones KA, Rozman ME, et al.: Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology 2011; 216: 131–44 CrossRef MEDLINE
e20.Meier MH, Caspi A, Abler A, et al.: Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci 2012; 109: 15970–1 CrossRef MEDLINE PubMed Central
e21.Lisdahl KM, Gilbart ER, Wright NE, Shollenbarger S: Dare to delay? The impacts of adolescent alcohol and marijuana use onset on cognition, brain structure, and function. Front Psychiatry 2013; 4: 53 MEDLINE PubMed Central
e22.Cousijn J, Vingerhoets WAM, Koenders L, et al.: Relationship between working-memory network function and substance use: a 3-year longitudinal fMRI study in heavy cannabis users and controls. Addict Biol 2013; 19: 282–93 CrossRef MEDLINE
e23.Zalesky A, Solowij N, Yücel M, et al.: Effect of long-term cannabis use on axonal fibre connectivity. Brain 2012; 135: 2245–55 CrossRef MEDLINE
e24.Lee MH, Hancox RJ: Effects of smoking cannabis on lung function. Expert Rev Respir Med 2011; 5: 537–46 CrossRef MEDLINE
e25.Hancox RJ, Poulton R, Ely M, et al.: Effects of cannabis on lung function: a population-based cohort study. Eur Respir J 2010; 35: 42–7 CrossRef MEDLINE PubMed Central
e26.Owen KP, Sutter ME, Albertson TE: Marijuana: respiratory tract effects. Clin Rev Allergy Immunol 2014; 46: 65–81 CrossRef MEDLINE
e27.Tessmer A, Berlin N, Sussman G, Leader N, Chung EC, Beezhold D: Hypersensitivity reactions to marijuana. Ann Allergy Asthma Immunol 2012; 108: 282–4 CrossRef MEDLINE
e28.Herkenham M, Lynn AB, Little MD, et al.: Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87: 1932–6 CrossRef MEDLINE PubMed Central
e29.Joshi M, Joshi A, Bartter T: Marijuana and lung diseases. Curr Opin Pulm Med 2014; 20: 173–9 CrossRef MEDLINE
e30.Reid PT, Macleod J, Robertson JR: Cannabis and the lung. J R Coll Physicians Edinb 2010; 40: 328–3 CrossRef MEDLINE
e31.Hezode C, Roudot-Thoraval F, Nguyen S, et al.: Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology 2005; 42: 63–71 CrossRef MEDLINE
e32.Galli JA, Sawaya RA, Friedenberg FK: Cannabinoid hyperemesis syndrome. Curr Drug Abuse Rev 2011; 4: 241–9 CrossRef
e33.Gessford AK, John M, Nicholson B, Trout R: Marijuana induced hyperemesis: a case report. W V Med J 2012; 108: 20–2 MEDLINE
e34.Fisher BA, Ghuran A, Vadamalai V, Antonios TF: Cardiovascular complications induced by cannabis smoking: a case report and review of the literature. Emerg Med J 2005; 22: 679–80 CrossRefMEDLINE PubMed Central
e35.Reece AS: Chronic toxicology of cannabis. Clin Toxicol (Phila) 2009; 47: 517–24 CrossRef MEDLINE
e36.Bachs L, Morland H: Acute cardiovascular fatalities following cannabis use. Forensic Sci Int 2001; 124: 200–3 CrossRef
e37.Mateo I, Infante J, Gomez Beldarrain M, Garcia-Monco JC: Cannabis and cerebrovascular disease. Neurologia 2006; 21: 204–8 MEDLINE
e38.Mukamal KJ, Maclure M, Muller JE, Mittleman MA: An exploratory prospective study of marijuana use and mortality following acute myocardial infarction. Am Heart J 2008; 155: 465–70 CrossRef MEDLINE PubMed Central
e39.Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE: Triggering myocardial infarction by marijuana. Circulation 2001; 103: 2805–9 CrossRef
e40.Muniyappa R, Sable S, Ouwerkerk R, et al.: Metabolic effects of chronic cannabis smoking. Diabetes Care 2013; 36: 2415–22 CrossRef MEDLINE PubMed Central
e41.Rubio F, Quintero S, Hernandez A, et al.: Flumazenil for coma reversal in children after cannabis. Lancet 1993; 341: 1028–9 CrossRef
e42.Hayatbakhsh MR, Flenady VJ, Gibbons KS, et al.: Birth outcomes associated with cannabis use before and during pregnancy. Pediatr Res 2012; 71: 215–9 CrossRef MEDLINE
e43.Gray KA, Day NL, Leech S, Richardson GA: Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age. Neurotoxicol Teratol 2005; 27: 439–48 CrossRef MEDLINE
e44.Gray TR, Eiden RD, Leonard KE, Connors GJ, Shisler S, Huestis MA: Identifying prenatal cannabis exposure and effects of concurrent tobacco exposure on neonatal growth. Clin Chem 2010; 56: 1442–50 CrossRefMEDLINE PubMed Central
e45.Feng BJ, Khyatti M, Ben-Ayoub W, et al.: Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa. Br J Cancer 2009; 101: 1207–12 CrossRef MEDLINE PubMed Central
e46.Berthiller J, Straif K, Boniol M, et al.: Cannabis smoking and risk of lung cancer in men: a pooled analysis of three studies in Maghreb. J Thorac Oncol 2008; 3: 1398–403 CrossRef MEDLINE
e47.Aldington S, Harwood M, Cox B, et al.: Cannabis use and risk of lung cancer: a case-control study. Eur Respir J 2008; 31: 280–6 CrossRef MEDLINE PubMed Central
e48.Aldington S, Harwood M, Cox B, et al.: Cannabis use and cancer of the head and neck: case-control study. Otolaryngol Head Neck Surg 2008; 138: 374–80 CrossRef MEDLINE PubMed Central
e49.Kessler RC, Berglund P, Chiu WT, et al.: The US National Comorbidity Survey Replication (NCS-R): design and field procedures. Int J Methods Psychiatr Res 2004; 13: 69–92 CrossRef CrossRef MEDLINE
e50.Lai H, Sitharthan T: Exploration of the comorbidity of cannabis use disorders and mental health disorders among inpatients presenting to all hospitals in New South Wales, Australia. Am J Drug Alcohol Abuse 2012; 38: 567 CrossRef MEDLINE
e51.Kvitland LR, Melle I, Aminoff SR, Lagerberg TV, Andreassen OA, Ringen PA: Cannabis use in first-treatment bipolar I disorder: relations to clinical characteristics. Early Interv Psychiatry 2014 [Epub ahead of print] CrossRef MEDLINE
e52.Silberberg C, Castle D, Koethe D: Cannabis, cannabinoids, and bipolar disorder. In: Castle D, Murray R, D’Souza D (eds.): Marijuana and madness. 2nd edition. Cambridge University Press. New York 2012; 129–36.
e53.Henquet C, Krabbendam L, de Graaf R, ten Have M, van Os J: Cannabis use and expression of mania in the general population. J Affect Disord 2006; 95: 103 CrossRef MEDLINE
e54.Manrique-Garcia E, Zammit S, Dalman C, Hemmingsson T, Allebeck P: Cannabis use and depression: A longitudinal study of a national cohort of Swedish conscripts. BMC Psychiatry 2012; 12: 112 CrossRef MEDLINE MEDLINE
e55.Pedersen W: Does cannabis use lead to depression and suicidal behaviours? A population-based longitudinal study. Acta Psychiatr Scand 2008; 118: 395–403 CrossRef MEDLINE
e56.Fergusson D, Horwood L: Early onset cannabis use and psychosocial adjustment in young adults. Addiction 1997; 92: 279 CrossRef
e57.Patton G, Harris J, Schwartz M, Bowes G: Adolescent suicidal behaviors: A population-based study of risk. Psychol Med 1997; 27: 715 CrossRef
e58.Watzke AB, Schmidt CO, Zimmermann J, et al.: Personality disorders in a clinical sample of cannabis dependent young adults. Fortschr Neurol Psychiatr 2008; 76: 600–5 CrossRef MEDLINE
e59.Lev-Ran S, Le FB, McKenzie K, George TP, Rehm J: Bipolar disorder and co-occurring cannabis use disorders: Characteristics, co-morbidities and clinical correlates. Psychiatry Res 2013; 209: 459–65 CrossRef MEDLINE
e60.Degenhardt L, Coffey C, Romaniuk H, et al.: The persistence of the association between adolescent cannabis use and common mental disorders into young adulthood. Addiction 2013; 108: 124–33 CrossRef MEDLINE
e61.Stinson FS, Ruan WJ, Pickering R, Grant BF: Cannabis use disorders in the USA: prevalence, correlates and co-morbidity. Psychol Med 2006; 36: 1447–60 CrossRef MEDLINE
e62.Galvez-Buccollini JA, Proal AC, Tomaselli V, et al.: Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis. Schizophr Res 2012; 139: 157–60 CrossRef MEDLINE PubMed Central
e63.Giovanni M, Giuseppe DI, Gianna S, Domenico DB, Luisa DR, Massimo DG: Cannabis use and psychosis: theme introduction. Curr Pharm Des 2012; 18: 4991–8 CrossRef
e64.Schafer G, Feilding A, Morgan CG, Agathangelou M, Freeman TP, Valerie Curran H: Investigating the interaction between schizotypy, divergent thinking, and cannabis use. Conscious Cogn 2012; 21: 292–8 CrossRef MEDLINE PubMed Central
e65.Degenhardt L, Dierker L, Chiu WT, et al.: Evaluating the drug use „gateway“ theory using cross-national data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys. Drug Alcohol Depend 2010; 108: 84–97 CrossRef MEDLINE PubMed Central
e66.van Gundy K, Rebellon CJ: A Life-course perspective on the “gateway hypothesis“. J Health Soc Behav 2010; 51: 244–59 CrossRef MEDLINE
e67.Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA: Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Ab 2013; 40: 23–30 MEDLINE
e68.Passie T, Emrich HM, Karst M, Brandt SD, Halpern JH: Mitigation of post-traumatic stress symptoms by Cannabis resin: a review of the clinical and neurobiological evidence. Drug Test Anal 2012; 4: 649–59 CrossRef MEDLINE
e69.Greer GR, Grob, CS, Halberstadt: PTSD symptom reports of patients evaluated for the new mexico medical cannabis program. Journal of Psychoactive Drugs 2014; 46: 73–7 CrossRef MEDLINE
e70.Gourlay D: Addiction and pain medicine. Pain Res Manag 2005; 10 Suppl A: 38A–43A.
e71.Nazeer A, Calles JL Jr: Schizophrenia in children and adolescents. In: Greydanus DE, Calles JL Jr, Patel DR, Nazeer A, Merrick J (eds.): Clinical aspects of psychopharmacology in childhood and adolescence. New York: Nova Science 2011; 152.
e72.Semple DM, McIntosh AM, Lawrie SM: Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 2005; 19: 187–94 CrossRef
e73.Fergusson DM, Horwood LJ, Ridder EM: Tests of causal linkages between cannabis use and psychotic symptoms. Addiction 2005; 100: 354–66 CrossRef MEDLINE
e74.Bender K, Tripodi S, Sarteschi C, Vaughn M: A meta-analysis of interventions to reduce adolescent cannabis use. Res Soc Work Pract 2011; 21: 153–64 CrossRef
e75.Denis C, Lavie E, Fatséas M, Auriacombe M: Psychotherapeutic interventions for cannabis abuse and/or dependence in outpatient settings. Cochrane Database Syst Rev 2006; (3): CD005336. Review. Update in: Cochrane Database Syst Rev 2013; 6: CD005336 MEDLINE
e76.Dutra L, Stathopoulou G, Basden SL, et al.: A meta-analytic review of psychosocial interventions for substance use disorders. Am J Psychiatry 2008; 165: 179–87 CrossRef MEDLINE
e77.Budney AJ, Moore BA, Rocha HL, Higgins ST: Clinical trial of abstinence-based vouchers and cognitive-behavioral therapy for cannabis dependence. J Consult Clin Psychol 2006; 74: 307–16 CrossRef
e78.Budney AJ, Roffman R, Stephens RS, Walker D: Marijuana dependence and its treatment. Addict Sci Clin Pract 2007; 4: 4–16 CrossRef
e79.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 CrossRef MEDLINE
e80.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 CrossRef MEDLINE
e81.Kadden RM, Litt MD, Kabela-Cormier E, Petry NM: Abstinence rates following behavioral treatments for marijuana dependence. Addict Behav 2007; 32: 1220–36 CrossRef MEDLINE PubMed Central
e82.Tait RJ, Christensen H: Internet-based interventions for young people with problematic substance use: a systematic review. Med J Aust 2010; 192: 15 MEDLINE
e83.Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV: Dronabinol for the treatment of cannabis dependence: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend 2011; 116: 142–50 CrossRef MEDLINE MEDLINE
e84.Allsop DJ, Copeland J, Lintzeris N: Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry 2014; 71: 281–91 CrossRef MEDLINE
e85.Benyamina A, Lecacheux M, Blecha L, Reynaud M, Lukasiewcz M: Pharmacotherapy and psychotherapy in cannabis withdrawal and dependence. Expert Rev Neurother 2008; 8: 479–91 CrossRef MEDLINE