The cannabis withdrawal syndrome: current insights

Abstract

The cannabis withdrawal syndrome (CWS) is a criterion of cannabis use disorders (CUDs) (Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition) and cannabis dependence (International Classification of Diseases [ICD]-10). Several lines of evidence from animal and human studies indicate that cessation from long-term and regular cannabis use precipitates a specific withdrawal syndrome with mainly mood and behavioral symptoms of light to moderate intensity, which can usually be treated in an outpatient setting. Regular cannabis intake is related to a desensitization and downregulation of human brain cannabinoid 1 (CB1) receptors. This starts to reverse within the first 2 days of abstinence and the receptors return to normal functioning within 4 weeks of abstinence, which could constitute a neurobiological time frame for the duration of CWS, not taking into account cellular and synaptic long-term neuroplasticity elicited by long-term cannabis use before cessation, for example, being possibly responsible for cannabis craving. The CWS severity is dependent on the amount of cannabis used pre-cessation, gender, and heritable and several environmental factors. Therefore, naturalistic severity of CWS highly varies. Women reported a stronger CWS than men including physical symptoms, such as nausea and stomach pain. Comorbidity with mental or somatic disorders, severe CUD, and low social functioning may require an inpatient treatment (preferably qualified detox) and post-acute rehabilitation. There are promising results with gabapentin and delta-9-tetrahydrocannabinol analogs in the treatment of CWS. Mirtazapine can be beneficial to treat CWS insomnia. According to small studies, venlafaxine can worsen the CWS, whereas other antidepressants, atomoxetine, lithium, buspirone, and divalproex had no relevant effect. Certainly, further research is required with respect to the impact of the CWS treatment setting on long-term CUD prognosis and with respect to psychopharmacological or behavioral approaches, such as aerobic exercise therapy or psychoeducation, in the treatment of CWS. The up-to-date ICD-11 Beta Draft is recommended to be expanded by physical CWS symptoms, the specification of CWS intensity and duration as well as gender effects.

Keywords: course; detoxification; humans; marijuana; neurobiology; symptoms; treatment.

Figure 1

Courses of overall CWS post-cessation. The CWS usually lasts up to 3 weeks and its average peak severity (burden) is comparable to that of a moderate depression or alcohol withdrawal syndrome or in outpatient settings, similar to that of a tobacco withdrawal syndrome. Data from previous studies.,, Abbreviation: CWS, cannabis withdrawal syndrome.

Figure 2

Mean and standard deviation of the (A) CWS checklist (MWC score according to previous studies24,26,37) and (B) the Clinical Global Impression Scale (CGI-S Score80) during the course of the study. Reduced sample sizes on day 12 (n=35) and day 16 (n=28) due to regular dismissals and missed assessments are indicated by dashed lines. The effect size according to Cohen (Cohen’s d) was 1.1 for the CWS (day 1 to day 16), Cohen’s d ≥0.8 is defined to reflect a strong effect. Vertical imaginary Y-axis: severity scores. Horizontal imaginary X-axis: time course. Note: Reproduced from Drug Alcohol Depend, 143, 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, 189–197. Copyright (2014), with permission from Elsevier. Abbreviations: CWS, cannabis withdrawal syndrome; MWC, Marijuana Withdrawal Checklist.

Figure 3

Mean rating of single symptoms of the MWC (MWC score according to previous studies24,26,37); 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = heavy). Note the delayed occurrence of strange dreams. Vertical imaginary Y-axis: severity scores. Horizontal imaginary X-axis: time course. Note: Reproduced from Drug Alcohol Depend, 143, 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, 189–197. Copyright (2014), with permission from Elsevier.

Figure 4

Significant improvement (p<0.001) of the subjective global distress of adult heavy cannabis users during inpatient qualified detoxification as measured by the Symptom Checklist 90, revised version (SCL-90-R). Y-axis: percent of the sample (N=35); X-axis: global distress according to T-values: T<60: normal global distress; T>70: severe global distress; T1 = admission day and T16 = last day (day 16) of the controlled inpatient qualified detoxification treatment. Note: Reproduced from Dtsch Med Wochenschr, 141(2), Bonnet U, Specka M, Scherbaum N, Häufiger Konsum von nichtmedizinischem Cannabis, 126–131. Copyright (2016), with permission from Georg Thieme Verlag.