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Udo Bonnet,1,2 Ulrich W Preuss3,4 1Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, Evangelisches Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg-Essen, Castrop-Rauxel, 2Department of Psychiatry and Psychotherapy, Faculty of Medicine, LVR-Hospital Essen, University of Duisburg-Essen, Essen, 3Vitos-Klinik Psychiatrie und Psychotherapie Herborn, Herborn, 4Martin Luther University Halle-Wittenberg, Halle (Saale), Germany 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: marijuana, humans, neurobiology, treatment, course, detoxification, symptoms