How effective and safe is medical cannabis as a treatment of mental disorder ? A systematic review
HOCH E., NIEMANN D., von KELLER R., SCHNEIDER M., FRIEMEL C.M., PREUSS U.W., HASAN A., POGARELL O.
European Archives of Psychiatry and Clinical Neuroscience, 2019
We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006—August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.
Keywords : Mental disorders · Cannabis · Cannabinoids · THC · CBD · Medical cannabis · Treatment
Mental disorders are among the leading causes of health impairments [25, 77, 89, 91] involving significant changes in thinking, perception, emotion, behavior and relationships . They are considered as strongly restricting conditions, leading to distress for both patients and their families . The etiology of mental disorders is complex, including genetic, neurobiological, psychological and environmental factors across the lifespan .
Recently, the efficacy and safety of cannabis-based medicines for treatment or alleviation of mental disorders has been tested more systematically. Cannabis is a flowering plant with different species producing major compounds such as the psychoactive component delta-9-tetrahydrocannabinol
(THC) and cannabidiol (CBD), which have partially antagonistic effects [9, 52, 69]. THC can change mood, sensation, perception, tension, appetite, and pain; CBD has shown anxiolytic, antipsychotic, neuroprotective, anti-inflammatory and antiemetic properties [8, 34, 54, 57]. The medical use of herbal cannabinoids declined early in the twentieth century due to emerging evidence of their health risks and addictive potential . However, growing interest in the substance as medicine was renewed in the 1990s with the discovery of cannabinoid receptors 1 and 2 (CB1 and CB2, respectively), endogenous ligands (endocannabinoids; N-arachidonoylethanolamine (anandamide/AEA) and 2-arachidonoyl-glycerol (2-AG)), and enzymes as part of an endogenous cannabinoid system (eCB) in the brain [49, 53]. The eCB is regarded as a fundamental regulatory apparatus connected with nearly every physiological and pathological aspects of mammalian biology . The correct interplay between all these endocannabinoid system elements plays an important role in central nervous system (CNS) development, synaptic plasticity, motor control, memory, cognition, stress, emotional responses, reward and motivated behavior, appetite, pain, development and homeostasis [58, 68, 72]. Outside the brain, the eCB system is one of the crucial modulators of the autonomic nervous system, the immune system, the endocrine network, the gastrointestinal tract, the reproductive system, and in microcirculation . Endocannabinoids are one of the most important systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity . They serve as retrograde signaling messengers in GABAergic and glutamatergic synapses, as well as modulators of postsynaptic transmission, interacting with other neurotransmitters, including dopamine. Endocannabinoids also participate in the modulation of the hypothalamic– pituitary–adrenal (HPA) axis and regulation of stress [30, 75]. Preclinical and clinical data support the involvement of the eCB in the etiopathogenesis of mental disorders
[24, 35, 44, 73]. Especially the CB1 receptor, which is the most abundant and widespread receptor throughout the mammalian brain, has become a target of interest [23, 38]. Reported findings from human brain studies are controversial  since different alterations in gene and/or protein expression of CB1 receptors have been shown to depend on the technical approach used or the brain region studied . Although the picture is complex and not fully understood, the neuromodulatory function of the eCB System could be an interesting target for pharmacotherapeutic interventions in mental disorders [24, 26, 50, 57, 67, 70]. The synthesis of cannabinoid receptor agonists and antagonists, anandamide uptake blockers and inhibitors of endocannabinoid anandamide degradation has further opened up new treatment strategies [26, 72]. On the other hand, cannabis is the most frequently used illegal substance worldwide  and scientific evidence indicates that chronic exposure to cannabinoids may increase
mental health risks, such as impaired cognition, depression, anxiety, psychoses and cannabis dependence in vulnerable persons [27, 32, 63, 86]. On a neurophysiological basis, chronic use of cannabinoids can impair CB1R function; create a loss of eCB-mediated synaptic plasticity in neural circuits, and cause addiction and negative affective states . Based on these cannabis-related controversies, this paper is aimed at systematically screening the scientific literature of randomized-controlled trials (published between 2006 and 2018) to assess the efficacy and safety of cannabis-based medicines as a treatment of mental disorders.
This systematic review followed guidance published by the Centre for Reviews and Dissemination and the Cochrane Collaboration . The study protocol is registered with the Centre for Reviews and Dissemination at the University of York (UK): http://www.crd.york.ac.uk/prosp ero/Displ ayPDF .php?ID=CRD42 01605 3592. This work is part of a large cannabis expertise on potential and risks of cannabinoids  commissioned by the German Ministry of Health.