Cannabinoids and their therapeutic applications in mental disorders

Maria Scherma, PhD; Anna Lisa Muntoni, MD; Gernot Riedel, PhD; Walter Fratta, PhD; Paola Fadda, PhD

Dialogues in Clinical Neuroscience, 2020, 22, (3), 271-279.

doi : 10.31887/DCNS.2020.22.3/pfadda

Mental disorders represent a significant public health burden worldwide due to their high prevalence, chronically disabling nature, and substantial impact on quality of life. Despite growing knowledge of the pathological mechanisms that underlie the development of these disorders, a high percentage of patients do not respond to first-line clinical treatments; thus, there is a strong need for alternative therapeutic approaches. During the past half-century, after the identification of the endocannabinoid system and its role in multiple physiological processes, both natural and synthetic cannabinoids have attracted considerable interest as putative medications in pathological conditions such as, but not exclusive to, mental disorders. Here, we provide a summary of cannabinoid effects in support of possible therapeutic applications for major depression, bipolar disorder, anxiety, posttraumatic stress disorder, and schizophrenia. Considering this evidence, highlighted benefits and risks of cannabinoid use in the management of these illnesses require further experimental study.

Keywords : anxiety; cannabinoid; cannabis; depression; mental disorders; pharmacotherapy; psychosis

Introduction

Mental disorders, including mood and anxiety disorders, posttraumatic stress disorder (PTSD), and schizophrenia, represent an important public health problem, affecting about 9.6% to 27.8% of the general population worldwide. The pathophysiology is complex and not yet completely understood, although genetic, biological, and environmental factors are probably critical for both onset and progression of these disorders. Antidepressants, benzodiazepines, and antipsychotic drugs represent the main pharmacotherapy; however, 40% to 60% of patients do not gain total relief from their impairing symptoms with such treatments. Thus, there is a strong need to develop alternative/complementary treatments. There are several lines of evidence suggesting that a promising pharmacotherapy may be based on drugs that target the endocannabinoid system, which in itself appears deregulated in psychiatric patients. This system is recognized as a fundamental modulator of a large variety of physiological processes, including neurodevelopment, emotional states, stress responses, and cognition, so much so that a defect in its signaling might play a role in the pathophysiological underpinnings of mental illnesses.

Cannabis has been used for millennia for therapeutic purposes, and there are several anecdotal reports of its consumption as a form of self-medication for the alleviation of psychiatric symptoms (eg, anxiety, depression, and mania). However, epidemiological studies consistently demonstrated that heavy cannabis use is associated with occurrence of psychiatric outcomes, especially in people at risk for psychosis or mood disorders. Hence, evidence supporting cannabis-based interventions for the treatment of mental disorders is equivocal, mainly due to the use of extracts from the whole plant. Cannabis contains various phytocannabinoids, among which ∆9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents. Both induce their pharmacological effect by interacting with the endocannabinoid system. THC is the main psychoactive ingredient responsible for either psychotic or affective mental health outcomes at higher doses; on the other hand, low doses can attenuate the subjective response to psychosocial stress and act as anxiolytics. In contrast, CBD represents the nonpsychoactive component of the plant that has been suggested to possess antipsychotic, antidepressant, anxiolytic, and procognitive properties. When the effects of THC or CBD were investigated in the management of psychiatric patients, preliminary results suggest that they both may have potential efficacy.

Currently, there are several clinical trials registered on Clin- icalTrials.gov, all aimed at evaluating the potential thera- peutic effects of cannabis and synthetic cannabinoids on mental disorders. Here, we provide a summary evidencing their possible therapeutic efficacy for the treatment of major depression, bipolar disorder, anxiety, PTSD, and schizophrenia. The term “medical cannabis” here refers to the use of cannabis preparations (raw cannabis, magistral preparations, and standardized cannabis preparations) as medical therapy to treat diseases or alleviate symptoms. “Medicinal cannabinoids,” by contrast, refers to medicinal products with marketing authorization: nabilone (synthetic cannabinoid similar to THC), dronabinol (synthetic THC), nabiximols (plant based with approximately equal quantities THC/CBD), and CBD (plant-based).

Major depressive disorder

Over the years, clinical evidence led to the hypothesis of a link between defects in the endocannabinoid system and depression. Specifically, under basal conditions, serum levels of the two primary endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), were found to be reduced in medication-free women diagnosed with major depression, indicating a deficit in peripheral endo- cannabinoid activity.1,2 Furthermore, the decrease in serum levels of 2-AG was strongly correlated with the duration of the depressive episode, whereas serum AEA levels were negatively correlated with anxiety symptoms. On the other hand, moderate exercise prescribed to improve mood states (ie, feelings of depression, total mood disturbance, and state anxiety) increased serum levels of AEA and related fatty acid ethanolamides (ie, oleoylethanolamide) in women with major depression.3 Similarly, 2-AG and AEA serum levels were elevated in patients with major depression treated with electrocon- vulsive therapy relative to baseline.4 In human postmortem studies, cannabinoid receptor type 1 (CB1) density and functionality, as well as CB1 messenger RNA (mRNA) levels, were elevated in the dorsolateral prefrontal cortex of suicide victims with major depression.5-7 These findings probably represent a compensatory upregulation to counteract endocannabinoid tone lowering in the central nervous system. In contrast, Eggan et al8 did not find any change in CB1-receptor mRNA and protein levels in the same brain areas of depressed individuals who committed suicide. However, the fact that the expression of CB1 receptor in the anterior cingulate cortex was decreased in depressed patients treated with serotonin-selective reuptake inhibitors is consistent with the notion of an enhanced receptor density in drug-naive patients suffering from major depressive episodes.9

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