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.

Long-term aberrations to cerebellar endocannabinoids induced by early-life stress

“…Such baseline sex differences may cause exogenous cannabinoids to differentially affect the brain in males and females. This serves as a potential explanation for the key differences in outcomes of exogenous cannabinoid exposure in animal 61,62 and human [63][64][65] models and perhaps also reflects sex differences in use rates 25,64 and adverse side effects 66,67 in humans. Similarly, understanding regional differences in cannabinoids may help predict directional impacts on behaviors emerging from region-specific neural circuits.…”

Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in <em>Cannabis</em> Users

“…Multiple studies show that CB1R is downregulated during Cannabis tolerance, and the receptor remains downregulated for about 3-4 weeks after cessation of use (D'Souza et al, 2016, Hirvonen et al, 2012, Ginsberg and Woods, 2009, Ceccarini et al, 2015, Dudok et al, 2015, Bonnet and Preuss, 2017.…”

“…According to this hypothesis, acute exposure results in the "munchies", stimulating appetite and energy consumption, and causes hypothermia as metabolic rates decrease. Regular Cannabis use is associated with desensitization and downregulation of CB1R, and CB1R levels remain depressed for 3-4 weeks following cessation of use (Bonnet and Preuss, 2017, D'Souza et al, 2016, Dudok et al, 2015, Ceccarini et al, 2015. Rapid downregulation of CB1R more than offsets the short-term increase in energy stores that follow acute exposures.…”

“…There is abundant evidence that Cannabis use, and/or exposure to THC, results in reduced BMI (Table 1, BMI is reduced in Cannabis users, and should decrease even more when users stop using Cannabis because CB1R remains downregulated for several weeks following chronic Cannabis consumption (Bonnet and Preuss, 2017, D'Souza et al, 2016, Ceccarini et al, 2015, Dudok et al, 2015, Hirvonen et al, 2012. Recently abstinent users would show reduced appetite and increased metabolic rates during this time.…”

“…Omega-3 FAs compete with omega-6 FAs for the enzymes synthesizing AEA and 2-AG from omega-6 FAs, and omega-3 supplements thereby reduce the synthesis of AEA and 2-AG and reduce stimulation of CB1R (Bisogno and Maccarrone, 2014, Freitas et al, 2017, Berge et al, 2013, Wall et al, 2010. Cannabis causes downregulation of CB1R (Bonnet and Preuss, 2017, D'Souza et al, 2016, Dudok et al, 2015, Ceccarini et al, 2015, reducing the sensitivity to elevated AEA and 2-AG. Thus, the theory predicts that omega-3 FA supplements and Cannabis use should have similar positive health impacts in the context of metabolic dysregulation from a diet with an elevated omega-6/omega-3 ratio.…”