The Potential of Cannabidiol Treatment for Cannabis Users With Recent-Onset Psychosis, Britta Hahn, 2018

The Potential of Cannabidiol Treatment for Cannabis Users With Recent-Onset Psychosis

Britta Hahn

Schizophrenia Bulletin, 2018, vol. 44, no. 1, 46–53


A major factor associated with poor prognostic outcome after a first psychotic break is cannabis misuse, which is prevalent in schizophrenia and particularly common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population. Cannabidiol (CBD) is a phytocannabinoid found in cannabis, although at low concentrations in modern-day strains. CBD has a broad pharmacological profile, but contrary to Δ9-tetrahydrocannabinol (THC), CBD does not activate CB1 or CB2 receptors and has at most subtle subjective effects. Growing evidence indicates that CBD acts as an antipsychotic and anxiolytic, and several reports suggest neuroprotective effects. Moreover, CBD attenuates THC’s detrimental effects, both acutely and chronically, including
psychotogenic, anxiogenic, and deleterious cognitive effects.

This suggests that CBD may improve the disease trajectory of individuals with early psychosis and comorbid cannabis misuse in particular—a population with currently poor prognostic outcome and no specialized effective intervention.

Keywords : cannabidiol, cannabis, psychosis, THC, first episode, Cannabis Use, Detrimentally Affects Outcome in Individuals With Recent-Onset Psychosis


The prevalence of cannabis misuse is significantly greater in people with schizophrenia (PSZ) than in the general population.1,2 Cannabis use disorders are especially common in younger patients and patients with first-episode psychosis. Estimates of cannabis use at first break range from one to two thirds of affected individuals.3–6 The impact on conversion to psychosis has been studied extensively; frequent use doubles the risk of developing schizophrenia7 and is associated with a younger age at first episode.8 After the first break, estimates of continued use range from just over 50%5,9 to 100% of users.6

Cannabis use after a first psychotic break is a major predictor of bad prognostic outcome. This is of particular significance given that the early clinical trajectory of psychotic disorders is thought to critically influence long-term outcome.10–13 Cannabis use, especially heavy use, is associated with more and earlier psychotic relapses.14 Among users with first-episode psychosis, heavier users tend to
experience more, and more severe, psychotic symptoms and show a poorer illness trajectory with regards to functional outcomes.15 Specifically, cannabis use is associated with more severe symptoms and poorer antipsychotic response in the positive and disorganized dimensions.16,17 Longitudinally, periods of cannabis use are accompanied by a dose-dependent increase in the odds of relapse to psychosis.18

Cannabis use is also associated with poorer medication adherence following a first break,6,19 and, in
part related to that, a lower probability of remission during the following year.6 Effects of cannabis use on cognitive outcome in PSZ are more controversial. Several studies suggest paradoxical positive associations between use history and cognition,20,21 which may however reflect selection bias due to a role of cannabis in precipitating psychosis despite lower biological vulnerability, and the cognitive challenges associated with obtaining an illicit substance.

The acute effects of cannabis, Δ9-tetrahydrocannabinol (THC), or of the THC analog nabilone in nonpsychotic individuals mimic positive, negative, and cognitive symptoms of schizophrenia,22–24 as well as neurophysiological phenomena associated with psychosis.25–28 In PSZ, THC acutely worsens psychotic symptoms and cognitive functions, 29 and there is evidence that individuals with a predisposition for psychosis are more vulnerable to these acute psychotomimetic and cognitive-impairing effects.30 Chronically, cannabis abuse has detrimental effects on brain morphology specifically in PSZ with continuing consumption after conversion.31,32

Behavioral interventions targeted at reducing cannabis use in individuals with first-episode psychosis have been consistently unsuccessful (reviewed by Wisdom et al9). An effective treatment framework for this population is individuals with early psychosis actively exclude for heavy, unmanaged cannabis abuse. Thus, there is an urgent need for novel treatments that reduce cannabis use or its detrimental consequences in people with recent-onset psychosis.


Cannabis contains >100 different cannabinoids; however, the phytocannabinoid THC is the main psychoactive component, thought responsible for the deleterious effects described above. Cannabidiol (CBD) is another phytocannabinoid in cannabis. Contrary to THC, it has at most subtle subjective effects and no euphorogenic properties,33 and it does not activate CB1 or CB2 cannabinoid receptors. Despite its very low affinity and absence of intrinsic activity, CBD appears to reduce the efficacy of THC and other agonists at CB1 and CB2 receptors. 34–37 CBD antagonizes THC effects also via GPR55
receptors, which are activated by THC and blocked by CBD.35 CBD’s pharmacological profile further includes 5-HT1A receptor activation (in common with antidepressant drugs), adenosine reuptake inhibition,38–43 antioxidant44 and anti-inflammatory effects,45,46 suppression of immunoactivation-induced tryptophan degradation,47 binding and transient activation of TrpV1 vanilloid receptors, 38 and upregulation of the endocannabinoid anandamide (N-arachidonoylethanolamine, AEA), the latter by
interacting with fatty acid-binding proteins that mediate AEA’s cellular reuptake and transport to its catabolic enzyme fatty acid amide hydrolase (FAAH).38,48 CBD also inhibits T-type calcium channels,49 and the conversion of THC to the more psychoactive 11-OH-THC.36,50 Furthermore, there is evidence that CBD is a partial agonist at dopamine D2High receptors.51 For an in-depth review of CBD’s pharmacological actions, see Gururajan and Malone.52

While an early, small-N study suggested that CBD attenuates THC-induced euphoria,53 a recent investigation did not find that CBD alters the positive reinforcing effects of THC.54 However, lower appetitive effects of THC-associated stimuli were observed after smoking low- CBD than high-CBD strains of cannabis.55 Combined, these findings may suggest that chronic treatment with CBD has the potential of reducing cannabis use; however, there are to date no direct tests of this hypothesis.
Evidence that CBD counteracts detrimental effects of cannabis misuse is more plentiful :

CBD Counteracts Deleterious Effects of THC

Given acutely to healthy volunteers, oral CBD has been reported to reverse the acute psychotomimetic effects of THC,56,57 attenuate the anxiogenic and other subjective effects of THC,58,59 and counteract detrimental effects of THC on delayed episodic recall (but not on immediate recall or digit span)56 and of the THC analog nabilone on binocular depth inversion.24 Similarly, inhaled CBD was reported to counteract detrimental effects of THC on prose recall60 and facial emotion recognition.61 In parallel, several preclinical reports also suggest reversal of THC-induced cognitive deficits (reviewed by Osborne et al62). In an fMRI study, effects of acute CBD on BOLD responses were opposite to acute THC effects in regions including striatum, hippocampus, amygdala, and sensory cortex.57

That chronic CBD may attenuate psychotogenic effects of chronic THC was suggested by findings that higher levels of CBD in hair samples from cannabis users were associated with lower psychosis-like symptoms.63,64 Similarly, smokers of cannabis strains known to contain a higher proportion of CBD had lower positivelike symptoms than smokers of low-CBD cannabis.65 Furthermore, reductions in hippocampal volume and NAA, seen in chronic cannabis users, were not observed in users exposed to larger concentrations of CBD, consistent with neuroprotective effects.66

The CBD content of street cannabis has steadily decreased over the last two decades, resulting in a
THC:CBD ratio of ~80:1 today, as compared with 14:1 in 1995.67 Thus, the fact that variation in CBD content of current street cannabis has detectable effects suggests that larger amounts, administered chronically in a controlled manner, may have clear protective effects. Interestingly, evidence was presented at a recent conference that chronic THC use increases striatal D1–D2 dopamine receptor heteromerization, 68 a mechanism suggested to be associated with reduced hedonic value of stimulant drugs and natural rewards, depression, anxiety,69 and reduced reward learning in cannabis dependence.70 CBD attenuated the THC-induced increase in D1–D2 heteromerization,68 suggesting that it may help restore healthy reward processing, a mechanism of high relevance to schizophrenia71 and substance use disorders.72 Through this mechanism, as well as through potential attenuation of THC’s acute positive reinforcing effects,53,55 chronic CBD administration may not just reduce the deleterious effects of THC but also cannabis consumption itself, a hypothesis that remains to be tested.

Effects of CBD Alone