Amir Englund

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ2=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Traditional marijuana, high-potency cannabis and synthetic cannabinoids: increasing risk for psychosis

Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose‐response relationship between the level of use and the risk of later psychosis. High‐potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co‐administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high‐potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high‐potency cannabis and synthetic cannabinoids.

Can we make cannabis safer

Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm. Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use. Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.

The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial

Rationale: Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main cannabinoid ∆-9-tetrahydrocannabinol (THC). ∆-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC. Objectives: To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers. Methods: Ten male cannabis users (<25 use occasions) were recruited for this within-subjects, placebo-controlled, double-blind, cross-over pilot study. 10mg oral pure THCV or placebo were administered daily for five days, followed by 1mg intravenous THC on the fifth day. Results: THCV was well tolerated and subjectively indistinguishable from placebo. THC did not significantly increase psychotic symptoms, paranoia or impair short-term memory, while still producing significant intoxicating effects. Delayed verbal recall was impaired by THC and only occurred under placebo condition (Z=-2.201, p=0.028), suggesting a protective effect of THCV. THCV also inhibited THC-induced increased heart rate (Z=-2.193, p=0.028). Nine out of ten participants reported THC under THCV condition (compared to placebo) to be subjectively weaker or less intense (χ2=6.4, p=0.011). THCV in combination with THC significantly increased memory intrusions (Z=-2.155, p=0.031). Conclusion: In this first study of THC and THCV, THCV inhibited some of the well-known effects of THC, while potentiating others. These findings need to be interpreted with caution due to a small sample size and lack of THC-induced psychotomimetic and memory-impairing effect, probably owing to the choice of dose.

Cannabis-associated psychosis: Neural substrate and clinical impact

Abstract Prospective epidemiological studies have consistently demonstrated that cannabis use is associated with an increased subsequent risk of both psychotic symptoms and schizophrenia‐like psychoses. Early onset of use, daily use of high‐potency cannabis, and synthetic cannabinoids carry the greatest risk. The risk‐increasing effects are not explained by shared genetic predisposition between schizophrenia and cannabis use. Experimental studies in healthy humans show that cannabis and its active ingredient, delta‐9‐tetrahydrocannabinol (THC), can produce transient, dose‐dependent, psychotic symptoms, as well as an array of psychosis‐relevant behavioral, cognitive and psychophysiological effects; the psychotogenic effects can be ameliorated by cannabidiol (CBD). Findings from structural imaging studies in cannabis users have been inconsistent but functional MRI studies have linked the psychotomimetic and cognitive effects of THC to activation in brain regions implicated in psychosis. Human PET studies have shown that acute administration of THC weakly releases dopamine in the striatum but that chronic users are characterised by low striatal dopamine. We are beginning to understand how cannabis use impacts on the endocannabinoid system but there is much still to learn about the biological mechanisms underlying how cannabis increases risk of psychosis. This article is part of the Special Issue entitled “A New Dawn in Cannabinoid Neurobiology”. HighlightsHeavy use of cannabis increases the risk of later psychosis.Administration of THC to volunteers induces transient psychosis and increases release of dopamine in striatum.However in chronic users, synthesis of dopamine in striatum is decreased.The proportion of THC in “street” cannabis is rising.There are plausible biological explanations for the psychotogenic effects of cannabis.

Towards a personalized treatment in depression: endocannabinoids, inflammation and stress response

The complex nature of depression is mirrored by difficulties in tailoring its treatment. Key underlying mechanisms of this mental disorder include elevated inflammation and a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. More recently, the endocannabinoid system has been proposed as another important component in the pathogenesis of depression, and strong evidence suggests that all three systems communicate with each other. A growing number of genetic studies have investigated polymorphisms in depression in each of these systems separately. However, no study to date has looked at these genes in conjunction. In this article we will review the crosstalk between the endocannabinoid system, immune system and HPA axis; and discuss the evidence of gene polymorphisms and their relation to the risk of depression and its treatment. We propose future directions where genes of these three systems are considered from a joint perspective to improve prediction of treatment response, taking into account potentially overlooked genetic variations.

Cannabis in the Arm: What Can we Learn from Intravenous Cannabinoid Studies?

Cannabis is widely used recreationally and for symptomatic relief in a number of ailments. However, cannabis has been implicated as a risk factor for the development of psychotic illness. For forty years researchers have utilised intravenous preparations of Δ(9)-THC, as well as several other phytocannabinoids, in a laboratory setting. The intravenous route has the most reliable pharmacokinetics, reducing inter-individual variation in bioavailability and is well suited for the delivery of synthetic compounds containing a sole pharmacological moiety. Given the association between cannabinoids and psychotic illness, there has been a resurgence of interest in experimental studies of cannabinoids in humans, and the intravenous route has been employed. Here in a critical review, we appraise the major findings from recent intravenous cannabinoid studies in humans and trace the historical roots of this work back to the 1970s.

The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group

Background: Previous studies have suggested that cannabidiol has anxiolytic and antipsychotic properties, raising hopes that cannabidiol will translate to the psychiatric clinic. Cannabidiol may be particularly useful for anxiety and paranoia in those at-risk of major mental illness. Methods: Immersion in a controlled 3D virtual-reality scenario was used to assay persecutory ideation and anxiety in a sample of non-clinical volunteers (n=32) pre-selected for high paranoid traits. Participants were randomised to receive oral cannabidiol (600 mg) or placebo 130 min prior to entering virtual-reality. Well-validated rating scales were used to assay persecutory thinking and anxiety. Salivary cortisol concentration, heart rate and blood pressure were measured over the course of the experimental session. Results: Immersion in the virtual-reality session elicited anxiety as indexed by the Beck’s anxiety inventory (p<0.005), and increased cortisol concentration (p=0.05), heart rate (p<0.05) and systolic blood pressure (p<0.05). However, cannabidiol had no impact upon any of these effects, except for a strong trend to increase anxiety (p=0.09). Cannabidiol had no effect on persecutory ideation as assayed by the Community Assessment of Psychic Experiences questionnaire or the State Social Paranoia Scale. Conclusions: In contrast to previous studies, there was no evidence of any benefits of cannabidiol on anxiety or persecutory ideation in healthy volunteers with high trait paranoia. However, a larger sample will be required for a definitive study.