A single dose of tetrahydrocannabinol (THC), roughly the equivalent of one marijuana joint, can induce psychotic and other psychiatric symptoms in healthy adults with no history of a major mental illness, results of a new meta-analysis suggests.
The research shows large effect sizes for these symptoms, which were induced even with low doses of THC, which is the psychoactive component in cannabis.
Dr Oliver Howes
The new findings underscore that a single, “one-off exposure” to THC, even in a fit and healthy person, increases vulnerability to experiencing psychiatric symptoms, including psychotic symptoms, senior investigator Oliver D. Howes, MD, PhD, professor of molecular psychiatry, King’s College London, UK, told Medscape Medical News.
“As clinicians, we need to be aware that the medical use of marijuana comes with a risk of inducing psychiatric symptoms, even in people with no vulnerability, and this needs to be factored into decisions to prescribe and to monitor,” he said.
“That’s not to say we shouldn’t use cannabis where there’s good evidence of potential benefit, but this is something we need to think about,” Howes added.
He noted that even if these symptoms are short-lived, people need to be aware of them because they can be distressing and affect decision-making and behavior.
Notably, the review failed to show clear evidence that concurrent administration of cannabidiol (CBD), another constituent of cannabis, mitigates THC-related psychiatric symptoms.
“That goes against some of the suggestions that have been out there,” Howes said, “that if we increase the amount of CBD in cannabis that would help counter the effects of THC. I think this tells us we need to do more work before we come to any conclusions about whether CBD is going to help or not.”
The study was published online March 17 in Lancet Psychiatry.
Widespread Use
Cannabis is among the most widely used psychoactive substances in the world. In the US, estimates show more than 15% of the population uses cannabis annually.
In addition, there’s a global trend toward decriminalization and legalization. To date, cannabis is legal for recreational use in 11 states, Canada, and Uruguay.
Previous research into the effects of THC in healthy subjects has been inconsistent.
The aim of the current study was to examine the effect of THC alone, and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy participants.
“While there’s a lot of evidence that cannabis is associated with a risk of psychotic symptoms, the big question has been whether this was due to the cannabis constituents or whether people who already had symptoms or vulnerabilities were using cannabis to try to cope with that, and so we didn’t really know the direction of causality,” said Howes.
The meta-analysis included 15 studies that examined acute administration of THC and four studies on CBD plus THC. Inclusion criteria included studies that reported symptoms using the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS) following acute administration of intravenous (IV), oral, or nasal THC, CBD, and placebo.
These scales measure changes in symptoms relevant to schizophrenia, including positive symptoms such as hallucinations and delusions; negative symptoms such as blunted affect, anhedonia, and amotivation; and general psychopathology, including depressive, cognitive, and anxiety.
The studies included in the analysis used doses of THC ranging from 1.25 mg to 10 mg, leading to peak THC blood concentrations of 4.56 to 5.1 ng/mL when orally administered and 110 to 397 ng/mL following IV or inhaled administration.
Howes noted that the doses used in the study “were designed to represent the amounts of THC that people get from smoking a fairly typical cannabis joint.”
No Protective Effect of CBD
All participants were screened to rule out a history of mental illness, other vulnerabilities, and physical health issues.
Compared with placebo, THC significantly increased total symptom severity with a large effect size (standardized mean change [SMC] in score 1.10; 95% confidence interval [CI], 0.92 – 1.28; P < .0001), as well as positive symptom (SMC, 0.91; 95% CI, 0.68 – 1.14; P < .0001) and negative symptom severity (SMC, 0.78; 95% CI, 0.59 – 0.97; P < .0001).
“What was surprising to me was that there were quite similar effects across all the psychiatric symptoms that we looked at,” Howes said.
There was no clear evidence of an impact of dose on symptoms. However, this is not a “very solid finding” because the dose varied by route of administration, with higher doses given orally leading to “a different uptake profile,” said Howes.
In addition, the investigators found no evidence that CBD moderates the psychotic effects of THC. Although a single, small study reported a significant reduction in THC-induced positive symptoms by CBD, three larger studies failed to replicate this finding.
“Overall, I think it’s fair to conclude there’s a lack of consistent evidence that CBD is protecting against THC’s effect,” said Howes.
Finally, the researchers found a negative association between tobacco smoking and positive symptoms induced by THC (P = .019). However, the investigators note that further work is needed to test this finding and that it should not be taken as a recommendation to use tobacco to counter the effects of THC.
The mean age of subjects in the various studies ranged from early to late 20s. The analysis showed age had no effect on psychotic-like symptoms, but that older age was associated with being more sensitive to negative symptoms such as social withdrawal and lack of motivation.
While the review does not shed light on the risk of THC in individuals who are vulnerable to psychiatric illness, it’s likely that such patients “are going to be at least as sensitive to the effect and might be more sensitive” than the healthy subjects in the studies, said Howes.
“Important, Worrying”
Commenting for Medscape Medical News, Petros Levounis, MD, professor and chair, Department of Psychiatry, Rutgers New Jersey Medical School, Newark, describes the results as “very strong and consistent” and said the study makes “a significant contribution to the literature.”
As with alcohol, cocaine, and other drugs of abuse, it’s important to know what to expect with THC intoxication, so the information provided in the review is clinically useful, he said.
“Because of this article, we now have very good evidence that intoxication with cannabis in the short run gives you significant psychosis, which is very important,” Levounis explained.
He says he now will counsel his patients who use marijuana to expect psychotic symptoms following marijuana intoxication.
“This is very significant because of accidents and the trouble you can get into if you get intensely paranoid during this stage, especially nowadays with very high concentrations of THC,” Levounis said.
However, cautioned Levounis, the review provides no information about long-term psychosis risk with THC.
The findings that CBD does not have antipsychotic properties, he added, are “a little surprising” as this has been “a very widely-held belief.”
In an accompanying editorial, Carsten Hjorthøj, PhD, MSc, and Christine Merrild Posselt, PhD, from the Copenhagen Research Center for Mental Health, Copenhagen University Hospital, Denmark, note the finding that even low-doses of THC can induce psychotic symptoms are “extremely important and worrying” since these doses are similar to those used in medical cannabis.
However, they add, this does not mean that single doses of THC “will eventually lead to schizophrenia or other severe disorders.”
The finding that there’s no clear evidence that concurrent administration of CBD reduces symptoms induced by THC “is notable” because CBD “is being touted as a potential wonder drug with antipsychotic, anxiolytic, and other properties,” they write.
“Although it is quite possible that CBD will have some therapeutic applications (once proper randomized trials have been done), this supports suggestions that many of the initial reports and public discourses regarding the usefulness of both pure CBD and whole-plant-based extracts of cannabis might be somewhat exaggerated compared with what we can expect in clinical practice,” say the editorialists.
Howes reports grants from Angellini, AstraZeneca, Autifony, Biogen, Eli Lilly, Heptares, Janssen, Lundbeck, LydenDelta, Otsuka, Sunovion, Rand, Recordati, and Roche (outside the submitted work). Levounis and the editorialists have disclosed no relevant financial relationships.
Lancet Psychiatry. Published online March 17, 2020. Full text
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