A single THC dose can induce psychotic side effects, new review finds

Some people associate smoking marijuana with waves of euphoria or pain relief. But for certain individuals, consuming cannabis can lead to a far worse experience: According to a recent research review, a single dose of tetrahydrocannabinol (THC), one of the major active compounds in marijuana, can induce a host of psychiatric symptoms in people without a history of mental illness.

A review of 15 studies suggests that after consuming THC, people can experience short-lived mental side effects including anxiety, paranoia, and hallucinations. On average, these side effects lasted between one to two hours. Meanwhile, cannabidiol (CBD), another chemical compound in marijuana, didn’t lead to the same mind-altering changes seen with THC.

These symptoms were seen at relatively low doses of THC, like those found in medical marijuana. Although the effects passed relatively quickly, their manifestation might give people pause before lighting up recreationally or taking medical marijuana, the review authors suggest.

“These symptoms may be distressing and affect people's judgment,” co-author Oliver Howes, a professor at King’s College London, tells Inverse. Howes and his team published the meta-analysis on Tuesday in the journal Lancet Psychiatry.

“Policy should consider this risk and the need for public education about it," Howes says.

Tracking how cannabis can influence mental health

This review aimed to clarify what’s been a mixed bag of research on the effects of THC and CBD on mental health. The researchers analyzed 15 studies that explored how THC and CBD impacted the mood and behavior of a collective 331 healthy people. These participants had no history of psychiatric or psychotic disorders.

Howes and his colleagues examined a variety of psychiatric symptoms, including: delusions, paranoia, and hallucinations (“positive” psychiatric symptoms); lack of motivation or social withdrawal, (“negative” ones); and depression and anxiety (“general” symptoms).

The team tracked if and how these symptoms manifested after eating, inhaling, or injecting substances containing THC, CBD, or a combination of the two. Symptoms were compared with experiments where people instead consumed a “placebo,” which tricked them into thinking they were taking an active compound.

The doses of THC in the review ranged from 1.25 to 10 milligrams. That amount is roughly the equivalent of the amount of THC in a joint.

The link between THC and psychiatric symptoms

This review found that a single dose of THC can induce significantly more severe psychiatric symptoms than a placebo. Howe explains that this finding bolsters previous studies, which found an association between cannabis use and these symptoms. THC, Howe says, can be "a risk even in healthy people who have no risk factors for mental illness."

The team also found that injecting THC resulted in more severe symptoms than inhaling the substance. Still, symptoms were seen regardless of the administration method.

At the same time, CBD use didn't appear to lead to any psychiatric symptoms. Interestingly, CBD also didn't mitigate any of the psychological effects of THC, when people consumed the two together. In September, a study published in The Journal of Neuroscience argued the opposite and found that CBD could offset THC's negative side effects.

"... there is a risk of inducing temporary psychotic and other symptoms that patients should consider before taking it."

The new analysis also revealed that tobacco smokers didn’t seem to experience as severe psychiatric symptoms compared to only-THC consumers, suggesting cigarette smokers may be less sensitive to THC’s effects. (The study authors also acknowledge that this finding is preliminary, and don't recommend anyone use tobacco.)

While this review can't explain why THC can trigger these mental changes, Howes speculates it comes down to THC’s ability to disrupt neural communication.

“Other studies have shown that THC binds to a protein in the brain, altering the release of chemical messengers that disrupt brain function,” Howes says. In 2019, Howes and another research team showed that this protein is also altered in people with schizophrenia.

In turn, the psychiatric symptoms analyzed in the review, such as hallucinations or paranoia, are associated with severe mental health disorders like schizophrenia. But the authors note, this research doesn't suggest smoking weed or taking medical marijuana puts you at higher risk for psychiatric illness.

What the research does suggest, is that consuming THC comes with temporary psychological risks — risks that may inform policymaking and legalization efforts around cannabis and THC.

“Our findings suggest that if medical marijuana contains THC, then there is a risk of inducing temporary psychotic and other symptoms that patients should consider before taking it," Howes says.

Abstract:

Background: Approximately 188 million people use cannabis yearly worldwide, and it has recently been legalised in 11 US states, Canada, and Uruguay for recreational use. The potential for increased cannabis use highlights the need to better understand its risks, including the acute induction of psychotic and other psychiatric symptoms. We aimed to investigate the effect of the cannabis constituent Δ9-tetrahydrocannabinol (THC) alone and in combination with cannabidiol (CBD) compared with placebo on psychiatric symptoms in healthy people.

Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published in English between database inception and May 21, 2019, with a within-person, crossover design. Inclusion criteria were studies reporting symptoms using psychiatric scales (the Brief Psychiatric Rating Scale [BPRS] and the Positive and Negative Syndrome Scale [PANSS]) following the acute administration of intravenous, oral, or nasal THC, CBD, and placebo in healthy participants, and presenting data that allowed calculation of standardised mean change (SMC) scores for positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms. We did a random-effects meta-analysis to assess the main outcomes of the effect sizes for total, positive, and negative PANSS and BPRS scores measured in healthy participants following THC administration versus placebo. Because the number of studies to do a meta-analysis on CBD’s moderating effects was insufficient, this outcome was only systematically reviewed. This study is registered with PROSPERO, CRD42019136674.

Findings: 15 eligible studies involving the acute administration of THC and four studies on CBD plus THC administration were identified. Compared with placebo, THC significantly increased total symptom severity with a large effect size (assessed in nine studies, with ten independent samples, involving 196 participants: SMC 1·10 [95% CI 0·92–1·28], p<0·0001); positive symptom severity (assessed in 14 studies, with 15 independent samples, involving 324 participants: SMC 0·91 [95% CI 0·68–1·14], p<0·0001); and negative symptom severity with a large effect size (assessed in 12 studies, with 13 independent samples, involving 267 participants: SMC 0·78 [95% CI 0·59–0·97], p<0·0001). In the systematic review, of the four studies evaluating CBD’s effects on THC-induced symptoms, only one identified a significant reduction in symptoms.

Interpretation: A single THC administration induces psychotic, negative, and other psychiatric symptoms with large effect sizes. There is no consistent evidence that CBD induces symptoms or moderates the effects of THC. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes.

Funding: UK Medical Research Council, Maudsley Charity, Brain and Behavior Research Foundation, Wellcome Trust, and the UK National Institute for Health Research.