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The psychoactive components of cannabis were linked to new-onset psychotic symptoms even at low doses, according to a systematic review and meta-analysis.

Across nine studies involving 196 healthy young adults, tetrahydrocannabinol (THC) was associated with significantly increased total symptom severity on the Brief Psychiatric Rating Scale compared with placebo (standardized mean change 1.10, 95% CI 0.92-1.28, P<0.0001) even at low doses, ranging from 1.25 mg to 10 mg, reported Oliver Howes, MD, PhD, of King's College London, and colleagues.

Also, just one of four studies in which cannabidiol (CBD) was administered concurrently with THC found CBD administration reduced these symptoms, they wrote in the

"Our findings highlight the risk of psychiatric symptoms after even a single dose of some THC-containing cannabis products," Howes told MedPage Today in an email.

These findings add to the "growing scientific consensus" in support of the psychosis-cannabis link, an association that appears to be bidirectional, wrote Carsten Hjorthøj, PhD, and Christine Merrild Posselt, PhD, both of the University of Copenhagen in Denmark, in an

"In some people, cannabis leads to incident psychosis, whereas in other people, psychosis leads to incident cannabis use," they wrote.

Hjorthøj and Posselt cautioned against extrapolating these findings to assume "single doses of THC will eventually lead to schizophrenia," but also emphasized that "caution should not be thrown to the wind."

For example, CBD in particular has been touted as a potential "wonder drug" with antipsychotic, anxiety-reducing effects, but the findings here suggest the usefulness of CBD and other cannabis extracts "might be somewhat exaggerated compared with what we can expect in clinical practice," they continued.

This meta-analysis involved double-blind, placebo-controlled studies of healthy participants administered IV, oral, or inhaled THC with or without CBD. Individuals were generally in their mid-20s and predominantly male.

Of the 15 studies included, 13 were considered to have a "low" risk of bias and two studies had a "moderate" risk, as measured through the Newcastle Ottawa Scale. The authors calculated the SMR scores for "positive (including delusions and hallucinations), negative (such as blunted affect and amotivation), and general (including depression and anxiety) symptoms," they explained.

Compared with placebo, THC was associated with significantly increased positive symptom severity scores in 14 studies (SMC 0.91, 95% CI 0.68-1.14, P<0.0001), negative symptom severity scores in 12 studies (SMC 0.78, 95% CI 0.59-0.97, P<0.0001), and general symptoms in eight studies (SMC 1.01, 95% CI 0.77-1.25, P<0.0001), researchers reported.

THC was also associated with increased total symptom severity versus placebo regardless of whether it was administered intravenously or inhaled (P=0.37), and regardless of whether participants were frequent or current cannabis users (P=0.73, P=0.95, respectively), the authors noted.

However, intravenous THC was associated with slightly "more pronounced" increased symptoms than inhalation, although this may be confounded by dose, they added.

The induction of psychotic symptoms was also lower in people with higher versus lower tobacco use, suggesting tobacco use may be a "protective factor," the authors noted, although they cautioned against using tobacco to "counter" THC effects.

Howes told MedPage Today that "[another] possibility suggested by other evidence is that tobacco reduces the levels of the protein in the brain that THC binds to so it has less effect. This needs testing, and it is important that people don't think tobacco will protect against the effects of THC containing cannabis."

Many of the meta-regression analyses used involved fewer than 10 studies and were underpowered to detect small or moderate effects, which is a limitation, the authors noted. More participants were male than female, so the generalizability of these findings is also limited, they added. Researchers were additionally unable to differentiate the effects of THC on specific symptoms, like hallucinations or delusions.

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