Hallucinogens Tied to Striking Increased Risk of SSD

Emergency department (ED) visits related to hallucinogen use are linked to a 21-fold increased risk of schizophrenia spectrum disorder (SSD), results of a large population-based study show.

Results of the cohort study that included nearly a million people: Those with no history of psychosis who had an ED visit involving hallucinogen use had a significantly increased risk of SSD compared to their age- and sex-matched counter parts after adjusting for comorbid mental and substance use disorders (SUDs).

“I hope this study can be a reminder or fuel a discussion about how little we actually know about both the potential health benefits and the potential health risks of hallucinogens,” study investigator Daniel T. Myran, MD, a Canada research chair, Department of Family Medicine, University of Ottawa, and an investigator at Bruyère Health Research Institute, Ottawa, Canada, told Medscape Medical News.

The findings were published online November 13 in JAMA Psychiatry.

Buzz and Hype

There’s increasing social and research interest in hallucinogens, including lysergic acid diethylamide, psilocybin, and methylenedioxymethamphetamine for the treatment of psychiatric illnesses including SUDs.

Recent clinical trials suggest psychedelic-assisted psychotherapy may be beneficial for treatment-resistant depression, posttraumatic stress disorder, and alcohol use disorder. While the underlying mechanism is not fully understood, hallucinogens are thought to enhance cortical neuroplasticity and neuro-connectivity.

Meanwhile, recreational hallucinogen use appears to be rising among young adults. As of 2023, an estimated 8.9% of Americans aged 19-30 reported using hallucinogens in the past year, more than double the 4.1% reported in 2015.

Amid the “buzz and hype” surrounding the potential health effects of hallucinogens, “we were really interested in understanding the other side of the coin — the potential health risks,” said Myran. 

Previous studies have been limited by small sample sizes, reliance on self-reports, and use of less clinically relevant exposures to hallucinogens such as ever use.

Using linked databases, researchers collected data on all ED visits, hospitalizations, and outpatient physician visits from 2008 to 2021 across Ontario, as well as sociodemographic data.

The study included 9,244,292 individuals, mean age 40.4 and 50.2% female, without a history of substance-induced psychosis or SSD. They were followed for a median of 5.1 years. Of these, 0.1% had an ED visit involving hallucinogen use (the exposed group), and 99.9% did not (the general population).

The researchers highlighted a recent surge in hallucinogen use, with their study showing that emergency department visits related to hallucinogens rose by 86.4% between 2013-2021.

One of the most common types of ED visits involving hallucinogen use was “hallucinogen-induced psychosis.” This describes individuals “who are profoundly paranoid, who may be seeing things that aren’t there and are having a total departure from reality,” said Myran.

This is likely a marker of a substance that was particularly strong or an underlying susceptibility to psychosis, he added.

Clinical Guidance

The study’s primary outcome was development of SSD, which was determined using a medical record validated algorithm.

Within 3 years, 3.99% of individuals with an ED visit involving hallucinogens developed an SSD compared to 0.15% of individuals in the general population (hazard ratio [HR], 21.32; 95% confidence interval [CI], 18.58-24.47). 

“The risk for those with an ED visit related to hallucinogens is 21 times the risk of someone of the same age and sex in the general population,” said Myran, adding he found the magnitude of the risk surprising.

The results showed 20.11% of individuals with an ED visit for hallucinogen-induced psychosis went on to develop an SSD.

After accounting for differences in sociodemographic and comorbid mental and SUDs, those with an ED visit involving hallucinogen use (HR, 3.53; 95% CI, 3.05-4.09) and those with ED visits involving hallucinogen-induced psychosis (HR, 14.66; 95% CI, 10.53-20.41) had a greater risk of developing an SSD compared to the general population.

A secondary analysis examined ED visits for other types of substance use showed that individuals with an ED visit involving hallucinogen use had a greater risk of SSD within 3 years compared with ED visits involving alcohol (HR, 4.66; 95% CI, 3.82-5.68).

In addition, compared to ED visits linked to cannabis, which has been associated with an increased risk of schizophrenia, adjusted analyses showed the risk was still higher for hallucinogen use (HR, 1.47; 95% CI, 1.21-1.80).

Results of a sensitivity analysis that excluding individuals with any outpatient, ED, or hospital-based care for mental health or substance use in the past 5 years showed those with ED visits involving hallucinogens had a higher risk of developing SSD vs the general population (fully adjusted HR, 20.94; 95% CI, 12.79-34.28).

The fact that this exclusion resulted in a higher HR than the primary analysis reduces the likelihood of reverse causation — namely, that individuals with schizophrenia symptoms may have been self-medicating with hallucinogens, said Myran. 

These new findings suggest individuals presenting to the ED with, for example, a family history of schizophrenia or psychosis who have used hallucinogens and experience an episode of severe paranoia, may benefit from follow-up intervention efforts such as counselling and medications, said Myran.

“What you don’t want is for them to just disappear, not have follow-up and then come back several years later with schizophrenia that has gone untreated for several years,” he said. 

In addition, those with a strong family history of psychosis and schizophrenia “should probably avoid using hallucinogens,” he added.

The study could not establish a causal link between hallucinogen use that requires ED care and SSD. Other potential limitations included the lack of detailed data on the specific hallucinogen used, possible misclassification of individuals identified as having SSD, and lack of control for established environmental factors and genetic risk factors that may confound the relationship between hallucinogen use and schizophrenia.

Myran noted the risk uncovered in the study relates to those treated in the ED because of hallucinogenic use. “We have not assessed whether or not there’s a risk for someone who, for example, is using a small amount of psilocybin occasionally,” he said. 

Helpful Data

Commenting on the research for Medscape Medical News, Michelle B. Riba, MD, professor, department of psychiatry, University of Michigan, Ann Arbor, described the research as a valuable, data-driven study that contributes to essential literature, especially as psychedelic-assisted psychotherapy gains traction in psychiatry. 

However, she added, as a population-based, retrospective cohort study, it has inherent limitations. “Causal results can’t be made between hallucinogen use as a reason for an emergency visit and risk of schizophrenia spectrum disorder,” Riba said. 

She added that prospective, longitudinal studies are needed “to better understand such relationships.”

The investigators and Dr. Riba report no relevant disclosures. Thestudy was supported by the University of Ottawa site of ICES, which is funded by an annual grant from the Ontario Ministry of Health and Ministry of Long-Term Care.