Adverse Effects of Therapeutic Psilocybin Are “Tolerable” and Resolve in 48 Hours

Akhila Yerubandi, PharmD

Credit: University of Georgia, College of Pharmacy

A new study found therapeutic doses of psilocybin for depression and anxiety treatment can cause 5 acute adverse effects with statistical significance—headache, nausea, anxiety, dizziness, and elevated blood pressure—but they appear to be “tolerable.”¹

“In this systematic review and meta-analysis, therapeutic doses of psilocybin appeared to produce tolerable acute adverse effects that typically resolved within 24 to 48 hours,” wrote investigators, led by Akhila Yerubandi, PharmD, PhD candidate, from the College of Pharmacy at the University of Georgia.

Clinical studies assessing psilocybin in the treatment of depression and anxiety focused primarily on efficacy rather than safety. A 2023 phase 2 trial demonstrated how psilocybin treatment improved major depressive disorder symptoms within 8 days, but despite the positive data, investigators observed severe adverse events and no increased rate of remission among psilocybin-treated patients.² Yerubandi and colleagues also analyzed a meta-analysis evaluating the adverse effects of psilocybin as a secondary aim, particularly looking at select adverse effects.¹

Psilocybin, a serotonergic psychedelic and a prodrug of psilocin (4-hydroxy-dimethyltryptamine), is comparable to lysergic acid diethylamide, but research suggests it is more “vividly visual, less emotionally intense, more euphoric, and less likely to cause panic attacks or paranoia.” However, since the drug’s safety profile was not explored in depth, investigators sought to assess the acute effects of psilocybin at therapeutic doses in depression and anxiety treatment.

Yerubandi and colleague’s primary outcome was the adverse effects of psilocybin at high (20 – 30 mg) and moderate (10 – 20 mg) therapeutic dose regimens. They compared this to placebo, low-dose psilocybin (1 – 3 mg), or other treatment options for depression and anxiety including niacin and escitalopram.

For a meta-analysis, they leveraged data from several databases (MEDLINE via PubMed, Web of Sciences, and ClinicalTrials.gov) available between 1966 and November 30, 2023, on clinical trials reporting the adverse effects of psilocybin in patients treated for depression and anxiety. The studies were all randomized, double-blind trials.

In total, 6 studies met the inclusion criteria, and the team ended up with a sample of 528 participants including approximately 51% female, > 90% White, and many middle-aged adults with a mean age of 39.8 years. Participants reported 7 adverse effects, 5 of which had statistical significance: headache (relative risk [RR], 1.99; 95% confidence interval [CI], 1.06 – 3.74), nausea (RR, 8.85; 95% CI, 5.68 – 13.79), anxiety (RR, 2.27; 95% CI, 1.11 – 4.64), dizziness (RR, 5.81; 95% CI, 1.02 –33.03), and elevated blood pressure (RR, 2.29; 95% CI, 1.15 – 4.53). However, paranoia and transient thought disorder were not statistically significant and thus were not associated with psilocybin use.

Only the adverse effects of headaches and nausea appeared in all 6 studies. The incidence of headaches ranged from 2% to 66%, and nausea ranged from 4% to 48%.

Investigators stated 6 acute adverse effects appeared in > 5% of the population, such as elevated heart rate (76%), visual perceptual effects (44%), physical discomfort (21%), fatigue (approximately 6%), euphoric mood (approximately 5%), and mood alteration (approximately 5%). However, these adverse effects only were reported in 1 study, so the data was excluded from the meta-analysis.

The team outlined several limitations, including only 6 studies that had small sample sizes, focusing only on acute adverse effects, assessing specific adverse effects, selection bias, and not evaluating suicidality.

Overall, the safety profile showed psilocybin for the treatment of depression and anxiety seemed to be “tolerable” with no serious adverse events and resolved within 24 to 48 hours.

“Larger trials are necessary to fully assess these adverse effects, particularly in populations with comorbid health conditions,” investigators concluded. “Recommendations for solicited acute adverse effects should, at a minimum, include headache, nausea, anxiety, dizziness, paranoia, blood pressure and/or heart rate changes, visual perceptual effects, physical discomfort, and mood changes.”

^References

1. ^{Yerubandi, A, Thomas, J, Bhuiya, M. Acute Adverse Effects of Therapeutic Doses of Psilocybin. JAMA Network Open. 2024;7(4):e245960. doi:10.1001/jamanetworkopen.2024.5960}
2. ^{Kunzmann, K. Single-Dose Psilocybin Significantly Improves Major Depressive Disorder Symptoms Within 8 Days. HCPLive. August 31, 2023. https://www.hcplive.com/view/single-dose-psilocybin-improves-major-depressive-disorder-symptoms-8-days. Accessed April 9, 2024.}