California Bill to Decriminalize Natural Psychedelics Passes State Legislature on the Heels of Phase 2 Data Showing Safety, Efficacy of Psilocybin for MDD

California is possibly on the verge of decriminalizing natural psychedelics after the bill SB58 passed the legislature. The bill would remove criminal penalties for those aged 21 years and older for the personal possession of natural psychedelics, such as psilocybin, psilocin, dimethyltryptamine, and mescaline. Once signed into law by Governor Gavin Newsom, SB58 will not go into effect until January 2025.¹

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State Senator Scott Wiener had written and previously pushed for the legalization of psychedelics with a prior bill, SB519, that was introduced in 2021; however, the bill initially did not pass through the committee. SB58, which has progressed past the California State Assembly, is a new bill focused on decriminalization of certain psychedelics rather than legalization of psychedelics more broadly. Currently, Colorado, Oregon, and multiple cities in California (eg, Santa Cruz, Oakland) have already decriminalized the personal use of psychedelics.¹

The news of SB58 moving to Governor Newsom’s desk for a signature comes on the heels of a phase 2 clinical trial (NCT03866174) published in JAMA Network Open investigating efficacy and safety of psilocybin. The randomized, placebo-controlled, 6-week trial examined the efficacy and safety of psilocybin compared to placebo when used to treat major depressive disorder (MDD). Efficacy was assessed with a MADRS score, a 10-item scale with a scoring range of 0 to 60 with higher scores indicating more severe symptoms of depression. Primary and secondary outcomes as well as adverse events (AEs) were assessed at baseline (7 days prior to dosing) and again at 2, 8, 15, 29, and 43 days after dosing.²

A total of 104 adults with MDD aged 21 to 65 years were involved in the study. Participants were randomized 1:1 and orally received a 25-mg dose of psilocybin or a 100-mg dose of the placebo niacin. Niacin was used as the active placebo because it produces an acute physiological response—flushing—thought to aid blinding. Patients were excluded from the study if they had a history of mania or psychosis, active substance use disorder, or active suicidal ideation with intent. Those who were taking psychotropic agents were eligible for the study following medication taper.²

Of the 104 participants, 50 received psilocybin and 54 received niacin. Compared to niacin, psilocybin treatment was associated with significantly reduced MADRS scores from baseline to day 43 (mean difference, −12.0 [95% CI, −16.6 to −7.4]; P < .001) and from baseline to day 8 (mean difference, −12.0 [95% CI, −16.6 to −7.4]; P < .001). Additionally, participants receiving psilocybin treatment had a better sustained response than those receiving niacin; however, they did not have a significant sustained remission compared to niacin (12/48 [25%] for psilocybin vs (4/44 [9.1%]) for niacin, with an adjusted absolute difference of 15.9 [95% CI, 1.0-30.8]; P = .05; OR, 3.4 [95% CI, 1.0-11.5]). Further, results showed more participants receiving psilocybin than niacin had sustained depressive symptom response (20/48 [42%] vs 5/44 [11%], with an adjusted absolute difference of 30.3 [95% CI, 13.5-47.1]; P = .002; OR, 5.6 [95% CI, 1.9-16.7]; P = .002).²

Overall, psilocybin was generally well-tolerated, with most AEs being mild or moderate in severity for those limited to the acute dosing period. From day 1 through day 9, a total of 41 of 50 participants (82%) in the psilocybin group had reported experiencing at least 1 drug-related treatment-emergent AE (TEAE), vs 24 of 54 (44%) in the niacin group (difference, 38% [95% CI, 20.6%-41.3%]; relative incidence [RI], 1.8 [95% CI, 1.3-1.8]). Severe TEAEs were only reported by 4 of 50 participants in the psilocybin group through day 9 (8%; migraine, headache, illusion [all solicited], and panic attack and paranoia). Additionally, visual perceptual effects following resolution of acute drug effects were reported by 22 of 50 (44%) psilocybin participants on the day of dosing, and 3 of 50 after the dosing day.²

Further, solicited AEs were reported by 38 of 50 participants (76%) who received psilocybin, compared to 16 of 54 (30%) who received niacin (difference, 46% [95% CI, 29.4%-63.4%]; RI, 2.6 [95% CI, 1.7-4.0]). Of the solicited AEs, the majority were mild (73 of 91 total events [80%] in psilocybin group, 22 of 23 total events [96%] in niacin group) with a few being severe (3 participants receiving psilocybin and 1 participant receiving niacin). The most common solicited AEs reported were headaches (33 of 50 participants [66%] in the psilocybin group and 13 of 54 participants [24%] in the niacin group) and nausea (24 of 50 participants [48%] in the psilocybin group and 3 of 54 participants [6%] in the niacin group). Further, 1 participant who received psilocybin and 5 participants receiving niacin had an increase in Columbia Suicide Severity Rating Scale suicidal ideation score from baseline to the trial’s end.²

Limitations of the trial include the use of niacin as active placebo increasing believability therefore enhancing the placebo response, the trial’s duration compared to prior trials, and the lack of participant racial diversity. Finally, the success of allocation blinding was not assessed, so it is possible that the psychoactive effects of psilocybin produced some degree of functional unblinding that could have contributed to the observed effect in the participants treated with psilocybin.²

Psychedelics, like marijuana, is classified as a Schedule 1 substance and remains federally illegal. If the bill in California were to be signed into law, the decriminalization of psilocybin in the state will support efforts toward the goal of providing a safe and effective treatment option for patients with MDD.^1,2

Reference

1. California bill that would legalize psychedelics like magic mushrooms heads to Gov. Newsom’s desk - CBS Sacramento. CBS News. September 7, 2023. Accessed September 8, 2023. https://www.cbsnews.com/sacramento/news/california-bill-that-would-legalize-psychedelics-like-magic-mushrooms-heads-to-gov-newsoms-desk/

2. Raison CL, Sanacora G, Woolley J, et al. Single-Dose Psilocybin Treatment for Major Depressive Disorder: A Randomized Clinical Trial. JAMA. 2023;330(9):843-853. doi:10.1001/jama.2023.14530