Commentary on Darkeet al.: Expanded psychedelic access requires new safety monitoring systems

As psychedelic use expands, the number of adverse effects will increase proportionally. New frameworks for monitoring safety outcomes on a population level are required to limit potential harms. Darke et al. characterized 33 lysergic acid diethylamide (LSD) and 10 psilocybin-related deaths in Australia between 2000 and 2023 using the country's sophisticated national coroner data system. Traumatic accidents and physical self-harm in private settings accounted for most deaths [1]. The authors appropriately highlight the rarity of psychedelic-related deaths, contextualizing these 43 deaths over 24 years against 1.6% of Australians aged 14 and older (more than 325 000 people) who reported using hallucinogens in 2019 alone [2]. While coroner data under-report deaths due to limited testing for psychedelics and the number of psychedelic-associated deaths are dwarfed by mortality from drugs such as opioids and stimulants [3, 4], the current study demonstrates, again [5], that psychedelics are not without risk of harm. This raises questions of how best to assess and monitor safety as regulated markets and unregulated psychedelic use expand. Based on clinical trials that suggest benefit for various mental health conditions [6], Australia approved a regulated framework for psychedelic services within its health-care system [7], while Oregon [8] and Colorado services operate in systems that parallel and variably interface with health-care. Clinical trials may not completely assess mental, physical or spiritual risks [9, 10] due to narrowly defined harms, perceived bias towards positive effects among trial patients and investigators and blinding challenges [6, 11]. Thus, the minimal harms observed in controlled trials may not translate when larger populations with more comorbidities are exposed under expanded access frameworks. Darke et al.’s findings suggest that regulated services must carefully consider key aspects of harm reduction. The role of trauma and private settings in these deaths suggests unsupervised use, consistent with other studies [5, 12, 13]. Cross-sectional studies suggest that harms of psychedelics may be lower when consumed under skilled supervision [5, 13]. One of the hopes of regulating psychedelic services is that careful preparation, supervision and follow-up counseling might decrease adverse psychedelic outcomes, yet this remains an untested hypothesis. Older people and those with medical and psychiatric comorbidities may experience elevated risk of harms, as demonstrated by cardiovascular events in Darke et al. [1] Co-use of other substances was also common in these individuals: 75% of LSD cases and 80% of psilocybin cases involved other substances [1], similar to the Poison Center calls [5, 13]. Regulated services must foster skilled supervision to reduce trauma, screen for comorbid conditions that elevate risk and counsel against other drug use to limit potentiated toxicities. Demonstration of the safety of non-health-care psychedelic service models depends upon adherence to these protocols. For most substances, as public perceptions of risk decrease, unregulated/unsupervised use increases, with attendant increase in population harms. For example, past- year hallucinogen and cannabis use grew among the US young adults from 2017 to 2022 [14], coinciding with a decreased public perception of risks. More widespread use expands the pool of individuals who may experience harms, as observed following cannabis legalization and decriminalization, particularly in young people [15]. It appears that this pattern may repeat for psychedelics [16]: hallucinogen-associated emergency department visits in California increased 54% from 2260 visits in 2016 to 3476 visits in 2022 [17], and US Poison Center calls for psilocybin toxicity among adolescents tripled among adolescents between 2018 and 2022 [13]. Although regulated services prohibit administration to clients younger than 21 years [8], messaging is needed to prevent harms for young people and those using in unsupervised settings. Better systems for assessing population risks in both regulated and unregulated settings are urgently needed [16, 18]. Public health and regulatory agencies must track population-level longitudinal adverse effects and benefits, as legal frameworks for psychedelic services are implemented internationally. Jurisdictions should support publicly funded, population-based event tracking that probably requires different approaches for different use settings (e.g. regulated services versus unlicensed services versus recreational use), all compared to non-users, because trauma and suicide occur in all groups. Current US monitoring frameworks do not capture high-resolution data regarding the context, reasons or meaningful health outcomes of psychedelic use. Enrolling people who use psychedelics through state and nationally regulated pathways in confidential, secure data collection systems could explicitly define the exposed population, capture accurate health outcome measures and demonstrate the safety of state-run programs. Community-driven consensus safety and outcome measures should be harmonized across jurisdictions [16, 19]. Although psychedelics hold the promise of new pathways to healing [6], associated harms and deaths will inevitably increase as the number of people exposed to psychedelics increases. Expanded access must be matched by expanded data monitoring frameworks and harm reduction interventions to maximize safety. P. Todd Korthuis: Conceptualization (lead); writing-original draft (lead); review and editing (equal). Adrianne R. Wilson-Poe: Writing-review and editing (equal). Joshua C. Black: Review and editing (equal). Andrew Monte: Conceptualization (supporting); writing-review and editing (equal). This study was funded by the US Department of Health and Human Services, National Institutes of Health, National Institute of General Medical Sciences, R35GM152157; US Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse, R01DA057670, UG1DA015815; US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, 75S20123P00003, SAM318573; US Department of Health and Human Services, US Food and Drug Administration, BAA no. 75F40122C00165. P.T.K. receives research grants from the US National Institutes of Health, National Institute on Drug Abuse (R01DA057670, UG1DA015815). P.T.K. and A.R.W.-P. receive funding from a project order with the US Substance Abuse and Mental Health Services Administration (75S20123P00003). A.M. and J.C.B. receive research grants for studying drug use by project order with the US Substance Abuse and Mental Health Services Administration (no. SAM318573), the US Food and Drug Administration (BAA no. 75F40122C00165) and the National Institute of General Medical Sciences (R35GM152157). N/A.