A Strategy for Rescheduling Psilocybin

Public and scientific interest in psychedelics such as psilocybin and MDMA is expanding. Once off-limits because of federal prohibition, a trickle of research from the 1990s has grown into a stream. But despite increasing acceptance by the public, and commercial investment in psychedelic therapies, aging federal laws stem the flow of vital research.

Psilocybin, a compound produced by many species of fungi, is one of the most well-studied psychedelics. To acknowledge its impressive safety record and potential for treating depression more effectively than existing therapies, the Food and Drug Administration designated psilocybin a breakthrough therapy in 2018 and 2019 for treating drug-resistant depression and major depressive disorder.

Despite these developments, most psilocybin research is still conducted overseas, and FDA approval remains years away. Psilocybin’s federal status as a Schedule I controlled substance is to blame. Despite overwhelming evidence that psilocybin is misclassified, this barrier restricts research, stifles competition and innovation, and inhibits access. Amid a worsening mental health crisis, the dam preventing scientific progress must be broken.

For two decades, U.S. suicide rates have steadily increased, and drug overdose rates have skyrocketed. The COVID-19 pandemic made things worse. Since 2019, anxiety rates tripled, and overdose rates surged. Meanwhile, innovation in mental health care has stagnated. Most new drugs for treating depression and anxiety are subtle variations on selective serotonin reuptake inhibitors (SSRI) like Prozac, which was introduced in 1985. None work reliably, and most can have unpleasant or dangerous side effects.

Psilocybin may be safer and equally effective with more enduring benefits. It could help reverse worsening mental health trends. But only if it is made affordable and accessible. Research was permitted in the mid-20th century, until the law stepped in. In the 1950s and 1960s, therapists experimented with psilocybin as a therapeutic aid. They observed its ability to alter consciousness and increase openness. However, during the 1960s, psychedelics became associated with the countercultural movement and rising opposition to the Vietnam War.

In 1970, Congress enacted the Controlled Substances Act (CSA). The following year, President Richard Nixon declared drug abuse public enemy number one, and in 1973, he formed the Drug Enforcement Administration (DEA). The CSA sorted dozens of substances into a five-tiered list according to their perceived potential for abuse. Drugs in Schedules II through IV could be prescribed by health care providers. But substances in Schedule I were prohibited and said to have “no currently accepted medical use,” “a lack of accepted safety” for supervised use, and a “high potential for abuse.” Though thrown into this category, psilocybin fits none of these descriptions.

The CSA does not define currently accepted medical use. But federal lawsuits on cannabis rescheduling provide guidance and suggest that FDA approval is not a requirement for meeting that criterion. Instead, qualifying evidence may come from adequate and well-controlled clinical trials. Phase I trials should be sufficient, and many have been completed using psilocybin.

In Oregon, the Research Subcommittee of the Oregon Psilocybin Advisory Board, composed of physicians, biologists and public health officials, analyzed the research and concluded that “high quality phase [I and II] clinical trials suggest that psilocybin is efficacious in reducing depression and anxiety, including in life-threatening conditions.” One recent phase II trial, discussed in the New England Journal of Medicine, demonstrated that two doses of psilocybin administered three weeks apart treated depression as effectively as six weeks of daily escitalopram, a common SSRI.

Some critics disparage such results and argue that existing trials are not large enough. They say researchers could overestimate treatment effects because it’s difficult to find placebos to match the effects of psilocybin, causing clinicians and research participants to be unblinded. Rescheduling can help solve this problem by promoting larger trials. The Schedule I status of psilocybin artificially restricts clinical trial enrollment. The DEA limits how much psilocybin can be produced annually, which drives up costs, and the agency imposes other unnecessary burdens on researchers. Regardless, unblinding is likely less of a problem than critics claim.

Psilocybin has now been administered to more research subjects than some FDA-approved psychiatric medications. Moreover, psilocybin trial results involve direct observation of clinical benefits. The FDA approves an increasing number of drugs, including the controversial Alzheimer’s drug aducanumab, based on changes in surrogate endpoints, measurements such as blood tests that substitute for clinical outcomes and constitute lower-quality evidence than direct observations. If surrogates for clinical improvement are good enough for the government to establish clinical efficacy, then direct observations of clinical benefit, a much higher bar, should suffice to establish currently accepted medical use.

Other evidence of currently accepted use is available. Citing the medical benefits of psilocybin, nine U.S. cities and the State of Oregon have decriminalized or legalized psilocybin. The Canadian government makes it available through compassionate-use laws and a special exemption to its Controlled Drugs and Substances Act.

Regarding safety and abuse potential, many experts agree that psilocybin has a low risk of toxicity and very low potential for addiction or dependence. In clinical trials, side effects are usually temporary and mild, and though psilocybin experiences are sometimes challenging because they can bring up difficult emotions, participants often report they are among the most meaningful experiences of their lives, producing benefits that frequently last for months.

Considering the totality of the evidence, and the urgent need for effective treatments, rescheduling psilocybin is crucially important. Last week in Nature Medicine, I. Glenn Cohen and I provided a roadmap for wider acceptance and utilization of psychedelic therapies, which includes rescheduling and other policy recommendations.

Substances can be rescheduled through three legal pathways. The first is legislative. Congress could reschedule psilocybin by amending the CSA. Historically, attempts to reschedule cannabis through this pathway have failed. But in late September, the Marijuana Opportunity Reinvestment and Expungement (MORE) Act cleared the House Judiciary Committee. Because the evidence supporting psilocybin’s efficacy and low abuse potential is at least as strong as the data regarding cannabis, the legislative pathway should be a viable option. But advocates for legislative reform may encounter political opposition from drug companies that benefit from prohibition and legislators influenced by lingering Vietnam War–era stigma and misinformation.

The second rescheduling pathway is administrative. The CSA gives the federal attorney general power to schedule and reschedule substances or remove them from the controlled substances list. That power is typically delegated to the DEA. President Biden could sign an executive order compelling the DEA to reschedule psilocybin. Alternatively, members of the public, and government officials, could petition the DEA to act. However, though the rescheduling process is distinct from FDA approval, the DEA typically resists rescheduling without it. While rescheduling FDA-approved therapies containing THC, the DEA has denied several petitions to reschedule cannabis and would likely deny similar requests regarding psilocybin.

The third pathway to rescheduling is judicial, which involves suing the DEA after it denies a scheduling petition. Though lawsuits filed to compel rescheduling of cannabis have been unsuccessful, they have provided a roadmap for rescheduling psilocybin, including the required standards for reviewing a petition and evaluating currently accepted use. Considering potential DEA and Congressional opposition to psilocybin rescheduling, the judicial path may be the most effective. But legislative approaches may soon become more feasible because psychedelics law reform is increasingly a bipartisan issue.

Representative Alexandria Ocasio Cortez (D–N.Y.) recently sponsored legislation to remove barriers to funding for psychedelics research, former Texas Governor Rick Perry supported a Texas bill to study psilocybin therapy for post-traumatic stress disorder (PTSD), and Representative Dan Crenshaw (R–Texas) sponsored a measure to unlock Defense Department funding for research on psychedelics to help active duty servicemembers.

Despite the strong evidence that psilocybin is misclassified, its Schedule I status stifles research, innovation and access. Rescheduling would address all these concerns in one fell swoop. An abundance of science and public health data supports it.

Editor’s Note: This article was first published in Scientific American on October 11, 2021.