This post is part of Notice & Comment’s symposium on psychedelics and the law. For other posts in the series, click here.

Imagine two competent adult patients, each of whom is living with treatment-resistant major depressive disorder (MDD) and struggling with suicidal ideation.

Patient A asks her doctor about Pretendazine®, an (imaginary) injectable drug FDA-approved exclusively for schizophrenia. The drug has not been studied for MDD but is getting attention for this use on some patient forums. Patient A’s doctor believes that the drug’s mechanism of action suggests a reasonable chance of success.

Meanwhile, Patient B seeks advice from his physician about treatment with psilocybin, a psychedelic compound that naturally occurs in Psilocybe mushrooms and can be manufactured through chemical synthesis. Although psilocybin has not been FDA-approved for any use, it has been the subject of a significant amount of peer-reviewed research. This research preliminarily supports both the safety of psilocybin-assisted psychotherapy and its efficacy for MDD. Based on this evidence, Patient B’s physician agrees psilocybin is worth trying.

Under current federal law, Patient A’s doctor could legally administer Pretendazine in hopes of alleviating her condition, while Patient B’s doctor could not legally offer him psilocybin. How can this distinction be normatively justified? Is it defensible to interfere with Patient B’s autonomy by making him wait until psilocybin achieves FDA approval while Patient A is allowed to proceed, even based on weaker evidence?

Legal Background

Although FDA has approved numerous drugs for MDD, psychiatrists commonly prescribe other medicines off-label. This practice is completely legal under federal law; the Food, Drug, and Cosmetic Act (FDCA) has long been interpreted not to regulate doctors prescribing FDA-approved drugs for unapproved uses. Such off-label prescribing is subject only to the restraints of state malpractice law and board discipline. Thus, Patient A has a clear course to trying Pretendazine, even though FDA has not deemed it safe and effective for treatment of MDD. Her only barriers are convincing her physician to prescribe the drug and perhaps getting her insurer to pay.

Patient B is in a very different situation. Under the federal Controlled Substances Act (CSA), psilocybin is currently a Schedule I substance, a category reserved for drugs with a high potential for abuse, no currently accepted medical use in the United States, and a lack of accepted safety for use under medical supervision. It is illegal to possess, manufacture, distribute, or dispense a Schedule I substance except pursuant to research authorized and regulated by the Drug Enforcement Administration (DEA).

Thus, while Patient B could pursue psilocybin access in a state that allows regulated use, such as Oregon or Colorado, possessing the drug remains federally illegal under the CSA. He could grow his own mushrooms, but this also remains federally illegal. He could seek psilocybin in a clinical trial, but he may be ineligible or otherwise unable to participate in such a trial, and—if he does participate—he may receive a placebo or other control instead of psilocybin. He could work with his doctor to receive the product from a commercial or nonprofit developer through FDA’s Expanded Access (EA) pathway or the federal Right to Try (RTT) law. However, the developer may be unwilling to provide access prior to obtaining FDA approval, and the patient’s doctor would need to obtain DEA registration as a Schedule I researcher. There is a substantial push to down-schedule psilocybin and other psychedelics, but for now the CSA remains a major obstacle to obtaining the drug outside of the two states with operational psychedelic access programs, which the federal government has so far not interfered with. (New Mexico’s medical psilocybin program may open treatment sites as soon as the end of 2026.)

Even if the CSA were not an issue, however, the FDCA would likely impede Patient B’s access to psilocybin treatment. The FDCA would not prohibit a patient’s home cultivation, as its drug provisions apply only to products in interstate commerce. However, in light of the natural variability among Psilocybe mushrooms, Patient B and his physician would probably prefer a standardized product tested for psilocybin potency, such as  homogenized mushroom powder in capsules or whole mushrooms bred for uniformity over many growth cycles. Unless such a product were grown and processed entirely within Patient B’s state, any grower, processor, seller, or purchaser in the interstate chain of distribution could be charged with FDCA violations. Synthetic psilocybin is also likely to be shipped in interstate commerce and thus subject to the FDCA’s prohibitions.

In short, despite neither drug being FDA-approved for the intended use, Patient A could legally access her desired treatment, while Patient B would face substantial legal impediments under the CSA and FDCA. Especially given that both patients are struggling with life-threatening mental illness but remain competent adults, the government should not interfere with their self-regarding activities without a strong justification—even more so given that the activities in question are treatments endorsed by the patients’ physicians as learned intermediaries.

Justifying Government Interference

Although some government actions are motivated by paternalism (e.g., requiring that children go to school) or simple imposition of the values of some onto others (e.g., efforts to ban gay marriage), these rationales are generally insufficient to justify government interference with the purely self-regarding actions of competent adults. However, there may be other legitimate justifications for government interference.

The most obvious is that the action in question is not truly just self-regarding but instead poses the risk of harm to others. For example, laws prohibiting medical aid in dying are sometimes supported by concerns that they will heighten stigma and discrimination against disabled individuals and those who choose not to end their lives, while motorcycle helmet laws are sometimes justified through claims about externalized health care costs. Government interference may also be justified when it aims to ensure only that a competent adult’s decision is truly autonomous, a principle sometimes described as “soft paternalism.” Consider, for example, laws requiring informed consent before surgery, or those requiring waiting periods, interviews, and witnesses as assurance against coercion or undue influence before provision of aid-in-dying drugs. Such measures do not impede autonomy but rather enhance it. A related concept, “group soft paternalism,” suggests that government interference can be justified at a population level to account for some members of a population acting under autonomy constraints, even if other members of that population are capable of behaving autonomously. This reasoning has been put forth to justify requirements for institutional review board oversight of research in addition to participant consent, and also for limiting some drugs to prescription-only status.

Some of these rationales can explain both the CSA and FDCA as general statutory approaches, even though they may fall short in specific cases, as discussed below. The CSA is directed at avoiding addiction, a behavior that inhibits autonomy and can cause harm to others, and at preventing diversion of drugs that could lead to public harm, while not unduly interfering with accepted medical uses of controlled substances.

The FDCA’s prohibition against introducing unapproved drugs into interstate commerce, in addition to protecting patients against harmful products, forces the production of evidence regarding drug safety and effectiveness by blocking market access—and profit—until such evidence is produced. This information, which is unlikely to be sufficiently generated through market forces alone, is critical to supporting autonomous decision-making by patients (and their clinicians) about which drugs to pursue for treatment and which to avoid. Although some patients might be willing to proceed with less information or certainty, without an FDA approval requirement, evidence of safety and effectiveness would be less available for those patients who want it.

The FDCA’s approval requirement also helps avoid exploitation of desperate patients whose autonomy is challenged by their circumstances, leaving them susceptible to snake oil salesmen and interventions with risks that outweigh likely benefits. Desperation does not invariably inhibit autonomy, however; sometimes it rationally alters autonomous choices. The FDCA accounts for this fact by allowing flexible approvals for serious diseases with unmet treatment needs (e.g., through the accelerated approval pathway), as well as by permitting patients in some cases to be treated with unapproved drugs through EA.

Gatekeeping Psychedelic Drugs

Returning to our case examples, how do these rationales for government interference apply to Patient A and Patient B—can the seeming inconsistency in their access to unapproved drug uses be justified?

Starting with the FDCA, let’s begin with the government’s aim to support evidence generation. Allowing Patient A’s doctor to administer Pretendazine off-label for MDD preserves some incentive to generate evidence about that unapproved use, both because the drug’s sponsor cannot market it for that use until FDA grants approval and because insurance reimbursement is less likely for off-label uses. Thus, allowing off-label prescribing does not necessarily foil the government’s goal of promoting the generation of evidence needed to guide patient care. The same is true for allowing Patient B to access psilocybin through EA or RTT, since both pathways preclude pre-approval access for patients who could participate in a clinical trial, and neither allows marketing or profit prior to drug approval. Similarly, allowing Patient B to grow his own psilocybin mushrooms for personal use intrastate, which the FDCA does not prohibit, is not likely to meaningfully disrupt incentives toward evidence generation.

The more interesting question is whether the goal of producing evidence justifies the FDCA’s ban on interstate distribution of psilocybin before FDA approval. Here, it is important to differentiate between synthetic and natural psilocybin. Synthetic psilocybin has a clearer claim to intellectual property protection (although that is somewhat disputed), and its developers thus have commercial incentives to seek FDA approval—and to generate the evidence needed to secure that approval. Thus, the justification for prohibiting interstate distribution of unapproved synthetic psilocybin stands. But is there adequate motivation for any sponsor to generate sufficient evidence to support FDA approval of natural psilocybin, say in the form of powdered, homogenized capsules at a specific dosage? If not, this justification for the FDCA’s prohibition on introducing the drug into interstate commerce before approval seems to fall away.

At present, the incentives to commercially develop natural psilocybin are fairly poor. FDA has an industry guidance on botanical drug development that acknowledges key challenges compared to traditional drug development that arise, for example, from the heterogenous nature of botanical drugs, possible uncertainty about their active constituents, and distinctive manufacturing requirements. The agency has approved a few botanical drugs, but the challenges in meeting FDA’s standards for marketing approval are steep. Another deterrent to commercial development of natural psilocybin drug products (and corresponding evidence production) is natural substances’ ineligibility for composition of matter patents. Unsurprisingly, commercial sponsors have focused on developing synthetic psilocybin instead.

So, should patients have legal access to unapproved natural psilocybin moving in interstate commerce, given weakened incentives to develop evidence about it? Before reaching that conclusion, at least two critical questions remain.

First, is there a combination of existing and new incentives to research and develop natural psilocybin that could justify rigorous regulatory gatekeeping designed to encourage evidence production? This is an open question. Natural psilocybin products may be eligible for method of use patents and FDCA exclusivity provisions. In addition, Congress could devise new intellectual property protections, or it could offer public funding or prizes. Similarly, states can support research and development, as some have.

Nonprofit organizations and public benefit corporations (PBCs) can also make important contributions. For example, the Multidisciplinary Association for Psychedelic Studies (MAPS) pioneered psychedelic development while advancing open science and eschewing monopoly approaches to intellectual property. However, MAPS eventually spun off a Public Benefit Corporation to pursue pharmaceutical development, and this PBC unsuccessfully sought intellectual property protection for MDMA, with some criticism. Usona Institute is a 501(c)(3) nonprofit medical research organization, funded by donors, pursuing development of synthetic psilocybin with the goal of placing “research results in the public domain” without commercial gain. The Scottsdale Research Institute Foundation is another nonprofit working in this space, conducting research with whole Psilocybe mushrooms (in addition to other substances). These initiatives suggest that patents and profit-motivation are not always necessary to stimulate research, although the challenges are steep. 

Second, would allowing treatment access to unapproved natural psilocybin incidentally inhibit evidence generation regarding synthetic psilocybin, perhaps by deterring people from participating in clinical trials of synthetic psilocybin drugs and threatening their financial viability if approved? To answer this question, we must ask how many individuals who would otherwise participate would avoid controlled clinical trials of synthetic psilocybin if they could assuredly and legally obtain natural psilocybin—or, stated differently, whether trials of synthetic psilocybin would still be able to adequately recruit participants. We must also consider factors a patient might weigh in choosing between natural psilocybin and synthetic psilocybin, including the possible presence of entourage effects, dosing certainty, ease of access, and cost. It is important to note that if FDA approval helped commercial sponsors secure insurance coverage of their synthetic psilocybin products, sufficient incentive for development might exist even if natural psilocybin became more accessible.

On both these questions, cannabis provides helpful insights—or a cautionary tale. Although FDA has approved some cannabinoid products, widespread availability of cannabis for recreational use and state endorsement of “medical marijuana” may have contributed to the generally poor evidence base for health-related uses.  As the director of the Cannabis Science Lab at Johns Hopkins University put it: “There’s no business incentive for a company to spend $20 million on a randomized controlled trial because they can sell their products without it.” The same concern might arise if natural psilocybin were widely accessible.

With these open questions, the benefits of anticipated evidence production seem to provide at least a plausible justification for banning interstate commerce in both natural and synthetic psilocybin until FDA approval is achieved, even while allowing off-label use of other psychiatric drugs. By contrast, the goal of avoiding exploitation of desperate patients cannot easily explain the distinct legal approaches to Patient A and Patient B. In both of our scenarios, the patients, though desperate, have the protection of a learned intermediary subject to professional regulation. Concededly, a physician’s involvement  doesn’t offer complete protection against purveyors of useless or dangerous treatments. But the use of psilocybin for MDD seems well past the snake oil threshold, even if not yet proven effective to FDA’s approval standards. And its risks appear to be fairly low in clinical settings, so long as patients susceptible to psychosis are excluded and other precautions are followed. In short, Patient B, who seeks psilocybin, does not seem more vulnerable to exploitation than Patient A, who wants to try Pretendazine off-label. As with off-label prescribing, patients receiving unapproved psilocybin therapy could be protected through informed consent requirements, a less restrictive alternative than prohibition.

So far, we have discussed justifications for the FDCA’s approach to psilocybin without regard to the CSA’s prohibitions. Moving to the CSA, we see that the general justifications for a government ban via imposition of Schedule I status do not stand up to scrutiny for psilocybin. Although its medical use is not yet accepted in the sense of having FDA approval, the drug has been substantially studied for treatment of MDD and it is being developed as a medicine for this use. Setting that aside, psilocybin’s addiction potential is very low, as is its diversion potential if used under clinical supervision or grown in limited amounts for personal use.

Conclusion

Drug regulation is not a binary choice between laissez-fairism and complete government control. But any government interference with the medical decisions of competent adults needs substantial justification. Here, we’ve identified at least one plausible justification—incentivizing evidence generation—for prohibiting introduction of natural and synthetic psilocybin into interstate commerce for medical use prior to FDA approval, while challenging justifications based on concerns about protecting desperate patients, reducing addiction, and preventing diversion. Further analysis should explore whether a federal ban on unapproved natural psilocybin via application of the FDCA is in fact justified in the name of evidence generation.

In the meantime, what can be done for Patient B, who is seeking to try psilocybin? Ideally, he could take advantage of EA (which has greater FDA oversight and protections than the RTT pathway). Here, the obstacle is not government interference, since FDA approves nearly all requests. Instead, sponsors are often reluctant, for various reasons, to distribute their products prior to approval. RTT sought to address some of those reasons, but it has not led to greater sponsor willingness to make unapproved drugs available. Policymakers should devote further attention to buttressing the EA pathway for psychedelic medicines while evidence generation to support their approval continues.  

Holly Fernandez Lynch is Associate Professor of Medical Ethics in the Department of Medical Ethics and Health Policy at the Perelman School of Medicine, University of Pennsylvania.

Dr. Lewis A. Grossman is the Ann Loeb Bronfman Professor of Law at the Washington College of Law, where he has taught since 1997 and where he served as Associate Dean for Scholarship from 2008 to 2011 and 2022.