Over the past quarter century, we have witnessed a resurgence in medical, scientific, and societal interest in a broad family of psychoactive compounds that itself somewhat defies very clear pharmacological classification. Yet, these compounds have captured our attention given their unique and somewhat peculiar effects on the mind, and their growing potential as novel and rapid therapeutics for an increasing range of psychiatric and other medical conditions. These compounds were extensively studied and explored in scientific laboratories and clinics as well as in the cultural and societal “laboratories” of the 1950s and 1960s in the United States. However, very few scientific products from this era meet modern criteria for rigor and reproducibility, and the social experiment that occurred led to political suppression of these compounds that lasted for decades. In the wake of the early 1970s, we were left with a rift between policy, culture, and science that has only recently begun to close. Though these are powerful compounds that pose clear psychiatric risks (and some that carry medical risks) for some individuals, we are now beginning to better understand their remarkable potential for therapeutic benefit under certain conditions.

What is a Psychedelic?

The word “psychedelic” was coined by a British psychiatrist named Humphrey Osmond who was among the first to utilize these compounds in a western medical setting. Much in the tradition of psychedelic use in the 1950s and 1960s, Osmond personally experimented with these compounds and shared them with his friends in an attempt to better understand how such compounds may be of clinical benefit, especially to his many patients with alcohol use disorder. He coined the term “psychedelic” to describe these compounds, from the roots of “psyche” (ψυχή, meaning “mind” or “soul”) and “delos” (δήλος, meaning “to manifest” or “to make clear”), as he believed that they revealed something fundamental about the mind to the individual experiencing them that they may not have otherwise had access to or awareness for. He also believed that this “psychedelic” property of lysergic acid diethylamide, or LSD (a laboratory chemical), mescaline (derived from psychoactive cacti), and other related drugs was the key to their potential therapeutic value. However, the etymology of the word “psychedelic” leaves an imperfect and imprecise basis for classification at best.

Some have attempted to define psychedelics by their pharmacology, while others have attempted to define psychedelics by the nature of the experiences that they evoke. Earlier medical and scientific definitions of this class of drugs relied on terms such as “hallucinogenic” and “psychotomimetic”. These are now considered narrow and inaccurate characterizations of these compounds (Dourron et al., 2026). Others have limited the scientific definition of psychedelics to compounds that yield psychoactive effects by activating serotonin 2A (5-HT2A) receptors in the brain (Nichols, Nichols, & Hendricks, 2022). This includes LSD and mescaline as well as psilocybin, which is derived from many species of mushroom (these three are considered exemplars of the class). However, classification of psychedelics as 5-HT2A agonists or partial agonists also does not yield a clean parsing of chemical categories, as the “classic” psychedelics fall into at least three chemical classes of tryptamines, phenethylamines, and ergolines. Further, this does not reflect the broader application of the term to compounds that seem to yield similar psychoactive effects yet that do not have the 5-HT2A receptor as their primary target. These “atypical” psychedelics include ketamine (an NMDA-receptor agonist and anesthetic), salvinorin-A (a k-opioid agonist derived from the salvia divinorum plant), and ibogaine (a complex polypharmacological compound derived from the iboga plant).

Psychedelics in the modern era have been found to induce dose-dependent shifts toward non-ordinary states of consciousness of a varying and sometimes heterogenous character, but often including perceptual disturbances, complex close-eyed visualizations, a breakdown of the perceived barrier between self and other, emotional lability, feelings of insight and “expanded” awareness, and selective cognitive impairments. The time course and duration of these psychoactive effects somewhat depend on route of administration (being generally shorter in duration for inhaled and injected delivery, and longer in duration for oral delivery), but may last from 15 minutes for dimethyltryptamine (DMT) to 4-6 hours for psilocybin and 8-12 hours for LSD. Both “classic” and “atypical” psychedelics can share these psychoactive properties to varying degrees. Many have argued that classic and atypical psychedelics at the very least should be considered together as they may share treatment models, clinical applications, and psychological milieu (O’Donnell et al., 2023) in addition to potential underlying molecular- and systems-neurological effects (Ly et al., 2018; Nardou et al., 2023).

Do Psychedelics Have Clinical Benefit?

Many people appeal to archeological evidence suggestive that primal, animist, or earlier tribal communities somehow utilized psychedelic-containing plants and fungi, and rely on this as evidence that these compounds are safe and effective for modern applications relating to spirituality, consciousness, and healing. This is at best a stretch, as archeological evidence itself may be suggestive of consumption of psychedelic-containing plants and fungi, but it gives no clear basis for understanding the actual practices, boundaries, and outcomes of such use, nor does it provide a roadmap for translating how utilization of psychedelics in any prior context should inform current medical, spiritual, or other use. A similar appeal to contemporary tribal practitioners of psychedelic shamanism and other related traditional practices may present a challenge in translation, as it is not always clear whether these traditional practices truly inform or provide a robust and comprehensive evidence base for understanding safety parameters for psychedelics, or that they provide clear application to modern medical contexts and diagnostic categories.

The strongest empirical evidence for the potential safety and efficacy of psychedelic therapeutics currently exists for a handful of psychiatric conditions. Controlled randomized clinical trials have been conducted primarily in mood disorders, substance use disorders, and post-traumatic stress disorder (PTSD), with somewhat fewer studies examining other psychiatric and neurological disorders. Among these, psilocybin for the treatment of depression represents the most robust evidence base (Goodwin et al., 2022; Raison et al., 2023). Two companies (the Usona Institute and Compass Pathways) have been issued Commissioner’s National Priority Vouchers from the FDA that are intended to accelerate FDA review of drug and biological product applications, and both are expected to submit New Drug Applications to the FDA soon for the approval of psilocybin to treat depression and treatment-resistant depression, respectively. While reported effect sizes across published trials have varied widely, a remarkably consistent finding across institutions, populations, and continents has favored highly psychoactive doses of psilocybin over placebo, lower doses of psilocybin, first-line antidepressant therapies, and other psychoactive comparator conditions in the treatment of depression.

The MDMA story, however, illustrates just how challenging this regulatory pathway can be. Despite considerable evidence for efficacy in treating PTSD, Lykos Therapeutics’ application was rejected by the FDA in 2024 due to several concerns: lack of data on the durability of MDMA’s therapeutic effects, the inclusion of participants who had prior recreational MDMA experience (approximately 37% of trial participants), and a failure to adequately collect standard adverse event data. Notably, the FDA did not explicitly cite blinding issues or the role of psychotherapy in the delivery of MDMA as reasons for rejection, contrary to what many in the field assumed, though the broader questions of functional unblinding and the role of psychotherapy in psychedelic interventions remain significant methodological challenges for the field.

Ibogaine presents perhaps the most intriguing paradox in the field. Derived from the root bark of the Tabernanthe iboga plant native to Central Africa, ibogaine produces an experience that can last 12 to 36 hours and is described by participants as confronting a full review of one’s life. Though not recreationally popular, it has been claimed to yield astounding therapeutic properties. Anecdotal and observational evidence suggests that ibogaine can successfully treat patients with traumatic brain injury and ameliorate physical dependence (including craving and withdrawal syndromes) in patients with opioid use disorder. The molecular mechanism of ibogaine involves multiple receptor systems, including µ-opioid, NMDA, and sigma receptors, as well as upregulation of GDNF (glial cell line-derived neurotrophic factor). Critically, ibogaine evinces a serious cardiotoxicity, likely even at doses below the expected therapeutic dose, that prolongs the QT interval (a measure of heart rhythm) to a degree that can disrupt heart function and lead to heart attack. Due to this toxicity, ibogaine has been associated with multiple documented fatalities, and this has proven a barrier to conducting robust clinical trials or advancing ibogaine as a therapeutic in the US. Synthetic analogues, including 18-methoxycoronaridine (18-MC) and tabernanthalog (TBG), are under active development specifically to preserve ibogaine’s therapeutic properties while reducing or eliminating its cardiac liability, though human trials of these derivatives remain in early stages.

Is the Trip Part of the Treatment?

A question generating rigorous debate in psychedelic science is whether the subjective psychedelic experience itself is an “active ingredient” in the therapeutic process (Yaden & Griffiths, 2021; Olson, 2021). This question has substantial implications for drug development, clinical practice, and regulatory approval. On one side are researchers who have demonstrated an association between the subjective effects of psychedelics (often operationalized using questionnaires on “mystical experience” or “ego dissolution”) and resulting therapeutic outcomes. On the other side are those developing what have been called “non-hallucinogenic psychedelics”, which are ideally 5-HT2A receptor agonists that are non-psychoactive. Adding to the potential evidence (though limited) for the potential therapeutic value of non-psychoactive psychedelics is an intriguing case report of a patient in a psilocybin trial who was surreptitiously taking trazodone (a serotonin antagonist medication) who experienced no psychedelic effects yet still showed therapeutic response. This is ultimately an empirical question that requires proper controlled studies to resolve.

What is the Role of Psychotherapy, Set, and Setting?

The term “psychedelic-assisted therapy” has become ubiquitous in the field, but some researchers argue it may be misleading (Goodwin et al., 2023). The core argument rests on whether the pharmacological effects of the drugs alone, or additional study team interaction and psychotherapy, are necessary and/or sufficient for a therapeutic response to psychedelics.

Many of our current assumptions about set (expectancy) and setting (the context in which psychedelic therapy occurs), the use of psychotherapy, as well as the use of pre-drug preparation visits, careful monitoring of drug effects, and post-drug integration visits derive from practices in the previous era of psychedelic research. While most will agree that it is at least reasonable or plausible that these factors contribute to the safety and efficacy of psychedelic therapy, surprisingly little rigorous empirical work has tested these concepts (Golden et al., 2022). One small study in patients with tobacco use disorder manipulated setting by exposing participants to different types of music during their psychedelic experience. No statistically significant difference in clinical outcomes was observed, though there was a slight preference for and a numerically greater “mystical experience” score during those sessions in which overtone music was presented rather than a playlist including primarily western art music (Strickland, Garcia-Romeu, & Johnson, 2020).

The consensus remains that a safe, controlled setting is a common-sense protective factor, and no credible researcher suggests people should use psychedelics unsupervised. But the specific elements that matter, and how much they matter relative to pharmacology, require much more study.

The Blinding Problem and Expectancy Effects

Clinical trials, especially those involving psychoactive substances, are subject to myriad sources of bias and confound, with participants and researchers alike as potential sources. To the degree that participants and/or researchers expect a particular outcome from a given intervention or a comparator to that intervention, and to the degree that they believe they’ve been assigned to one or another intervention, they may then alter their behavior either consciously or unconsciously in alignment with the expected outcome. Blinding is the attempt to obscure the conditions of an experiment or an intervention to the degree that it undermines the influence of expectancy on outcomes. The effects of expectancy on outcomes are real and significant. A notable example of this is one of many studies demonstrating that instructing someone that they received an opioid, when in fact they received an inactive placebo, can lead to both a reduction in self-reported pain and a modulation of the brain’s response to pain (Schafer, Geuter, & Wager, 2017).

A substantial methodological challenge in psychedelic research is the difficulty of maintaining blinding of active psychedelic drug conditions. It is incredibly challenging to convince someone they received a highly psychoactive dose of a psychedelic if they didn’t, and vice versa. This creates “functional unblinding” (in this case, accurately identifying a condition based on unmistakable signs of that condition, despite attempts to blind that condition) which can confound interpretation of results. Given the near certainty of functional unblinding with psychedelics in many clinical trials, it can be difficult to determine whether outcomes of a given study were truly due to the intended intervention, or if they were a product (at least in part) of expectancy. This is compounded by recent observations that placebo effects observed in clinical trials of typical antidepressants (e.g. SSRIs) can be substantial, but such placebo effects are quite attenuated in clinical trials with psychedelics such as psilocybin. This suggests that functional unblinding may be in fact undermining placebo effects in the comparator conditions, and that the magnitude of observed effects with psilocybin (e.g. the difference in outcomes between psilocybin and placebo groups, or between high-dose psilocybin and low-dose psilocybin groups) may be artificially inflated by this weaker placebo effect.

There are, however, some signs that expectancy may not be as determinative of psychedelic outcomes as we suspect. A study comparing psilocybin and the SSRI escitalopram found no difference in treatment response between groups (Carhart-Harris et al., 2021). A secondary analysis demonstrated that the expectation of escitalopram efficacy was predictive of treatment outcome in those who received escitalopram, but expectancy of psilocybin efficacy was not predictive of treatment outcome in those who received psilocybin (Szigeti et al., 2024).

Researchers are exploring various solutions to this problem. Some have proposed using psychoactive comparator drugs rather than inactive placebos: for example, comparing MDMA to high-dose amphetamine, or psilocybin to high-dose THC. Very high doses of the cough suppressant dextromethorphan (which can be highly psychoactive and psychedelic-like) has also been used as a comparison condition. In the case that participants are naïve to both conditions, one might expect that they would not easily determine which intervention they received. However, each approach has limitations, and no consensus solution has emerged.

The FDA’s guidance on psychedelic drug development proposes at least two sets of clinical trial designs to address this question: one comparing the active compound to inactive placebo (primarily for safety data), and another using a dose-escalation or dose-comparison approach to better control for functional unblinding. The challenge with dose-comparison studies is that detecting differences between high and moderate doses may require very large samples.

Where Do We Go From Here?

Psychedelic science stands at a remarkable moment. Some percentage of patients with depression and PTSD for whom the standard of care approach is ineffective appear to respond to psychedelics. For these patients, psychedelic therapy offers genuine hope. Yet the field must maintain scientific rigor even as enthusiasm builds. The methodological challenges are real, the mechanisms incompletely understood, and many foundational questions remain unanswered. The path forward requires careful empiricism, adequate independent funding for independent investigator-initiated research, and a regulatory frameworks that balance access with safety. What is clear is that we are witnessing a potential paradigm shift in psychiatric treatment that deserves both excitement and scrutiny in equal measure.

Frederick S. Barrett is the Shih Yin Professor in Psychedelics and Consciousness Research and the Director of the Center for Psychedelic and Consciousness Research in the Department of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine.