Overview of Psychedelic Medicine

EXPERT COMMENTS

• Editor’s Note: We are thrilled to introduce this update to the psychiatry POC-IT guide featuring several new sections on psychedelic medicine. As psychedelic medicine emerges as subfield of Psychiatry, we recognize the need to educate providers on the rapidly shifting scientific landscape where media hype has often outpaced evidence-based recommendations[1]. The POC-IT platform we believe is uniquely suited to provide expert-reviewed information on psychedelic medicines that can be updated in real-time to reflect the evolution of this rapidly changing field.
• The initial sections covered by this guide seek to highlight the three primary medications, their chemical properties and methods of clinical use, that are under investigation using the psychedelic treatment model: Psilocybin, methylenedioxymethamphetamine (MDMA), and Ketamine.
  • Ketamine, a dissociative anesthetic, often prompts confusion when discussed within the context of psychedelic medicine because it has several clinical uses that do not employ the psychedelic treatment model, i.e. a model where a non-ordinary state of consciousness is induced with deliberate attention to mindset, preparation and psychological integration that altered state.
• While these three substances are most likely to be seen in clinical research or in early adoption within clinical practice (as is the case with ketamine), other novel psychedelic medicines are currently under investigation and may progress toward clinical use in the future.
• In addition to featuring these medications, we also elected to share important considerations around ethical concerns within the field of psychedelic medicine, safety and harm reduction with recreational users, as well as opportunities for enriching diversity equity and inclusion within psychedelic clinical research.

DEFINITION

• The definition and scope of “psychedelic medicine” is debated within the field of Psychiatry and can refer to mechanistically distinct psychoactive substances depending on the phenomenology of their psychoactive effects and clinical applications[2].
• A pragmatic definition that incorporates many of the most common uses of the term “psychedelics” relies on three conditions.
  • Psychedelic medicine may refer to a psychoactive substance that has a primary mechanism of action at the 5HT2A receptor. These substances are often referred to as “classic” psychedelic medicines.
    • Lysergic acid diethylamide (LSD), psilocybin, mescaline, dimethyltryptamine (DMT) are all considered classic psychedelic medicines due to their 5HT2A receptor activity.
  • Psychedelic medicine may refer to a psychoactive substance that induces a non-ordinary state of consciousness (NOSC) which results in a shifting of attentional scope, diminished self-referential thought, and hyper-associative processing.
    • While MDMA’s mechanism of action is not primarily at the 5HT2A receptor and it is not considered a “classic psychedelic,” MDMA can induce a NOSC that impacts perception, self-referential thinking, and associative processing.
  • Psychedelic medicine may refer to a psychoactive substance that is coupled with a clinical model of support attending to mindset, clinical setting, and preparation for and integration of a NOSC.
    • Ketamine, as mentioned above, is not considered a classic psychedelic medicine and may not share the same phenomenological characteristic of primarily serotonergic medications; however, it frequently induces a NOSC that can be supported using the psychedelic treatment model.

HISTORY OF PSYCHEDELIC MEDICINE

• Pre-Columbian cultures of Central and South America are known to have used hallucinogens in magical, therapeutic, and religious settings.[3][4]
• Iconography from both Andean and Mesoamerican traditions show visual representations of trance states and shamanic rituals involving hallucinogenic plants.[4]
• The earliest known use of hallucinogens involved the chemical mescaline. Archaeological findings have revealed the presence of hallucinogenic cacti, such as peyote in rituals dating back nearly 6000 years and San Pedro appearing around 2,500 years ago. Scientific investigation of mescaline gained momentum in the late 19th century. Arthur Heffter isolated the compound in 1896, and mescaline’s presence in San Pedro was confirmed in 1960.[5]
• LSD was synthesized in 1938 by Swiss chemist Albert Hofmann. Not long after, it moved beyond psychiatric research settings and entered wider cultural awareness. By 1965, over 1,000 scientific papers had been published, involving approximately 40,000 participants. Despite widespread scientific interest, methodological issues, sensational media reports, and growing recreational use led to a shift in public and political sentiment. LSD was eventually categorized as a Schedule I substance under the 1970 Controlled Substances Act, which brought most clinical research to a halt.[6][7]
• Psilocybin, the psychoactive compound found in over 200 species of mushrooms, has a long history in Mesoamerica ritual use. It was referred to as teonanacatl, or “God’s Flesh,” in sixteenth-century accounts like the Florentine Codex. Scientific investigation began in 1955, after R. Gordon Wasson took part in a Mazatec ceremony led by María Sabina, which was written about in Time magazine. Roger Heim later identified and cultivated Psilocybe species, and in 1958, Albert Hofmann at Sandoz isolated psilocybin and identified psilocin as its active metabolite. These breakthroughs laid the groundwork for current psychiatric research focused on treating depression, anxiety, and substance-use disorders.[8][9][10]
• Ketamine was first synthesized in 1962 by Calvin Stevens at Parke Davis, intended as a safer, shorter-acting alternative to Phencyclidine (PCP), which was known to induce agitation and psychosis. Early human trials conducted by Edward Domino and Guenter Corssen in 1964 showed promising results with rapid pain relief while maintaining a better safety profile. These findings supported its FDA approval in 1970, marketed under the name Ketalar.[11]
• In the late 1960s, growing social and political pressure prompted a shift in policy that prohibited ongoing research in psychedelic medicines with the 1970 US Controlled Substances Act. This resulted in LSD and psilocybin receiving a Schedule I designation, specifying that there was no accepted medical use, despite decades of initial safety and clinical research outcomes.[12]
• MDMA, which was initially synthesized by Anton Kollisch at Merck in 1912, gained both clinical and illicit recreational popularity in the 1980s. While the medication was briefly studied by the military in the 1950s, it was mostly popularized by chemist Alexander Shulgin, who shared the compound with psychotherapists in the late 1970s. The adoption of MDMA by mental health providers prompted initial academic interest; however, increasing recreational abuse and toxicity reports led to its prohibition and status as a Schedule I by the mid-1980s.[13]
• In 1986, Rick Doblin established the Multidisciplinary Association for Psychedelic Studies (MAPS) as a nonprofit pharmaceutical company to pursue research and medicalization of MDMA for clinical use. This organization funded and executed initial clinical research for the treatment of PTSD using MDMA.[14]
• The field of psychedelic medicine remained mostly stagnant in the U.S. until the late 1990s when the founding of the Heffter Research Institute reignited interest and funding opportunities for psychedelic trials.[15]
• Landmark studies in the early 2000s, especially by Roland Griffiths at Johns Hopkins as well as scientists at the University of Arizona, NYU and UCLA, demonstrated that psilocybin could produce lasting reductions in depression, anxiety, and other psychiatric symptoms.[16][17]
• The FDA designations of MDMA as a breakthrough therapy for PTSD and psilocybin for treatment resistant depression in 2017 and 2018, respectively, were major strides towards widespread recognition of psychedelics’ clinical legitimacy.[16][18]
• Ketamine, which was widely used as an anesthetic, garnered significant interest as a rapid antidepressant in the early 2000s spearheaded by researchers at Yale. This led to several studies establishing the anti-depressant effects of Ketamine and the development of the Ketamine enantiomer, esketamine, nasal spray (Spravato) which was FDA approved from treatment resistant depression (TRD) in 2019.[19]
• Within the last decade, clinical Ketamine treatment has incorporated the psychedelic treatment model, utilizing similar preparatory and integration practices typical of psychedelic treatment with MDMA or psilocybin, to further support therapeutic outcomes.[20]
• After the completion of two Phase III clinical trials investigating MDMA for PTSD, the pharmaceutical company Lykos (previously MAPS) put forward a new drug application to the FDA in 2024 which was later denied. This decision was highly controversial given the strong positives outcomes for the treatment of PTSD.[21]
• Clinical studies of psilocybin have further advanced for a number of different indications with the most robust evidence mounting for depressive disorders.[22]

References