The Renaissance of Psychedelic Research: History, Protocols, and Forward Trajectories

Psychedelic medicine has re-emerged as one of the most exciting frontiers in psychiatric and psychological research. Once relegated to the fringes of countercultural movements and criminalized under federal law, substances like psilocybin, MDMA, LSD, and DMT are now at the center of rigorous scientific inquiry. This dramatic shift in public perception and regulatory acceptance has opened new doors for exploring the therapeutic potential of psychedelics in treating conditions such as PTSD, depression, and anxiety disorders (Carhart-Harris & Goodwin, 2017; Reiff et al., 2020).

Historical Context and Cultural Roots

The term "psychedelics" may evoke images of the 1960s, but the use of psychoactive plant-based substances spans millennia. From the Amazonian rituals involving ayahuasca to the African ceremonial use of ibogaine, early civilizations have long revered psychedelics for their capacity to induce transcendental and spiritual experiences (Schultes et al., 2001). These substances were not used casually but were embedded in structured rites of passage, healing ceremonies, and religious practices.

Western engagement with psychedelics did not take hold until the 18th century and only gained popular momentum in the mid-20th century. By 1957, the term "psychedelic" had entered public consciousness, and substances like LSD and psilocybin were catapulted into the mainstream (Osmond, 1957). Unfortunately, their association with controversial figures and counterculture movements in the 60s and 70s led to a significant backlash, resulting in The Controlled Substances Act of 1970 which classified psychedelics as Schedule I drugs, stalling research for decades (Dyck, 2005).

The Rebirth of Psychedelic Research

The resurgence began subtly in the 1990s, fueled by growing interest in MDMA's potential to enhance psychotherapy, particularly in PTSD treatment. Organizations such as MAPS (Multidisciplinary Association for Psychedelic Studies) spearheaded this movement pioneering clinical trials that would lay the groundwork for broader psychedelic acceptance (Doblin, 2002).

A major turning point came in 2019 when the FDA granted breakthrough therapy status to psilocybin for treatment-resistant depression (FDA, 2019). That same year, Johnson & Johnson’s Spravato™ (a ketamine-derived compound) received FDA approval, signaling a dramatic regulatory shift toward openness in evaluating previously stigmatized substances (Daly et al., 2019).

Clinical Protocol: The Role of “Set and Setting”

One of the most critical components of modern psychedelic trials is the incorporation of “set and setting” — the mental state of the participant and the physical or social environment during the experience. This protocol is considered essential for maximizing therapeutic benefit and minimizing psychological risk (Hartogsohn, 2016; Johnson et al., 2008).

Participants typically engage in three types of sessions with trained facilitators: preparatory, dosing, and integration. Preparatory sessions involve rapport-building, education on potential psychedelic effects, and mindfulness practices like meditation or breathing exercises. Dosing sessions are carefully structured and supervised for several hours, while integration sessions help patients process their experience and derive lasting meaning from it.

This holistic approach, while widely supported, has also introduced a methodological challenge. Critics argue that the therapeutic support embedded in the set and setting protocol may obscure the true pharmacological impact of the psychedelic compound, making it difficult to isolate the “active ingredient” of healing — the drug or the therapy (Yaden et al., 2022).

Functional Unblinding and the Placebo Problem

Another methodological hurdle in psychedelic research is “functional unblinding.” Due to the unmistakable and often intense effects of psychedelics, it is difficult to maintain participant blindness in controlled trials (Muthukumaraswamy et al., 2021). Unlike traditional pharmaceuticals, where placebo effects can be more easily accounted for, the vivid perceptual and physiological changes induced by psychedelics render placebos like niacin inadequate. This has prompted regulatory agencies and researchers to develop more sophisticated strategies, such as functional unblinding questionnaires, blinded raters, and expectation management (Davis et al., 2021) to reduce expectation bias and enhance the integrity of trial data.

Evolving Standards and Future Directions 

In response to regulatory feedback, particularly from the FDA, trial designs are undergoing important refinements. One notable shift is the replacement of intensive therapeutic guidance with Dosing Session Monitors (DSMs), whose role is to ensure participant safety without offering psychotherapeutic intervention (Nutt & Carhart-Harris, 2021). This minimalistic approach aims to clarify the direct effects of the drug while improving trial scalability and accessibility. Preliminary data suggest that therapeutic benefits may still emerge even with reduced interpersonal support, a finding that could shape future protocols and broaden clinical application (Nichols et al., 2017).

Collaboration between regulatory bodies and researchers has been instrumental in overcoming the unique challenges posed by psychedelics. The integration of scientifically validated tools for assessing bias and enhancing trial design reflects a growing maturity in the field. As psychedelic research becomes more standardized, the prospect of safe and effective integration into mainstream psychiatry becomes increasingly feasible.

Conclusion

The resurgence of psychedelic research reflects a confluence of cultural reappraisal, scientific innovation, and regulatory evolution. While debate continues over the ideal therapeutic framework — intensive support versus minimal monitoring — both approaches share a commitment to ethical responsibility and empirical rigor. The historical trajectory of psychedelics, from sacred medicine to Schedule I prohibition and now to clinical reintegration, underscores the importance of context in both public policy and scientific inquiry. As research progresses, psychedelics may not prove to be universal cures, but they stand poised to become vital components in the modern therapeutic arsenal.

About the Author 

Djouher Hough, Psy.D., Executive Director of Clinical Sciences at CRC

Dr. Djouher Hough is a licensed clinical psychologist with more than 15 years of experience in CNS research, specializing in psychedelic and addiction medicine. She has led and facilitated studies involving psilocybin, LSD, MDMA, DMT, and ketamine, advancing treatments for depression, PTSD, and substance use disorders. Her expertise spans trial design, Human Abuse Liability research, and regulatory compliance for Schedule I investigational products. At CRC, she guides scientific strategy and cross-functional collaboration to support the development of novel psychiatric and psychedelic therapies.