Psychedelic Medicines: The Future?

The uptick of interest in psychedelic medicines has launched a once-taboo topic into the medical mainstream. With respected academic and research institutions diving into comprehensive studies that chronicle the therapeutic uses of psychedelics (substances that can temporarily alter a person’s mood, thoughts and perceptions of reality¹), plus popular books and documentaries touting their benefits, it’s easy to wonder what all the buzz is about. While much of the research is focused on their reported benefits for mental health, researchers are increasingly looking at the use of psychedelics — primarily psilocybin, the psychedelic compound in mushrooms — for the treatment of everything from nicotine addiction and anorexia to Alzheimer’s disease.²

“One of the remarkably interesting features of working with psychedelics is they’re likely to have transdiagnostic applicability,” says Roland Griffiths, PhD, who heads the Johns Hopkins University Center for Psychedelic and Consciousness Research (a facility that has led some of the most promising studies evaluating psilocybin for treating depression and alcoholism). “The myriad applications suggested for these drugs may be a big part of what makes them sound, to many, like snake oil — but the data is very compelling.” Dr. Griffiths goes on to note that psychedelics provide an opportunity to “peer into the basic neuroscience of how these drugs affect brain activity and worldview in a way that is ultimately very healthy.”²

A Brief History of Psychedelics

For thousands of years, humans have used plant compounds capable of producing abnormal psychic effects to create altered states of consciousness for religious, mind expansion and recreational purposes. The earliest evidence of psychedelic use can be found in a cave in the Tassili-n-Ajjer region of the Sahara desert in Algeria. The cave features a mural depicting what is referred to as the “mushroom man” or “mushroom shaman,” a bee-headed figure with mushrooms sprouting out of his body. The mushrooms pictured are Psilocybe mairei psychedelic mushrooms, which are native to that region. The mural is estimated to be 7,000 to 9,000 years old; clearly, psychedelic use is nothing new.³

As far as Western culture’s history with psychedelics and the scientific study of their therapeutic uses, here are some timeline highlights:

• 1895: The first scientific trial was conducted for peyote in Washington, D.C., at Columbian University (now George Washington University).
• 1912: Anton Köllisch, a German chemist, became the first person to synth-esize 3,4-methylenedioxyamphetamine (MDMA).
• 1931: Richard Manske, a Canadian chemist, was the first to synthesize dimethyltryptamine (DMT).
• 1947: Sandoz Laboratories marketed lysergic acid diethylamide (LSD) under the brand name Delysid and distributed it as a treatment for psychiatric disorders.
• 1949: Psychiatrist Max Rinkel carried out the first LSD experiment in the United States, giving the substance to 100 volunteers at the Boston Psychopathic Institute.
• 1952: Charles Savage, MD, published the first study looking at LSD as a treatment for depression.
• 1958: Swiss chemist Albert Hofmann isolated and identified the structure of psilocybin and psilocin, the two psychoactive compounds in magic mushrooms.
• 1960-1967: Stanislav Grof, MD, a Czech psychedelic pioneer, conducted more than 4,000 LSD therapy sessions and reported that LSD could relieve anxiety and despair in terminal cancer patients.

The scientific interest in psychedelics shifted in the 1970s when LSD, DMT, MDMA, psilocybin, psilocin, mescaline, peyote and cannabis were all classified as schedule I drugs under the United States Controlled Substances Act. In a nutshell, psychedelics were legally said to have no recognized medical value and a high potential for abuse. As a result, the scientific study of psychedelics was ground to a halt.³ It would be another two decades before sanctioned research into psychedelics ramped up again.

Starting in the 1990s there was a resurgence of government-approved studies about psychedelic substances. In 2019, Imperial College London launched the world’s first Centre for Psychedelics Research, and months later, Johns Hopkins launched its own: the Center for Psychedelic and Consciousness Research. Both centers focused on what psychedelics reveal about consciousness and how these compounds can help treat conditions such as depression, addiction and post-traumatic stress disorder (PTSD). Then, a landmark 2006 Johns Hopkins study demonstrated that psilocybin can generate positive changes in attitude and behavior lasting several months, reigniting interest in psychedelics as a psychiatric treatment. Subsequent studies affirmed and expanded on these findings.⁴

A Shift Toward Social Acceptance

While the study of psychedelics as medicine is inching toward mainstream acceptance, it still remains somewhat controversial thanks to their solidly counterculture reputation. But, opinions may be shifting. In 2021, the U.S. Food and Drug Administration (FDA) granted “breakthrough therapy” status to study the medical benefits of psychedelics. Additionally, in 2019, FDA approved the psychedelic drug esketamine for use in treating depression.⁵

“The resurgence in interest in psychedelic medicine is likely related to multiple factors, including decreasing societal stigma regarding drugs like hallucinogens and cannabis, increasing awareness of the potential therapeutic compounds found naturally occurring in plants and fungi and the growing mental health crisis our nation faces,” said University of Nevada neuroscientist, Dustin Hines, PhD. “Because of the intersection between the great need for innovation and wider social acceptance, researchers have started to explore psychedelics as novel treatments for depressive disorders, including work with compounds that have been used for millennia.”⁶

The question of how psychedelics change the brain is not fully understood. The secret seems to lie in a neurological system called the default mode network (DMN). The DMN switches on when the brain is engaged in activities such as daydreaming or ruminating. For many, this function can lead to habitual worrying and obsessing about past mistakes, precursors to anxiety and depression. It’s thought that psychedelics can temporarily quiet the DMN and activate connections between other regions of the brain. Whereas the mind normally follows well-worn roads, psychedelics essentially open alternative routes, potentially offering refreshed perspectives. Studies have shown that the psychological changes sparked by controlled psychedelics can linger for months or even years, leading to long-term improvements in a range of mental-health disorders,⁴ including:

• Depression: A study of individuals diagnosed with major depressive disorder found that two sessions of psilocybin coupled with psychotherapy yields rapid, substantial and sustained easing of symptoms.
• Substance use: Eight in 10 cigarette smokers who received two or three sessions of psilocybin alongside traditional smoking-cessation treatment remained fully abstinent six months later. Another psychedelic, ibogaine, was found to reduce or eliminate opioid use after a single session.
• PTSD: In one study, MDMA diminished symptoms of PTSD so dramatically that after two sessions, 83 percent of study participants no longer met criteria for the disorder.
• Terminal illness: Several studies have shown that cancer patients treated with LSD and other psychedelics experienced significantly lower anxiety and depression stemming from their diagnosis. Participants also reported less fear of death.

While psychedelics do not have the same addictive properties as other drugs, they must be handled with care and administered in a controlled setting by a trained professional. Additionally, they’re not for everyone; individuals predisposed to certain mental illnesses such as schizophrenia may experience adverse reactions.

FDA Introduces Guidelines for Clinical Trials

In June 2023, FDA published a new draft guidance to highlight fundamental considerations for researchers investigating the use of psychedelic drugs for potential treatment of medical conditions, including psychiatric or substance use disorders. It is the first FDA draft guidance that presents considerations for designing clinical trials for psychedelic drugs.⁷

“Psychedelic drugs show initial promise as potential treatments for mood, anxiety and substance use disorders. However, these are still investigational products. Sponsors evaluating the therapeutic potential of these drugs should consider their unique characteristics when designing clinical studies,” said Tiffany Farchione, MD, director of the Division of Psychiatry in FDA’s Center for Drug Evaluation and Research. “By publishing this draft guidance, [FDA] hopes to outline the challenges inherent in designing psychedelic drug development programs and provide information on how to address these challenges. The goal is to help researchers design studies that will yield interpretable results that will be capable of supporting future drug applications.”⁷

Among the many safeguards the guidelines put in place, FDA suggests clinical trials may be subject to a clinical hold if they don’t include safety monitoring according to FDA’s recommendations. For example, the guidelines state that subjects receiving active treatment with psychedelic drugs remain in a vulnerable state for as long as 12 hours, and that safety monitoring should involve a healthcare provider with graduate-level professional training and clinical experience in psychotherapy, and an assistant monitor with a bachelor’s degree and at least one year of clinical experience in a licensed mental healthcare setting.

According to the report, the purpose of the draft guidance is to advise researchers on study design and other considerations as they develop medications that contain psychedelics. Within the draft guidance, the term psychedelics refers to “classic psychedelics,” typically understood to be drugs such as psilocybin and LSD that act on the brain’s serotonin system, as well as “entactogens” or “empathogens” such as MDMA.⁷

Considerations for Prescribing Psychedelics

Source: Adapted from The Rebirth of Psychedelic Psychiatry. Current Psychiatry, 2021 January;20(01):13-16, 18-19. Accessed at www.mdedge.com/psychiatry/article/233919/depression/rebirth-psychedelic-psychiatry/page/0/3?reg=1&icd=login_success_email_match_norm.

Understanding the Research

From a research perspective, one priority is to understand why only certain drugs work for some disorders and not for others, isolate those effective drug mechanisms and focus research efforts around those mechanisms to develop far more targeted, disorder-specific treatments.⁸ Scientists are now beginning to tease out the brain mechanisms behind the distinctive mind-altering properties of these different drug families, a critical step in turning them into mainstream treatments.

Researchers have already identified that certain psychedelics seem to work by binding to the serotonin 2a receptor, one of the 15 specialized receptor molecules the serotonin system uses to coordinate brain activity. Entactogens and dissociative anesthetics don’t directly act on this receptor, which is why they “feel” different from hallucinogens. By comparison, ketamine, a dissociative anesthetic that has some hallucinogenic effects, has been linked to a specific receptor in the brain’s glutamate system.⁷

“We need more research using the same rigorous methods applied to many other promising compounds for mental illnesses. By studying both efficacy and mechanisms, we can be more precise in developing better treatments with fewer side effects,” said Carolyn Rodriguez, MD, a professor of psychiatry and behavioral sciences who co-authored a July 2022 position statement by the American Psychiatric Association on the mental health uses of psychedelics and empathogens.⁷

Dr. Rodriguez, who directs Stanford Translational Therapeutics, is leading studies on the mechanisms underlying ketamine’s effects, a crucial component of her work on ketamine as a potential therapy for obsessive compulsive disorder (OCD). Her study on ketamine’s mechanism of action aims to better understand how ketamine helps OCD patients — one stepping stone toward a targeted OCD treatment.

Another key question is how these drugs change the brain itself to produce their unique mental states. Karl Deisseroth, MD, PhD, D.H. Chen Professor, professor of bioengineering and professor of psychiatry and behavioral sciences at Stanford and a Howard Hughes Medical Institute investigator, has studied how ketamine alters brain dynamics to produce the characteristic “dissociative” state that appears to help some patients with depression and other disorders. In a 2020 study, the Deisseroth lab linked these dissociative states to a specific rhythm of activity in particular circuits in the mouse brain. When the team artificially reproduced this rhythm in normal mice, they found they could directly trigger dissociation, even without ketamine.⁷

What the Future May Hold

With the field of psychedelics booming, researchers are operating in a high-stakes environment. On the one hand, it’s never been a better time to study these compounds: FDA has indicated their intent to approve both MDMA and psilocybin as mental health treatments in the next two years. The downside, according to Robert Malenka, MD, PhD, Nancy Friend Pritzker professor of psychiatry and behavioral sciences, is the risk that widespread medical legalization of these substances might lead to rampant misuse, which could threaten the future of psychedelic medicine altogether. “As soon as something bad happens, the pendulum will swing the other way,” he said. “We don’t want to return to the early 70s, where some individuals and communities used these substances inappropriately and bad things happened.”⁸

It remains to be seen how regulators will scale up and facilitate this pipeline from lab breakthrough to mainstream treatment. But for now, many researchers are excited to begin exploring and utilizing innovative options to help treat mental disorders that have long resisted traditional treatments. If these once-taboo drugs prove to deliver beneficial and lasting results, it could usher in a whole new era for medicine. And, while it’s been decades in the making, all signs indicate that even the medical field’s most conventional thinkers may be opening their minds to the possibilities psychedelics have to offer.