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National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Forum on Neuroscience and Nervous System Disorders; Stroud C, Posey Norris SM, Matney C, et al., editors. Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop. Washington (DC): National Academies Press (US); 2022 Sep 1.
Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders: Proceedings of a Workshop.
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To understand the potential role of psychedelics in the future of psychiatry, understanding where the field has been and where it is now may be helpful, said Charles Grob, professor of psychiatry and pediatrics at the University of California, Los Angeles, School of Medicine.
The first archaeological evidence of shamanic use of mushrooms dates back to well over 7,000 years, said Grob. “We know from the anthropologic record that the use of plant hallucinogens was integral to the religious and medicinal practices and customs of the time,” he said. However, the use of hallucinogenic plants for healing purposes was virtually unknown in the Western world until the early 1950s, when an amateur mycologist, R. Gordon Wasson, was invited by an Indigenous healer in central Mexico to participate in a healing ceremony. Wasson’s account of his experience with “magic mushrooms” was published in Life magazine (Wasson, 1957), marking the first report of the mushrooms’ psychedelic properties, said Grob.
Wasson sent the mushrooms to leading chemists around the world, including Albert Hoffman, who, only a decade or so earlier, had discovered that the synthetic chemical lysergic acid diethylamide (LSD) exerted powerful psychoactive effects. Hoffman, noted Grob, was also the first to identify psilocybin as the active alkaloid in the mushrooms. The British writer Aldous Huxley, best known as the author of the dystopian novel Brave New World, was also a proponent of psychedelic drugs during the 1950s, particularly in using them to “facilitate the passage of individuals from the end of life through dying,” said Grob. Huxley corresponded about these mind-altering compounds with the British Canadian psychiatrist Humphrey Osmond, who coined the term “psychedelic,” from the Greek word for mind manifesting. Other terms proposed included “hallucinogen,” “entheogen” (accessing the divine within), “allucinari” (mind journeying, mind wandering, mind traveling), “psychotomimetic,” “mysticomimetic,” and “phantasticant.” Even now, debate about nomenclature remains.
During the “golden era of psychedelic research” from the 1940s and 1960s, Grinspoon and Bakalar (1979) estimated that more than 1,000 published clinical papers detailed the experiences of some 40,000 patients treated with psychedelics, said Grob. Among the conditions targeted, some of the best outcomes were in the treatment of alcoholism, drug addiction, and PTSD, said Grob. Some studies have also indicated effectiveness in the treatment of chronic refractory obsessive-compulsive disorder (OCD), antisocial behavior, autism, depression, and profound reactive anxiety, such as the existential anxiety associated with terminal cancer, he said.
By the mid-to-late 1960s, however, psychedelics research unraveled as the drugs seeped out of research settings and began diffusing through the culture, said Grob. As they became increasingly linked to the politically active counterculture, Grob said they “became more and more outside the realm of what our society could deal with.”
Unlike the plant-derived psychedelics, 3,4-Methylenedioxymetham-phetamine (MDMA) was synthesized and patented by German chemists at Merck Pharmaceutical Company in 1912, but with the advent of hostilities in World War I, it was “put on a back shelf and forgotten,” said Grob. Structurally similar to both mescaline and amphetamine, MDMA and related compounds captured the interest of U.S. Army Intelligence in the 1950s, but pursuit of these compounds came to an abrupt end when a participant in these investigations died. Clinical interest in MDMA resurfaced in the mid-1970s, but by the early 1980s it had become “wildly popular as a club drug,” which led to its scheduling as a controlled substance, according to Grob. In the early 1990s, Grob and colleagues conducted the first Phase 1 study of MDMA to establish safety parameters (Grob et al., 1996).
THE PSYCHEDELIC PSYCHOPHARMACOLOGY PARADIGM
“Are we at the point where we might consider a paradigm shift [in psycho-pharmacology]?” asked Grob. Unlike conventional psychopharmacologic compounds, which are typically administered on a daily basis for weeks, months, or years, psychedelics are administered only once or a few times within the context of ongoing psychotherapy, he said. Conventional agents are also intended to ameliorate a pathological brain state and are not dependent on the patient’s attitude or insight, while psychedelics loosen defenses, facilitate insight, and may induce a mystical experience. Most importantly, although conventional agents can be valuable for some people, many people’s needs go unmet, said Grob.
Hallucinogens can be categorized as classic and non-classic, said Grob. Classic hallucinogens, such as mescaline, psilocin, and LSD have their primary effect on the serotonergic system and are primarily 5-HT2A receptor agonists. Non-classic hallucinogens include MDMA, known more popularly as ecstasy or molly, ketamine, and ibogaine. MDMA is also known as an entactogen, which reflects its ability to promote affiliative social behavior (Nichols, 2022). Many of these compounds were originally discovered in plants and “have been used by Indigenous people since time immemorial,” said Grob.
The subjective effects of psychedelics include stimulation of affect, enhanced capacity for insight and introspection, perceptual changes, and alterations of thought and time. It may feel like a waking, lucid dream, or a thematic vision that tells a story, said Grob. The psychedelic peak experience, a concept developed more than 50 years ago, includes a sense of awe and deeply felt reverence, a very positive mood, transcendence of time and space, and a sense of ineffability (Pahnke and Richards, 1966). According to Grob, “It’s very difficult to put these experiences into words, endowing the user with a profound sense of meaning of their psychological and/or philosophical insight.”
MDMA is relatively mild, easily controlled, and of moderate duration, said Grob, and has “the unique quality of facilitating profound empathy and compassion toward oneself and others.” Combined with its ability to facilitate insight, introspection, and positive mood, he said MDMA has been “found to be very valuable within a psychotherapeutic context.”
Looking to the future, Grob said optimizing safety and ethical parameters is critical. Two extrapharmacological variables—set and setting—greatly influence the outcome of treatment, he said. Set includes the personality, state of mind, vulnerabilities, expectations, and intentions of the person taking psychedelics. Setting refers to the physical, social, and cultural environment in which the compounds are taken. To ensure safe dosing, Grob said that the compounds should not be taken alone, but with a facilitator or therapist who can optimize the patient’s safety. The potential for rapid commercialization presents additional challenges with respect to the safety of individuals who could benefit from these treatments. “We need to avoid the temptation to cut down on cost in order to maximize return on investment,” which could put patients in jeopardy, he said. Grob also noted the need within the field to create opportunities for greater diversity among both investigators and study participants. These compounds offer great potential, he said, “but we need to avoid the mistakes of the past.”
PERSONAL EXPERIENCES OF PSYCHEDELIC TREATMENT
A better understanding of the lived experiences of individuals treated with psychedelics is essential to ensure that future research efforts are designed to optimize the efficacy of these compounds in real-world settings. To ensure that the workshop reflected the patient perspective, two volunteers were asked to share their personal experiences of being treated with psychedelics—both the benefits of treatment and the challenges encountered in accessing this treatment. These narratives are meant to illustrate the types of responses individuals may have, but are not intended to represent the diversity of individuals who can benefit from this treatment nor the diversity of responses they may have.
Psilocybin for Major Depressive Disorder
Nora Osowski said she did not escape her family history of major depressive disorder, but as one of seven children in the family with two busy working parents, she got through her 20s and early 30s undiagnosed and without ever seeking treatment. By her mid-30s, after dealing with some health problems and the end of a long-term relationship, she sought treatment: first with tricyclic antidepressants, then selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors, and other atypical antidepressants. “I stuck with them for the prescribed amount of time”—at least 3 to 6 months for every class of antidepressant, she said, but “nothing worked.”
Shortly before turning 39, she got married and immediately wanted to start a family, but 6 months into her pregnancy, she went into premature labor and lost her baby after an emergency cesarean section. On top of that loss, she went back to work at a stressful job. “Things just all came to a head and I experienced [such] a period of depression during which I couldn’t get out of bed. I could no longer function,” said Osowski.
A vacation to the Caribbean did not alleviate her depression, but on her way home from that trip, she decided to see if she could find something else to try in a clinical trial. Ketamine trials were no longer enrolling, but she found a psilocybin trial at Johns Hopkins University. “I would have tried anything at that time,” Osowski said. “I was desperate.”
Osowski went through the lengthy screening assessments, successfully enrolled, and began her preparatory visits with a social worker at Johns Hopkins who served as Osowski’s session facilitator. During these visits, the social worker talked to her about her history and frame of mind and prepared her for what to expect in the trial. “She did an excellent job of making me feel safe and comfortable,” including meeting with her in the treatment room, said Osowski.
Osowski described her first psilocybin session as “very intense.” Encouraged to bring items from home, she brought her baby’s blanket, ashes, photographs, and other meaningful belongings. Lying on the couch with eyeshades and headphones, listening to music (a playlist curated and standardized by the investigators and approved by an institutional review board), she said her mind was flooded with profound feelings of failure as a mother unable to protect her son. While it was a very emotional experience, she said, “I could look at that word ‘failure’ and feel very removed from it and objective.” The two psilocybin treatment sessions were followed by integrative sessions, designed to enable Osowski to integrate insights realized during treatment. These sessions allowed her to process these memories further, which Osowski said was extremely valuable.
In her second session, she had an entirely different experience, highlighted by “a profound feeling of relaxation.” She said that the entire experience of the trial brought her back in touch with her true core values and gave her the opportunity to reexamine her priorities and move beyond the negative thought patterns that had been so inescapable. She credited the trial with providing the spark she needed to go back to school and get a nursing degree. “I don’t think that would have happened without my experience at Hopkins in the psilocybin trial,” she said. “Psilocybin has had an enduring effect on the way I think, on how I’ve changed my priorities and my life,” said Osowski.
MDMA-Assisted Psychotherapy for PTSD
Growing up in a household with a mentally unstable parent did little to prepare Lori Tipton, executive director of the Psychedelic Society of New Orleans, for the multiple traumas she would experience in her 20s. First, her brother died of a drug overdose. A few years later, in 2005, she discovered the bodies of her mother and two people her mother had murdered before committing suicide. The traumas kept on coming: only a month and a half later, Hurricane Katrina destroyed much of the Gulf Coast where Tipton lived, and the following year she was raped by someone she knew and trusted, became pregnant, and had an abortion.
Tipton said the next decade of her life was filled with the many symptoms of posttraumatic stress disorder (PTSD): anxiety and hypervigilance, mood swings, panic attacks, insomnia, suicidal ideation, and the inability to feel joy. She sought help from psychiatrists and other physicians, psychologists, social workers, therapists, physical therapists, an acupuncturist, a massage therapist, practitioners of deep-tissue bodywork known as Rolfing, and other alternative and homeopathic approaches to mental wellness. At times, she said, some of these modalities would temporarily relieve her symptoms, but “nothing really lasted, nothing addressed the core trauma.”
In 2017, after reading about a study exploring the use of MDMA for the treatment of PTSD, Tipton applied and was accepted to participate in the Multidisciplinary Association for Psychedelic Studies (MAPS)1 trial. The client-led therapy model being used in this study appealed to her because it gave her control over what would be discussed in the sessions. At several 1- to 2-hour preparatory sessions before her treatment, she talked with her two therapists about her goals. “I started thinking of them more as trauma doulas, who were there to create a safe environment for me to do the work of inner discovery and potential healing,” she said. “It was clear to me that they weren’t going to heal me, that I was going to have to do the work for myself, but that they were there to completely support my process.” She added that these integrative sessions continued even after she had received the medication.
Tipton received MDMA three times over the course of approximately 3 months. She described these sessions as “very interesting and intense.” “Taking a powerful empathogen and having two people there to completely support you is an incredibly healing event in itself,” she said, adding that the effects of MDMA were also undeniable. “I felt embodied in a way that I hadn’t in years because PTSD had robbed me of the ability to feel safe in my own body,” she said.
A resurgence of memories flooded her mind during these sessions, said Tipton. “I felt everything—sadness, guilt, joy, loss, anger, surprise, understanding, confusion, and love. Everything and nothing.” Recalling a vivid memory of playing with her brother when they were children allowed her to feel joy and elation, she said. “If that embodied experience of being with my brother was all I got out of the entire experience, it would have been completely worth it.” She said she also recalled specifics about the murder scene at her mother’s house that had been completely missing from her internal narrative of the event. “It wasn’t like logically filling in the blank,” but more like finding a section of a videotape that had been removed, she said.
As a result of these sessions, Tipton said she found a new perspective on life that had eluded her for years. “I felt as if I had been viewing the world through dirty lenses, and in those sessions the glass had been wiped clean.” She learned to be more kind and patient with herself and others, to let go of the guilt she felt for people she had let down, and to cultivate love, understanding, and forgiveness for herself. Her personal therapist, whom she had continued to see throughout this time in the trial, commented that what Tipton had accomplished in less than 6 months would have taken decades to accomplish with traditional therapy. “I wouldn’t say that MDMA-assisted therapy completely cured me of my PTSD, but when I completed the trial in 2018, I no longer qualified for the diagnosis and I still don’t qualify for the diagnosis today,” she said. “I don’t suffer regularly from any of the symptoms that have plagued me for years.”
Footnotes
- 1
To learn more about the MAPS Phase 3 MDMA-Assisted Therapy for PTSD study, see https://maps
​.org/mdma/ptsd/phase3 (accessed May 9, 2022).
- History and Current Status of Psychedelics and Entactogens for the Treatment of ...History and Current Status of Psychedelics and Entactogens for the Treatment of Psychiatric Disorders - Exploring Psychedelics and Entactogens as Treatments for Psychiatric Disorders
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