Mind Menders: The Future of Psychedelics for Mental Illness

Batya Swift Yasgur MA, LSW

November 10, 2020

After a 50-year hiatus, psychedelic drugs are undergoing a research renaissance. Agents including psilocybin, methylenedioxymethamphetamine (MDMA), and others are all under investigation to treat a variety of psychiatric illnesses.

Medscape spoke with Roland R. Griffiths, professor in the Departments of Psychiatry and Neuroscience and the Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness, and director of the Center for Psychedelic and Consciousness Research at Johns Hopkins University, Baltimore, Maryland, to discuss the status of these drugs in the United States and their therapeutic potential.

Griffiths: Classic psychedelics are compounds that bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include the naturally occurring compounds psilocybin, N,N-dimethyltryptamine (DMT, a component of ayahuasca) and mescaline (peyote cactus), as well as the synthesized compound lysergic acid diethylamide (LSD).

Medscape: What are psychedelics?

Dr Roland R. Griffiths

Other drugs, such as ketamine, are sometimes referred to as "psychedelics" because they can produce subjective experiences that are similar to those of people who receive classic psychedelics. However, unlike classic psychedelics, the effects of ketamine tend to be short-lived. Ketamine also has addictive potential and can be lethal in high doses, which is not the case with psilocybin.

Another compound sometimes referred to as a "psychedelic" is 3,4-methylenedioxymethamphetamine (MDMA), also known as "ecstasy."

The US Food and Drug Administration (FDA) granted breakthrough approval for the study of MDMA for posttraumatic stress disorder (PTSD). FDA-approved registration trials are ongoing. MDMA differs from classic psychedelics in risk profile and pharmacology. In particular, MDMA was widely abused as part of the "rave culture," while classic psychedelic agents do not lend themselves to that type of misuse.

What is the current legal status of psychedelic agents in the United States? Can clinicians prescribe them, or are they available only in a research setting?

All classic psychedelics are considered to be "Schedule 1" which means they are illegal to possess and use except for research and only if approved by the FDA and under licensure of the Drug Enforcement Administration (DEA), so they are not available for clinical use.

In anticipation of the possibility that phase 3 research may support the efficacy and safety of psilocybin for one or more medical or mental health disorders, our team has reviewed available evidence regarding its abuse liability and concluded that if psilocybin were approved as medication, it could possibly be included in the Schedule IV category, with additional FDA-mandated risk management provisions. However, this is not yet the case.

Which psychedelic agents are under investigation in the United States, and for which indications?

Psilocybin is under investigation in our center, as well as elsewhere in the United States. We have previously found it to be effective for smoking cessation and we are conducting another study that is currently recruiting volunteers for this indication. We are also recruiting volunteers for studies on the use of psilocybin for major depression, Alzheimer’s disease, and anorexia nervosa. Further information about our studies can be found on our center's Web site.

Two companies — the Usona Institute and Compass Pathways — have received FDA Breakthrough Therapy Designation for their programs seeking approval of psilocybin as a treatment major depressive disorder and treatment resistant depression (TRD), respectively. In addition, an international multi-center study underway, which includes US centers in Houston, Baltimore, New York, San Diego, and Atlanta is investigating psilocybin for TRD.

A number of studies, including one conducted at our center, have investigated psilocybin for depression and anxiety in patients with cancer and found it effective.

Additional research showed that psilocybin alleviated symptoms of cancer-related anxiety and depression, both in the short-term and five years later.

LSD has been studied and found promising in the treatment of alcohol use disorder. Additional studies of LSD that are being conducted in Basel Switzerland and at the University of Chicago are examining its impact on mood in healthy volunteers.

Ayahuasca has been studied extensively for depression and anxiety and is also currently under investigation for PTSD. We found that its use in a naturalistic group setting was associated with unintended improvements in depression and anxiety.

Lastly, a lesser-known psychedelic agent is Salvinorin A, which our center has been studying, is the psychoactive constituent of the Salvia divinorum plant. While this is not a "classic" psychedelic compound, it is nevertheless the focus of much scientific interest because its effects are mediated at opioid receptors, rather than 5-HT2A receptors, and may prove to be a novel non-addictive opioid that may ultimately be a promising treatment for pain and addiction.

What is the typical treatment regimen for psychedelic agents?

It is hard to speak of a "treatment regimen" in agents that are not used in clinical practice. Ongoing clinical trials with psilocybin generally involve one or two 6 to 8 hour sessions involving the oral administration of a moderately high dose under psychologically supported conditions.

Based on the current evidence base, which agents show the most promise?

Psilocybin is currently the most promising classic psychedelic undergoing clinical trials.

Do psychedelics have to be administered in a controlled setting in order to be effective?

Although many people have had meaningful experiences whether inside or outside a controlled setting, there are serious potential risks associated with use of psilocybin and other classic psychedelics. The safety of psilocybin has been established in clinical studies in which participants have been carefully screened physically and psychologically, are psychologically prepared before their first session, and are psychologically supported during and after sessions. In vulnerable individuals, psilocybin has been associated with enduring psychiatric problems and sometimes persisting visual perceptual conditions. When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others — including life-threatening risk. Thus, for safety reasons, the optimal environment for using these agents is in a controlled setting.

Do results differ between patients who have used psychedelic agents previously vs those who have not?

We have not found any difference between psychedelic-naïve volunteers and those who have used psychedelics in the past.

Do you provide patient education prior to treatment initiation?

All of our study participants are thoroughly screened for medical concerns or mental health history such as psychosis, which would preclude their participation. They are educated about the effects of these agents and what they might expect and typically receive several hours of psychological preparation before the first session. They are also provided with psychological support after sessions. Additionally, we spend time developing trust and rapport prior to the first session.

How durable are the effects of psychedelic treatment?

Studies in patients and healthy participants suggest that the positive effects of psilocybin are long lasting, with most individuals reporting positive changes in moods, attitudes and behavior that they attribute to psilocybin and which endure months or years after the session. The qualities of the acute session experience can vary widely ranging from experiences of transcendence or psychological insight to experiences of intense anxiety or fear.

An enduring shift in worldview and sense of self as well as psychological insight may increase psychological flexibility thereby allowing individuals to subsequently avoid maladaptive patterns of behavior or thought and to make more healthy choices.

Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experience of their lives.

Do participants experience any adverse effects? If so, how are they managed?

Sometimes, despite all the preparation, screening, and support we provide, some participants can have frightening experiences, such as fear and anxiety during the session. When that occurs, it is often shorted-lived. The psychological preparation we provide before the session and the psychological support we provide during the session are important to managing such effects.

We provide support and encourage participants to stay with that experience, which may open to experiences of deep meaning or insight. A number of people report that these psychologically challenging states are a valuable part of the overall experience.

We conducted a survey of roughly 2000 people who took high doses of psilocybin mushrooms and then had a challenging experience. About 10% reported they put themselves or others at risk of physical harm. Of more concern, of those whose experience occurred more than 1 year before, 8% sought treatment for enduring psychological symptoms. These findings underscore potential risks of psilocybin use, but do not provide an estimate of the actual incidence of such effects.

Importantly, in our research at Johns Hopkins, we have not observed such effects in over 700 sessions that we have conducted with almost 400 participants, likely because we thoroughly screen and prepare participants and support them after they have completed the study. The potential for serious lasting harm represents a concern and points to the importance of adequate screening and aftercare.

What are the implications for future therapeutics?

We are living in exciting times, in terms of psychedelic research. The potential for a single treatment with a classic psychedelic to produce rapid and sustained therapeutic effects, possibly across a range of psychiatric conditions, is unprecedented in psychiatry. The effect appears to be an "inverse PTSD effect."

In PTSD, a single exposure to a traumatic event can rewire the nervous system to the point that it produces enduring harm and toxicity. In the case of psychedelics, a single exposure appears to have enduring positive effects in worldview, mood, attitude, behavior, and overall life satisfaction. We can look forward to continued growth and expansion of this research including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.

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