Brian Barnett, MD is a psychiatrist at Cleveland Clinic’s Center for Adult Behavioral Health. Exploring the medical potential of psychedelics, he sheds light on the ongoing research into using substances like psilocybin and MDMA to treat mental health conditions.

Read the Q&A with Dr. Barnett below.

WAM: What psychedelics are being studied for clinical use and what conditions are we looking to treat with them?
Dr. Barnett: Several psychedelics are under investigation for a variety of mental health conditions and substance use disorders. The psychedelic and indication combinations explored the most in contemporary clinical trials thus far have been: psilocybin for depression, treatment resistant depression, alcohol use disorder, nicotine use disorder, and psychological distress in patients with cancer and other serious medical conditions; MDMA for posttraumatic stress disorder; and LSD for generalized anxiety disorder and anxiety in people with serious medical conditions. Other psychedelics under investigation include DMT (dimethyltryptamine), 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), and ibogaine. Other conditions for which psychedelics are being investigate include cocaine use disorder, anorexia nervosa, and depression in people with Mild Cognitive Impairment or Early Alzheimer’s Disease.

WAM: Many people primarily associate psychedelics with parties and wild hallucinatory experiences. How can these drugs be used as medicine if they have these intense effects?
Dr. Barnett: Psychedelics are the most powerful psychoactive drugs known to humans, and as of now, it seems their intense effects are likely essential for their therapeutic benefits, though some companies are exploring the possibility of developing non-psychoactive compounds that also work on the serotonin 2A receptor, through which psychedelics exert their psychoactive effects. Psychedelics’ effects seem to be strongly influenced by the mindset of the person taking them, as well as the physical setting and circumstances of administration. Therefore, if someone is taking a psychedelic in a recreational manner, they may have a euphoric experience that doesn’t entail much that is helpful for dealing with psychological challenges (and they also run the risk of temporarily making their psychological problems worse if they have a bad trip). However, decades of experience with psychedelics within medicine and millennia of experience of ritualistic use among indigenous groups suggest that psychedelics can produce deeply meaningful experiences that yield important psychological insights when used with preparation and the intention of healing in a medicinal paradigm.

WAM: How do they work on the brain physically to treat psychological conditions?
Dr. Barnett: We still have much to learn about the potential therapeutic mechanisms by which psychedelics could exert psychological benefits. Though subject to change, the current prevailing theory within medicine is that psychedelics enhance neuroplasticity, the brain’s ability to change in response to learning and experience (i.e. they make our thinking temporarily more flexible, facilitating possible change in thought patterns). While psychedelics appear able to rapidly produce improvement in different types of psychological conditions, we think the key to maintaining those benefits lies in an enhanced ability to learn from experience and develop more adaptive coping skills in the weeks after a dosing session. This is why most psychedelic clinical trials involve what are called “integration” psychotherapy sessions afterwards, so that participants can learn how to turn their psychedelic-induced psychological insights into new, sustainable behaviors that promote long-term well-being.

WAM: You say in addition to the physical impact on the brain, there seems to be evidence-based value in experiencing something mystical when people are using psychedelics to treat depression. Do we know what’s a work there, why the brain benefits from this?
Dr. Barnett: Several clinical trials have shown correlations between therapeutic response and psychedelic-induced mystical experiences, which can be profound, spiritual experiences. In neuro-imaging studies of participants in psychedelic clinical trials, mystical experiences appear to occur when psychedelics strongly disrupt the default mode network (DMN), a brain network that is altered in a variety of psychiatric conditions, potentially allowing it to re-configure back to its pre-illness setting. Still, we don’t know whether the therapeutic effect is being derived from the mystical experience itself producing changes in the DMN, or whether the mystical experience is resulting from the psychedelic-induced change in the DMN and is thus a product, rather than a cause of potential therapeutic effects.

WAM: What are the safety concerns? Is there risk of abuse?
Dr. Barnett: Given how powerful psychedelics can be their use requires medical monitoring, which can range from 2-12 hours depending on the particular psychedelic. The psychedelic experience can be unpredictable, even with preparation, and patients sometimes experience anxiety and panic, which is usually handled with support from their dosing session therapist. However, sometimes this requires a medication treatment such as a benzodiazepine. Given how strongly psychedelics can alter the mind and how vulnerable people are under their effects, it is unlikely they would ever be prescribed for use outside of a medical setting should they gain FDA approval.

Psychedelics may precipitate psychotic or manic episodes in people with a personal or close family history of psychotic disorders such as schizophrenia or bipolar disorder. Therefore, these individuals have been excluded from most clinical trials of psychedelics, and the current thinking is that psychedelics are not safe to administer in this population.

Psychedelics also predictably raise blood pressure and heart rate during their acute effects. For most people this is not a significant concern, but this feature could pose serious risks for people with cardiac conditions and untreated hypertension. These populations have also been excluded from clinical trials.

As with any psychoactive drug that we are considering developing into a medicine, there is the risk of misuse and addiction. While this is possible with psychedelics, a special pharmacological property of these drugs means that most people cannot get psychoactive effects from psychedelics after more than 3 days of consecutive use without needing to stop for several days. The psychedelic experience can be emotionally exhausting and, unlike drugs such as heroin and cocaine, psychedelics are also not reliably pleasurable, which also appear to play a role in deterring regular use. Notably, clinical trial participants sometimes decline to undergo a second psychedelic session, even if they found their first session helpful. Of all the major psychoactive drug classes, psychedelics have the least addictive potential. Monitoring trial participants for outside use of psychedelics is done routinely in clinical trials and, thus far, development of an addiction to psychedelics has not emerged as a common side effect. Still, in this early stage of drug development, we remain vigilant for this possibility to ensure we are helping trial participants rather than creating a new problem for them.