Magic mushroom, computer-enhanced composite image.

Psychedelic agents are experiencing a veritable renaissance. And this time not as illicit mind-expanding drugs that helped give shape to the 1960s counterculture. In recent years a slew of psychedelic agents have filled the drug development pipeline. These therapeutics are being investigated for treating conditions, such as major depressive disorder, severe anxiety, and substance abuse. Psychedelic therapeutics have moved from the fringes of medicine to the mainstream.

In May, the journal Nature Medicine published findings from a study on MDMA - Methylenedioxymethamphetamine - commonly known as Ecstasy or Molly. The first Phase 3 clinical trial conducted with psychedelic-assisted therapy found that MDMA combined with psychological counseling yielded marked relief to patients with severe post-traumatic stress disorder.

In April, a study published in the New England Journal of Medicine highlighted the benefits of treating depression with psilocybin, the psychoactive ingredient in magic mushrooms, have excited scientists, psychotherapists and entrepreneurs in the rapidly expanding field of psychedelic medicine. Other studies suggest substantial rapid and enduring antidepressant effects of psilocybin-assisted therapy among patients with major depressive disorder. The Food and Drug Administration (FDA) granted psilocybin breakthrough therapy designation.

And, esketamine was approved by the FDA on March 5th, 2019, for treatment-resistant depression. It is sold under the trade name, Spravato. Esketamine became the first FDA-approved psychedelic treatment for a psychiatric disorder. In August of last year, the FDA extended its approval for esketamine to adults with major depressive disorder with acute suicidal ideation or behavior.

In a disease area such as mental health, with a significant amount of unmet need, any increase in promising treatment options is welcome. Major depressive disorder affects approximately 17 million Americans, many of whom currently suffer from a lack of adequate treatment alternatives. However, there are possible pitfalls associated with each of the aforementioned drugs where the precautionary principle may apply. In each instance, risks of abuse and diversion must be considered.

There is the potential for abuse and possible long-term negative effects related to MDMA, an amphetamine derivative. Research hasnt definitively answered whether MDMA is addictive, although data suggest that regular MDMA use yields adaptations in the serotonin and dopamine pathways in the brain and central nervous system that may be connected to substance use disorder as well as increased impulsivity. Clearly this is an important factor to consider as medical uses for MDMA are being pursued.

In the case of psilocybin, in the span of a couple of years, the drug has gone from being a completely prohibited Schedule I drug, defined by the Drug Enforcement Administration as a controlled substance having no currently accepted medical use and a high potential for abuse, to a what some researchers recommend should be a Schedule IV controlled substance drug with a relatively low potential for abuse.

Yet, psilocybin is considered to have abuse potential. While advocates assert that psilocybin is not addictive, chronic abuse and misuse can lead to hallucinogen use disorder.

The FDA is the focal point for abuse potential assessment, and works with sponsors of agents with possible abuse potential to determine the studies required to establish approval endpoints, scheduling recommendations, and all aspects of labeling. Psilocybin has not yet been examined in an abuse potential study that would meet the criteria recommended by the FDA in its 2017 Guidance: Assessment of the Abuse Potential of Drugs.

Furthermore, abuse and misuse are not the only problems that require investigating. However rare the risks appear to be from initial reports, possible adverse events must be looked into thoroughly, particularly since clinical trial and real-world settings are vastly different. Persistent use of psilocybin may lead to long-term psychosis, alter a persons personality and perception of reality, and produce hallucinations.

Dr. Bogenschutz, a professor of psychiatry at New York University, said that until now the majority of clinical studies on psilocybin have been conducted with relatively small numbers of individuals in clinical settings designed to exclude those with schizophrenia and other serious mental problems. It is precisely these subgroups that could be predisposed to psychotic episodes, exacerbated by possibly psychosis-inducing psilocybin.

And then theres the case of esketamine, which is the S-enantiomer of ketamine, a similar (in molecular structure) but more potent agent than ketamine.The FDA label for esketamine includes a black box warning of the potential for misuse.

The experience with off-label use of ketamine for clinical depression is a sobering reminder of the importance of close monitoring for the purpose of preventing abuse and misuse from occurring. As noted in several clinical studies, ketamine drug-seeking behavior has appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. In 2017, the American Psychiatric Association issued a consensus statement on ketamine for mood disorders: Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder.

Classified as a Schedule III substance, esketamines safety profile based on real-world data includes possible dissociation, sedation, and suicidal ideation. Mark Horowitz of University College London, asserted that what the sponsor demonstrated very clearly in the trials that theyve done is that esketamine gets you a bit high for a few hours and has little effect on depression scores at 4 weeks. Horowitz maintains that esketamine is an ineffective medication. On top of that, its also a reasonably dangerous medication.

Ignoring or downplaying possible downsides or risk factors isnt going to make these issues go away. The experience with prescription opioids and other drugs, such as benzodiazepines, should give pause. Despite the benzodiazepine clonazepam being the most commonly diverted pharmaceutical in the U.S., it remains the drug most prescribed by psychiatrists to Medicare beneficiaries.

Regulators are proactively establishing a strict set of protocols for psychedelic medications. Several regulatory barriers have already been erected for the approved drug esketamine. Presumably, a similar set of restrictions would be put in place for MDMA and psilocybin. With respect to psilocybin, it appears that only licensed therapists and manufacturers will be allowed to grow the mushrooms or extract psilocybin from them, or to synthetically produce the drug, set up a psilocybin therapy center or provide therapy. Importantly, individuals being treated with the drug may only ingest it at a licensed facility with a certified therapist present.

These safeguards will help, along with systematically implemented post-marketing surveillance plans. Still, regulators and treatment providers will need to work out safe ways of administering these powerful substances in the real world, which will be different from the highly circumscribed and controlled conditions of clinical trials.

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Psychedelic Drugs Are Moving From The Fringes Of Medicine To The Mainstream - Forbes