'A Promethean moment': Psychedelics could be prescribed in the next few years

Key takeaways:

• Psychedelics like psilocybin may be available for psychiatric treatment in the next few years.
• There are still many unanswered questions, though, like the potential harm these treatments could cause.

With potential FDA approvals on the horizon, the controversy surrounding psychedelics in clinical practice may soon reach a tipping point, according to experts.

There has been a strong, renewed interest in psychedelics as a potential treatment option for various psychiatric conditions, Jeffrey A. Lieberman, MD, the Lawrence C. Kolb Professor of Psychiatry at Columbia University Medical Center, told Healio. In fact, this summer, Australia became the first country to allow psychedelics — specifically, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin — to be prescribed for patients with depression or PTSD.

“This is what I would call a Promethean moment in medicine, the actual use of psychedelics for medical purposes,” Lieberman said. “Psychedelics are a very unique class of compounds that have extraordinary clinical effects inducing an altered state of consciousness.”

Ryan M. Smith, DO, PhD, a clinical associate professor of psychiatry at the Philadelphia College of Osteopathic Medicine, told Healio that various psychedelic drugs are currently being investigated as a potential treatment for PTSD, depression, anxiety and addictive disorders, as well as end of life care.

Smith said psychedelics were used in psychiatric practice “fairly routinely” through the 1960s — until the Controlled Substance Act of 1970 designated psychedelics as a Schedule I drug, “which thwarted their potential therapeutic use and most clinical research into them.”

“Fortunately, we are now in an era, some 50 years later, that research and some clinical uses of psychedelics are coming back into the spotlight,” Smith said.

Many studies, he added, from the 1960s “highlight the unique aspects of these drugs,” but Lieberman said this “only began to scratch the surface” in our understanding. Now that interest has been revived, Lieberman said that psychedelics are “available for further study and for clinical development for therapeutic use.”

“Although the basic pharmacology of classical psychedelics is known ... there’s no evidence that’s really definitive as to the mechanism of action and the uses to which they can be put, whether it's depression, anxiety, substance abuse, or simply as tools to explore the mind and understand mechanisms of consciousness or cognitive functions,” Lieberman said. “There's no very well-established rationale. It's kind of arbitrary and ad hoc.”

David Hellerstein, MD, director of the New York State Psychiatric Institute Depression Evaluation Service and a professor of clinical psychiatry at Columbia University, agreed that more research is needed to understand the mechanisms of psychedelics and how well they work, “whether it's a true drug effect or how much of it is driven by exploitation or placebo effects.”

“The literature is not at all settled in either of those areas,” he said.

Lieberman said psychedelics could be used in practice in the United States as soon as 2025. However, considering the controversy surrounding the drugs, many health care professionals are hesitant to accept their therapeutic use without more advanced research to adequately assess their benefit-harm balance.

Potential benefits

According to Smith, psychedelics might offer benefits to certain patients that “standard psychiatric treatments may not be able to achieve.”

Katherine Pannel, DO, FAPA, an osteopathic physician specializing in psychiatry and medical director at RightTrack Medical Group, said the drugs that currently show the most promise are lysergic acid diethylamide (LSD), MDMA and psilocybin.

Pannel, who is also a member of the American Osteopathic Association, explained that thus far, LSD has the most evidence for use in alcoholism. MDMA appears to have the most potential as a PTSD treatment, she said, especially when used in adjunct with standard therapy “as it allows the patient to open up more so that they are able to work through their trauma.”

"It causes the release of dopamine, serotonin and other feel-good hormones, which gives it consideration in the treatment of anxiety and depression as well,” Pannel said.

Finally, psilocybin has been considered potentially beneficial for treatment-resistant depression and cancer-related anxiety and depression.

“It has the most evidence for efficacy in the aforementioned illnesses, but there is weaker evidence showing potential benefit in other conditions such as tobacco addiction, alcohol dependence and obsessive-compulsive disorder,” she said.

Smith said one benefit of psychedelics could be their fast-acting nature.

“We recognize that most of our psychiatric medications, such as antidepressants, take weeks to months to have an effect on psychiatric conditions,” he said. “We have the potential to be able to intervene and affect a psychiatric disorder acutely, either as it is developing to halt its exacerbation, or to acutely deescalate a patient who is at the height of a depression or anxiety disorder exacerbation.”

That could mean a major breakthrough, Smith said, not only for psychiatric treatment, “but also to economic costs to lost work productivity, a decreased need for higher levels of mental health care at the inpatient level, and also potentially clearing EDs faster by being able to provide acute treatments to patients with select psychiatric disorders.”

Although it is not necessarily a psychedelic, Smith additionally pointed to ketamine, a dissociative anesthetic, which “has been used for the acute treatment of some psychiatric conditions with strong benefit for some patients.” Lieberman also mentioned how useful ketamine has been for patients who are actively suicidal.

“While not the same as a psychedelic in its pharmacological mechanism of action, its ability to acutely improve some psychiatric disorders, I hope, will pave the way for some psychedelics to enter the marketplace,” Smith said.

But whether psychedelics could actually have a role in clinical practice “is the million-dollar question,” according to Pannel.

“The idea of another tool being available to help with treatment-resistant depression and other psychiatric disorders is exciting. Currently, we just do not have an abundance of options,” Pannel said. “However, physicians should always consider risk vs. benefits with any treatment they provide patients.”

Smith said that, under the care of a physician, most psychedelics are “safe to administer” and “can be groundbreaking to patients in whom other more conventional treatments, such as pure psychotherapy or psychopharmacological treatments, were otherwise ineffective.”

“While psychedelics are not appropriate for all (or even most) patients, having them as a potential tool to combat mental illness may serve to lessen the debilitation of mental illness on the public, and in turn, help to decrease recidivism in the workplace and the cost to the economy for losses related to mental health issues,” Smith said. “Psychedelic-assisted psychotherapy is another avenue for treatment of mental illness which may be able to assist patients in working through trauma faster than with conventional talk-based psychotherapy.”

Although Pannel agreed that “there is huge therapeutic potential for psychedelics,” she also cautioned that “there are also huge risks.”

Possible harms

When used inappropriately, Pannel said psychedelics “can cause much harm.”

“If psychedelics do get approved for clinical use, it should be done with great respect and caution for the substance,” Pannel said. “Addiction is at an all-time high in our country, and we do not need for this to become part of that problem.”

Lieberman also mentioned the potential of bad trips in worsening issues for some patients.

“When people ... trip and they have this several-hour experience in an altered state of consciousness, which in many cases, can be very inspiring, very entertaining and very exciting, but for some people, it's also very scary. Very potentially detrimental,” he said. “There could be some adverse effects occurring psychologically. The good thing is that these drugs, medically, in terms of physical effects, are very safe, but they do have the potential for adverse psychological reactions.”

Another potential harm, Pannel said, is that even if psychedelics were declared legal for medical use, health care workers “have little to no guidance on how to use them.”

“We need these crucial studies to determine if the clinical promise is valid, if the benefits of these substances are greater than the risks,” Pannel said. “If so, how do we use these psychedelics in clinical practice?”

Lieberman also expressed concern that some researchers and clinicians could be driven more by “the mystical effects” psychedelics can offer, rather than science.

“My opinion is that it's unlikely to prove to be an effective agent for depression, if it is approved and used on a widespread basis, and the reason for that is because the pharmacology of what psychedelics do in no way matches what our understanding is of the underlying pathophysiology of depression,” he said. “Moreover, whatever beneficial effects are observed in people who are treated in these protocols are not necessarily enduring, meaning that they may be transient improvements in someone's mood state.”

At this point, Lieberman said companies “are rushing to try and commercialize something that will generate revenue based on a very limited scientific foundation.”

“I think that it's basically going to be fool's gold, so to speak,” he said.

But Lieberman stressed that psychedelics “could be immensely beneficial.”

“I genuinely believe that they have tremendous potential, but they're being rushed to judgment and they're being oversold,” he said. “And, frankly, the way it's been done is amateurish.”

Ready or not

In 2018, the FDA granted breakthrough therapy designation to psilocybin and MDMA, shortening the development and review time for substances “with promising benefits in the treatment of serious, life-threatening diseases,” Pannel said.

According to Hellerstein, much is uncertain about what the first FDA approvals may be, but “the fast-tracking of psilocybin for treatment-resistant depression and MDMA for PTSD seems likely that they'll proceed toward getting approved in the not-too-distant future.” Likely in 2024 or 2025, he said.

“MDMA, if it's approved, would be provided in the context of pretty extensive psychotherapy and probably two or three doses,” he said. “Psilocybin, if it gets through the FDA process ... would be presumably for people with treatment-resistant depression.”

As part of his concern, Lieberman pointed to what he described in an editorial in The New England Journal of Medicine as the “unusual process by which psychedelics are being developed.”

When a drug is developed, Lieberman told Healio, there is typically a biologic target: the molecular or cellular elements of the disease (this could be a germ, cancer cell, cholesterol, or insulin receptor, for example). Then, he said, a molecule is synthesized “to act on it in a way that would be therapeutic.” The molecule is then tested in animals and humans.

“None of this is done with the psychedelic drugs,” he said. “I've communicated with the FDA expressing my concerns ... but it seems that the train’s left the station and that we're going to learn the hard way ... and we’ll have to wait to see what the consequences are.”

Prescribing psychedelics

Pannel, Lieberman and Smith agreed that, today, clinicians in the U.S. are quite close to prescribing psychedelics, although Smith said they may be restricted to ensure safety.

Some states, according to Pannel, have already decriminalized certain psychedelics such as psilocybin and legalized it for therapeutic use.

“But it should be noted that even if legalized for therapeutic use, there are no solid clinical guidelines on how to properly use psychedelics,” she said.

There is also no guidance on who will be prescribing the drugs — if that will be left to psychiatrists or if primary care physicians could offer psychedelics.

Lieberman said, “the only people who should be doing that are psychiatrists.” However, Pannel said it will probably depend on the specific drug being used and for what purpose.

“For example, early evidence is showing that some psychedelics can be useful in end-of-life care,” she said. “PCPs are directly involved in palliative and end-of-life care and could therefore see themselves choosing whether or not to prescribe psychedelics.”

But if the drug is being used to treat PTSD or other psychiatric conditions, Pannel explained, “psychiatrists will find themselves the primary prescriber.”

“However, we have a shortage of psychiatrists and mental illness is on the rise. We need all hands on deck,” Pannel said. “I could see, if the research proves psychedelics efficacious and appropriate, PCPs being involved in the administration of psychedelics in collaboration with psychiatrists. We are already seeing this in states that have medical cannabis programs.”

Smith noted that “only a fraction of patients with psychiatric disorders see a psychiatrist for routine mental health care” and that PCPs “are the first-line treaters who are seeing patients with psychiatric disorders.”

“Educating PCPs on the use of psychedelics is critical, as I do think that PCPs should be able to prescribe these medications,” Smith said. “That said, I think a psychiatrist should be involved, at least at a consultation level, to evaluate the patient for suitability and to be available to answer questions of a PCP if they crop up.”

References:

• Australian psychiatrists can now prescribe MDMA and psilocybin: who can access them and how do they work? https://www.theguardian.com/australia-news/2023/jul/01/australian-psychiatrists-can-now-prescribe-mdma-and-psilocybin-who-can-access-them-and-how-do-they-work. Published June 30, 2023. Accessed Nov. 10, 2023.
• Lieberman JA. N Engl J Med. 2021;doi:10.1056/NEJMe2102835.