Aiming to tame psychedelics’ wild side in pursuit of FDA approval

Doors of perception: Psychedelic renaissance or Pandora’s box?

In one sense, psychedelics have always been divisive in mainstream Western culture. During their heyday in the 1960s, proponents lauded psychedelics’ virtues for psychological healing and exploration. Troubling reports also emerged — stories of bad trips, psychological breaks, and mostly apocryphal yet sensationalized reports of individuals leaping from buildings while under the influence. This darker side, combined with Nixon’s targeting of drugs popular with hippies, cast a pall over psychedelic research for decades, making the prospect of FDA approval seem like a practical impossibility.

Psychedelic resurgence and pursuit of FDA approval

Thanks to loosening restrictions, psychedelics are gaining traction in both popular culture and academic circles. In June, the FDA released guidance for psychedelic drug development. The Multidisciplinary Association for Psychedelic Studies (MAPS) is eyeing approval for MDMA-assisted therapy for PTSD. Moreover, with Compass Pathways spearheading a Phase 3 study, psilocybin might attain the FDA approval for treating depression soon.

Letting the psychedelic cat out of the bag

With the changing tide, Oregon has legalized psilocybin and several jurisdictions are mulling over the decriminalization of plant- or fungi-based psychedelics. Amid these shifts, mental health professionals, including Lyndsey Ryan, program director at Tara Mind, advocate for a medical framework to ensure safe usage.
She remarked, “If we moved straight into the recreational space, I think there would just be much more risk.”

Highlighting the potential of psychedelics, Ryan observed the promising effects they have shown in therapy. “After traditional therapeutic methods, the rising interest in substances like ketamine, MDMA, and other classic psychedelics provides a beacon of hope in treating challenging cases. I finally felt like I had solutions that were effective and safe,” shared Ryan, who has a track record of administering ketamine to a myriad of patients. “Patients witnessed symptom remission within months, contrasting sharply with the long-drawn agony often associated with conventional treatments,” she added.

A recent phase 2 study conducted by Compass Pathways underscored the potential of psilocybin in tandem with SSRIs. The research observed a notable decrease in Montgomery-Åsberg Depression Rating Scale (MADRS) scores, which gauge depression severity.

Medical protocols and the promise of psychedelics

Lyndsey Ryan emphasized the importance of channeling psychedelic therapies through a trusted medical framework. She noted, “*Research has shown that dosing, timelines, and comprehensive monitoring are paramount in psychedelic therapy.*” She further warned against deviating from these protocols, emphasizing that the outcomes seen in controlled environments might not be replicated without adhering to them.
Stanislov Grof, a key figure in psychedelic therapy during the 1960s, also underscored the significance of structured settings, suggesting that elements like supportive environments and music are essential for maximizing therapeutic benefits.

Recent scientific advancements and involvement of esteemed institutions, including Harvard, Johns Hopkins, and Imperial College of London, have propelled this field. Modern research methods, like advanced neuroimaging, grant a more evidence-based understanding of psychedelics compared to mid-20th-century studies.

“We’ve identified effective protocols,” shared Ryan, aligning with industry experts like Christian Angermayer, CEO of Atai Life Sciences, who believe that prioritizing medical frameworks over swift decriminalization efforts will maximize the therapeutic potential of psychedelics.

Caution in self-experimentation

Although there’s optimism around psychedelic therapies, the medical community has consistently raised alarms over the hazards of unsupervised use. As early as 1967, the Journal of the American Medical Association (JAMA) spotlighted several risks of psychedelic self-experimentation. Ryan accentuated the need for structured access, especially for individuals with addiction propensities.

Decriminalization trends and implications

The decriminalization movement for natural psychedelics is gaining traction. Cities including Denver, Oakland, and Seattle have taken steps to decriminalize substances like psilocybin. Moreover, Oregon stands out by legalizing magic mushrooms for therapeutic purposes, albeit with its own set of criticisms surrounding broader drug decriminalization efforts.
Highlighting the momentum, in May 2023, Washington’s Governor Jay Inslee signed the Washington Psilocybin Services Act, enabling a clinical trial program at the University of Washington. Meanwhile, states like Pennsylvania and California are exploring similar pathways.

Financial implications and gray markets

In early May, Oregon issued the first license for therapeutic psilocybin. The emergence of regulated psilocybin service centers in Oregon raises the question of cost. With some centers charging up to $3,500 for a single high-dose session, critics question the justification of such prices, which are not covered by insurance. Such hefty price tags could limit access to lower-income patients most in need while also scare away investors convinced that therapeutic psilocybin in Oregon will find a limited number of takers.

Simultaneously, Colorado’s more lenient stance concerning psilocybin has given rise to a gray market. Entrepreneurs there have identified legal loopholes such as guided psychedelic sessions and microdosing consults. Black-market sellers are also taking notice, selling wares on platforms like Facebook Marketplace.

Incidentally, while a 4-gram high dose trip cost five figures in Oregon, it would cost closer to roughly $40. While prices vary, magic mushrooms are often priced around $10 per gram, and even lower when bought in bulk. This vast price discrepancy, coupled with easy accessibility on platforms like Facebook Marketplace, has intensified the competition.

Investors, recalling the financial turbulence of the cannabis industry, are increasingly wary when it comes to investing in psychedelics, which remain Schedule 1 substances federally. Further complicating matters is the March financial collapse of the Synthesis Institute, a major training institution for psilocybin therapists in Oregon. Such incidents have magnified investor concerns, who worry that the psychedelic market may be more hype than substance.

Silicon Valley support a wild card

In tandem with growing decriminalization efforts, psychedelic drug use has entered the mainstream of Silicon Valley’s corporate culture, as WSJ has noted. Microdosing, taking sub-threshold dosing of drugs like psilocybin or LSD, is especially popular. Meanwhile, tech entrepreneurs like Elon Musk and Sergey Brin have openly used substances ranging from psychedelics to the dreamy dissociative anesthetic ketamine.

Venture capital isn’t far behind this trend. Prominent VCs have invested about $347 million in psychedelics startups, according to Business Insider. The Founders Fund, known for their investments in giants like SpaceX and Facebook, has vested interests in the psychedelic space, holding a stake in Compass Pathways, which is engaged in phase 3 psilocybin development. Peter Thiel, the co-founder of Founders Fund, has personal investments in Atai Life Sciences, another major player in psychedelic research. Spokespersons from Founders Fund have lent support to decriminalization efforts and have extolled their potential for mental health.

The struggles of psychedelic companies

To date, the VC focus on psychedelics hasn’t proven much of a return on investment. FDA approval of drugs like psilocybin and MDMA is likely years away. The stock price of psychedelic therapy companies has tanked in recent years. In March 2023, Atai Life Sciences noted that it had laid off roughly 30% of its employees. Psilocybin-derivative company Cybin cut 15%.

In 2022 alone, COMPASS Pathways (Nasdaq:CMPS) and ATAI Life Sciences both saw a 66% drop. Cybin (NYSEAMERICAN: CYBN), Numinus Wellness (TSE:NUMI) and Revive Therapeutics (OTCMKTS:RVVTF) faced declines exceeding 70%. MindMed (Nasdaq:MNMD) saw a 90% stock plunge and received a potential Nasdaq delisting notice in June.

A 2022 JAMA article foretold the decline. Invoking the Gartner Hype Cycle and the irrational exuberance that can accompany new technologies, authors David B. Yaden, Dr. James B. Potash and Roland R. Griffiths warned of a repeat bout of “blowback” in psychedelic research, similar to what happened in the 1960s.

Neuroplasticity and lasting change

Spravato, an isomer of ketamine, helped kickstart in various psychedelic-inspired drugs now in development consideration, notes Emma Wille, a healthcare analyst at Citeline.

Ketamine, a dissociative anesthetic long used in both human and veterinary medicine, has gained attention since the early 2000s for its rapid-acting antidepressant effects. Its ability to swiftly, although often transiently, relieve depression symptoms, has sparked interest in pairing it with talk therapy.

“The strength of many psychedelics lies in their synergy with talk therapy. It’s believed that the mechanism at work here is neuroplasticity, Wille said. “Administering these drugs places the brain in a state more conducive to reshaping thought patterns. When combined with talk therapy, the results tend to be lasting changes.”

She continues to highlight the regulatory challenges faced by other psychedelics like psilocybin, MDMA, and DMT in the US due to drug scheduling. “Ketamine, in contrast, wasn’t a Schedule I drug. It already had some approved indications. It’s worth noting that ketamine is a dissociative anesthetic. Its off-label use for depression paved the way for trials using it, thereby opening doors for the exploration of other psychedelics in treating depression and related disorders. This delineates a significant difference in the ease of access between ketamine and other psychedelics.”

Numinous experiences as a potential pillar of durability

A significant number of patients undergoing psychedelic experiences report profound spiritual experiences, including long-lasting feelings of interconnectedness. “We need to ensure we’re competently holding space for whatever experiences arise, ensuring that personal biases don’t hinder the patient’s integration process post-experience,” Ryan said.

Such experiences aren’t limited to the devout. “That can actually be really startling for people who don’t identify as religious, especially if they identify as an atheist or agnostic,” Ryan said. “They come in and then come out and say, ‘I think I just felt God. How did that happen?’”

Such experiences are more than anecdotal. They could be a key to psychedelics’ therapeutic potential. A recent systematic review published in Frontiers in Psychiatry looked at the association between psychedelic-induced mystical experiences and therapeutic outcomes across a dozen clinical trials involving psilocybin, ayahuasca or ketamine therapies. The review concluded that 10 out of the 12 studies found a significant correlation between mystical experiences and improved symptoms and quality of life. The study authors, however, noted that sample sizes tended to be small and lack diversity.

Ryan further elaborated on the therapeutic implications of the numinous, “From a psychotherapeutic perspective, this [spiritual dimension] is going to be a place we’re going to have to lean into and make sure  we have the openness and cultural competence around this component. “I’m very interested in seeing how we’ll be tethering in spiritual aspects.”

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Filed Under: Brain Breakthroughs, Drug Discovery, Psychiatric/psychotropic drugs
Tagged With: biopharma advances, Biotech Innovation, effective treatments, FDA approval, pharmaceutical safety, Psychedelic research, R&D studies
 

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