Navigating Research in Psychedelics: Investigators Face a Mosaic of Regulations, False Perceptions, and Therapeutic Potential

When paired with psychotherapy, psychedelic-assisted therapy (PAT) has the potential to treat a wide variety of mental health conditions with better and longer-lasting outcomes than the current available options, explained Mark Bleackley, PhD, chief scientific officer at Incannex Healthcare Limited, Melbourne, Australia, in an interview with Pharmacy Times. However, psychedelic medicine investigators must contend with strict guidelines and administrative burdens, which can slow research efforts and subsequent approvals that could improve wide-spread access and economic opportunities, Bleackley says.

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Further, after decades of prohibition of these medicines, psychedelics may continue to have a negative public perception, which can additionally impact research efforts.

“It's always hard to change somebody's mind and teach them something new,” says Bleackley. “It's about continuing to present good evidence [to] demonstrate that these molecules are now being developed as pharmaceuticals.”

There is a significant mental health crisis plaguing the United States today, which may partly be influencing the rampant emergence of psychedelic drug development companies, according to Dustin Robinson, Esq, CPA, the managing principal of Iter Investments and founding partner of Mr. Cannabis Law, in an interview with Pharmacy Times.

This mental health crisis is one that is vastly understood by the US public, with responses from a 2022 survey from KFF/CNN showing that 90% of the US public believe there is a nation-wide mental health crisis.¹ Further, almost half of survey respondents also believe that the pandemic worsened mental health outcomes.¹ According to a 2023 White House press release, 2 in every 5 American adults admitted to feeling symptoms of anxiety and depression in 2021 during the pandemic.

That same year, nearly half of high school students reported persistent feelings of sadness or hopelessness.²

Current agents indicated for mental and behavioral health are not optimized to lead to lasting behavioral and psychological changes, explained Robinson. According to the NIH, traditional pharmacologic antidepressants are effective for treating symptoms, but are not necessarily the root cause of the illness.³

In addition, these medications are costly to the national health care system, as patients need to stay on them for a long duration, according to Robinson. He added that many of these medications are also associated with adverse effects (AEs) that can augment the indirect economic burden associated with national health care.

“People are screaming out for alternatives,” Bleackley said in an interview with Pharmacy Times. “I think that psychedelics have a high potential to address that unmet need.”

Difficulties With Research in Psychedelics

The main psychedelic drugs being studied for their therapeutic effects include 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin (ie, the psychoactive compound found in various species of mushrooms). However, “there is definitely a cultural bias that they are drugs of abuse,” Bleackley said.

Some consider psychedelics within the scope of recreational drugs and party drugs, Bleackley explained. However, Bleackley noted that today, psychedelic medicine has gone beyond the “tie-dye and raves” of yesteryear.

Many psychedelics undergoing research and development for therapeutic use are chemically manufactured pharmaceutical products, meaning they are created in accordance with the good manufacturing practice (GMP) standards required of any pharmaceutical agent, Bleackley explained.

But conducting high-quality research on psychedelics is extremely difficult, as MDMA and psilocybin are Schedule I drugs per the US Controlled Substances Act (CSA), according to Bleackley. Schedule I classification means that the DEA does not recognize them as having any medical application, which means that research assessing the medical benefit of these drugs requires overcoming through multiple regulatory hurdles.

For example, investigators must be registered with the DEA to work with Schedule I psychedelics. They need to submit Form 510, which allows them to work with the Schedule I drug substance, Form 225 to register the drug product, and Form 224 to administer the drug to patients, according to Bleackley. Form 222 allows psychedelics to cross US state lines, and there are countless individual state laws and licenses which allow for drug storage and distribution, Bleackley explained.

Once registered with the DEA, investigators must then follow other measures in accordance with the CSA, such as storing and handling psychedelics, distributing and shipping them (including importing and exporting them between countries), and conducting research with fixed record-keeping, Bleackley said. Further, investigators must ensure that all participating vendors and partners have the exact same licenses and permits.

There is another layer of complexity to this research, which is figuring out the best way to administer psychedelics to their fullest potential, according to Bleackley. Administering psychedelics as part of a psychotherapy regimen could produces robust and durable outcomes, as psychedelics change a person’s perception and can make them more open to psychotherapy, Bleackley said.

“[But] mental health is such a complicated field to begin with, [and] nobody really understands how the brain works,” Bleackley said. “Once you throw psychedelics in there, you're changing the way the brain is perceiving things.”

Essentially, investigators still need to identify the methods of psychotherapy that are synergistic with psychedelic treatment, along with the frequency of psychedelic dosing, structure of treatment sessions, organization of check-in and follow-up, risk/benefits, AEs and medication interactions, and integration of sessions into current treatment regimens, Bleackley said.

In addition, the most common barometer for measuring the efficacy of psychedelics for mental health conditions is patient reported outcomes (PROs), which is a subjective measure that can be influenced by patient bias, Bleackley said. However, other therapeutics have been approved for mental health conditions based on validated PROs so the same could be possible for psychedelics.

“This validation is the result of extensive analysis and development of the PROs in patient populations to meet regulatory standards,” Bleackley said.

Psychedelics in the Pharmacy Landscape

Pharmacists can advocate for safe and effective use and administration of psychedelics; specifically, they are able to help patients manage drug interactions and AEs, Robinson explained.

Educating patients about drug-drug interactions doesn’t just promote safe use, but it can produce better clinical outcomes from PAT, according to Robinson. For instance, selective serotonin reuptake inhibitors (SSRIs) can render certain types of psychedelics ineffective, so educating patients about this risk, and weaning them off the SSRI before starting psychedelic therapy, can make the therapy work better, Robinson said.

According to public health estimates, MDMA is expected to receive FDA approval for PTSD by August 2024 and psilocybin is expected to receive approval for the treatment of treatment-resistant depression in 2027, Robinson explained. It's also worth noting that ketamine, sometimes considered to be a psychedelic (it is a Schedule III drug that has moderate to low risk of physical and psychological dependence, according to the DEA⁴) is already FDA-approved as an anesthetic and can be obtained via doctor’s prescription, Robinson said.

These are significant approvals, as they represent a shift in culture, but are still a relatively long ways away and remain limited to very specific patient subsets, so some patients may still be at risk of turning to black market psychedelics for various reasons, Robinson said. It becomes ever more important that pharmacists develop a trusting relationship with patients, as it can directly influence their safety and knowledge of associated risks with black market use of psychedelics, Robinson explained.

Conclusion

There will continue to be hurdles in the development and research of psychedelic medicines for mental health, including strict regulations and many unknowns regarding the integration of psychedelics into current therapeutic regimens.

2024 could also be a challenging year for the psychedelic therapy space, following 2 years of downturned investments for PAT research companies, according to Robinson. However, he says that “the companies that survive and are able to push forward their business during these tough times will have tremendous upside potential in 2025 and beyond."

There is also work being done to identify physiological biomarkers from brain imaging, which can provide objective evidence that psychedelics can be a supportive treatment for patients with mental health conditions, Bleackley said.

Changing the psychedelic landscape ultimately requires changing pharmacist and public perspective on psychedelics, according to Bleackley. Pharmacists need to be educated, just like patients, about safety and efficacy findings from well-controlled clinical trials.

“As we continue to build the high-quality evidence from well-regulated, well-controlled clinical trials, that's what helps inform the pharmacists and the physicians,” Bleackley said. “Psychedelics have pharmaceutical value [and] I think we're starting to appreciate that now.”

REFERENCES

1. Lopes L, Kirzinger A, Sparks G, Stokes M, Brodie M. KFF/CNN Mental Health In America Survey. News Release. October 5, 2022. Accessed on February 28, 2024. https://www.kff.org/report-section/kff-cnn-mental-health-in-america-survey-findings/

2. Fact Sheet: Biden-⁠Harris Administration Announces New Actions to Tackle Nation’s Mental Health Crisis. News Release. Whitehouse.gov. May 18, 2023. Accessed on March 7, 2024. https://www.whitehouse.gov/briefing-room/statements-releases/2023/05/18/fact-sheet-biden-harris-administration-announces-new-actions-to-tackle-nations-mental-health-crisis/

3. Overview – Antidepressants. NHS. November 4, 2024. Accessed on March 7, 2024. https://www.nhs.uk/mental-health/talking-therapies-medicine-treatments/medicines-and-psychiatry/antidepressants/overview/#:~:text=While%20antidepressants%20can%20treat%20the,or%20other%20mental%20health%20conditions.

4. Drug Scheduling and Penalties. Campus Drug Prevention. https://www.campusdrugprevention.gov/content/drug-scheduling-and-penalties#:~:text=Schedule%20III%20drugs%2C%20substances%2C%20or,but%20more%20than%20Schedule%20IV.