A federal health agency is giving researchers guidance on the types of studies it’s interested in funding for the development of psychedelic drugs to treat certain mental health conditions, pointing out limitations for animal-based research and rules for trials involving children.
The National Institute of Mental Health (NIMH) published a notice of information last week, providing additional information about research criteria and priorities for psychedelic studies.
“Psychedelic drugs such as psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), mescaline, and related compounds are being evaluated by the pharmaceutical industry for their therapeutic potential in treating depression, post-traumatic stress disorder, and other mental illnesses,” NIMH said.
Notice of Information on NIMH's Considerations for Research Involving Psychedelics and Related Compounds https://t.co/Srf03EYpIZ
— NIH Funding (@NIHFunding) November 15, 2022
“The hallucinogenic effects of psychedelics, their role in the larger psychotherapeutic process, and the poor predictive validity of current animal models in drug development for mental illness are critical factors that warrant careful consideration of the types of research questions that can be addressed using animal systems” it said.
Hence, the agency’s notice is meant to lay out some ground rules for researchers who wish to contribute psychedelics research as part of its active grant programs for mental health treatment.
Specifically, NIMH said it wanted to explain what it considers to be a “reasonable premise for pursuing basic mechanistic research on psychedelics and related compounds, and clarifies guidelines for reproducible and rigorous clinical research involving these agents.”
For grant applications that propose using an animal model, the agency noted that such studies “are not well suited to assess the therapeutic efficacy of psychedelics.” Rather, they should be used “to link mechanisms downstream of receptor activation to adaptive changes in the function of circuits relevant to mental health.”
“When determining funding priorities for animal studies investigating psychedelic actions, NIMH considers 1) whether the scientific question addresses a hypothesis generated from clinical research to test therapeutically relevant mechanistic hypotheses, and 2) whether the proposed research addresses intermediate circuit biology questions, with the goal of bridging the gaps between molecular, cellular, circuit, and network levels of analysis. Lower priority is assigned to animal studies comparing the effects of psychedelics to those of currently approved antidepressant treatments, unless there is a clear mechanistic hypothesis making such a comparison critical.”
NIMH said it prioritizes proposals for animal models that “utilize a reverse translational approach to test mechanistic hypotheses informed by observations made in human subjects.”
An example of that would be a study that identifies patterns of brain activity “associated with psychedelic-induced improvement in mental function in human subjects,” which would inform future research “investigating the molecular, cellular, and circuit-level processes underlying drug effects using parallel brain measures in a preclinical species.”
“NIMH prioritizes animal research designs and approaches that are clearly justified with respect to why the model system, levels of analysis, statistical design, and neural circuits under investigation are the most appropriate for addressing the proposed question in the context of psychedelic drug actions in humans. Investigators are encouraged to highlight ways their basic and preclinical research can inform subsequent translational and effectiveness clinical trials in humans with mental illness.”
Animal model studies should be narrowly tailored to look at the effects of psychedelic compounds on brain processes and circuits, “without making unsubstantiated links to human thoughts, emotions, or clinical diagnoses.”
NIMH also gave examples of what it considers to be low priority psychedelics research objectives:
Studies proposing to investigate therapeutic efficacy of psychedelics and/or related compounds using animal models ‘of’ mental illness
Studies designed to compare the neurobiological and/or behavioral effects of psychedelics and other approved antidepressant treatments
Behavioral studies that lack neurobiological measures
Research evaluating in vivo effects of psychedelics using dose ranges and/or treatment regimens (e.g., time course, route of administration) for which there is insufficient PK/PD data to support the proposed experimental design
Interestingly, the agency also reminded researchers that the guidelines that are in place for experimental exploratory therapeutics under a grant opportunity for basic and pre-clinical research for psychedelics should not be consulted for “projects in pediatric populations.”
“Pediatric testing of psychedelics will require performing pediatric bridging studies,” the notice says. “As such, pediatric testing cannot be performed until sufficient adult PK/PD/efficacy has been established for which to ‘bridge’ the data to pediatric trials.”
The agency laid out low priorities for “translational research on psychedelics” in humans:
Studies lacking rigorous and reproducible assessment of the integrity of the blind for patients, therapists, and raters
Studies lacking rigorous and reproducible assessment of expectancy effects
Studies that involve the use of psychosocial adjunctive interventions (e.g., to facilitate the delivery/exposure to psychedelics) without operationalizing and assessing the delivery of the psychosocial elements
Meanwhile, in June, officials with NIMH and the National Institution on Drug Abuse (NIDA) said in a letter to two U.S. senators that federal prohibition makes it harder to study the benefits of psychedelics, requiring researchers to jump through additional regulatory hoops.
NIDA Director Nora Volkow has said that she personally hesitates to study marijuana because of its Schedule I designation—a classification that also applies to psilocybin, MDMA and other therapeutically promising drugs.
Meanwhile, Sen. Cory Booker (D-NJ) and Rand Paul (R-KY) filed a bill recently that would require the Drug Enforcement Administration (DEA) to transfer breakthrough therapies like psilocybin and MDMA from Schedule I to II, while also removing research barriers for strictly controlled substances.
“This bill reduces these unreasonably burdensome rules and regulations that delay or prevent researchers from studying—and patients from accessing—this entire class of potential medicines,” the senator, who posted a video late last month similarly touting the therapeutic benefits of psychedelics, said.
The bill was introduced in the same week that bipartisan House lawmakers announced the formation of a congressional psychedelics caucus that’s meant to promote the development of novel treatments derived from currently controlled entheogenic substances.
Booker and Paul previously introduced separate legislation in July to clarify that federal “Right to Try” (RTT) laws give seriously ill patients access to Schedule I drugs, including marijuana and certain psychedelics.
Booker said last month that that the intent of that bill was to “open up more avenues to take drugs that are now banned and make them accessible, especially for people that are suffering.”
The earlier bill would make a technical amendment to the text of the existing statute, but the primary purpose is to clarify that RTT policy as signed into law by former President Donald Trump already means that patients with terminal health conditions can obtain and use investigational drugs that have undergone clinical trials, even if they’re Schedule I controlled substances.
These developments come amid a wave of local reform efforts—and just one week after Colorado voters approved a historic ballot initiative to legalize the possession of certain entheogenic substances and create psilocybin “healing centers” in the state.
NIDA’s Volkow said at the beginning of the year that the “train has left the station” on psychedelics, as people are going to keep using substances such as psilocybin—especially as the reform movement expands and there’s increased attention being drawn to the potential therapeutic benefits.
Advocates have been encouraged by the gradually growing interest in psychedelics policy and science issues within Congress.
Rep. Earl Blumenauer (D-OR) told Marijuana Moment that he “absolutely” sees parallels between the movements to reform laws around psychedelics and marijuana. He also accurately predicted the Colorado voters would approve the psychedelics legalization initiative at the ballot last week.
The congressman is well known for his marijuana reform advocacy on Capitol Hill, serving as a co-chair of the Congressional Cannabis Caucus. But he’s also become one of the most vocal members on psychedelics policy in recent years as his home state of Oregon has led the way in legalizing psilocybin services access and more broadly decriminalizing drug possession.
Blumenauer also recently spoke about the therapeutic potential of psychedelics during a congressional committee markup, saying the substances hold “real potential” as alternative mental health therapies with “less impact” than traditional pharmaceuticals.
He suggested that psychedelics policy should be part of the larger conversation about health care improvements, noting his interest in giving terminally ill patients access to investigative drugs like psilocybin, for example.
At the beginning of this year, Blumenauer led a bipartisan letter requesting that DEA allow terminally ill patients to use psilocybin as an investigational treatment without the fear of federal prosecution under federal RTT law.
In July, the House voted in favor of two psychedelics-related amendments to a defense bill, including one that would require a study to investigate psilocybin and MDMA as alternatives to opioids for military service members and another that would authorize the defense secretary to provide grants for studies into several psychedelics for active duty service members with PTSD.
But while advocates are encouraged by these incremental developments amid the national psychedelics decriminalization movement, some lawmakers feel that Congress isn’t keeping pace with the public and the science.
Rep. Jared Huffman (D-CA) told Marijuana Moment recently that he’s done his research and believes that natural plants and fungi like psilocybin can be a therapeutic “game changer,” but he said that it’s “embarrassing” how slow other federal lawmakers have been to evolve on the issue.
Other federal agencies, such as the U.S. Department of Defense’s Defense Advanced Research Projects Agency (DARPA), have separately expressed similar interests in discovering how psychedelics work in order to develop new drugs that exhibit similar therapeutic benefits—but without the accompanying psychedelic experience.
The U.S. Department of Health and Human Services (HHS) recently said that it is actively “exploring” the possibility of creating a task force to investigate the therapeutic of certain psychedelics like psilocybin and MDMA in anticipation of federal approval of the substances for prescription use.
That came in response to letters from bipartisan congressional lawmakers, state legislators and military veterans, who implored the HHS secretary to to consider establishing an “interagency taskforce on the proper use and deployment of psychedelic medicine and therapy.”
For its part, DEA said last month that it want to more than double the amount of marijuana that can be legally manufactured for research in 2023—and it’s also seeking to significantly increase the quota for the production of psychedelics like psilocyn, LSD and mescaline.
A top Canadian health official who heads up the country’s efforts to combat addiction recently visited Colorado, Oregon and Washington State to learn about their experiences implementing drug policy reform like broad decriminalization and harm reduction—meeting with the governor of Oregon and psychedelics activists, among others, on a week-long tour.
Photo courtesy of Dick Culbert.