November 16, 2022
NOT-MH-19-053 - Notice of NIMH’s Considerations Regarding the Use of Animal Neurobehavioral Approaches in Basic and Pre-clinical Studies
NOT-MH-18-058 - Notice of Information: NIMH's Interest in Areas of Stress Biology Research
NOT-MH-17-039 - Notice of NIMH's Interest to Highlight High-Priority Pediatric Pharmacologic Trial Research Areas
National Institute of Mental Health (NIMH)
The purpose of this Notice is to outline NIMH priorities and considerations for potential applicants investigating the effects of psychedelic drugs and their derivatives or analogues (i.e., related compounds) on mental health and mental illness.
Background
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.
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. As such, this Notice outlines what NIMH 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.
Basic and Preclinical Research
Grant applications proposing to use animals as model systems to study brain mechanisms of psychedelic action should take into consideration that animal systems are not well suited to assess the therapeutic efficacy of psychedelics. Instead, animal systems are better suited 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.
To elucidate the neurobiological actions of psychedelics and related compounds, NIMH prioritizes animal studies that utilize a reverse translational approach to test mechanistic hypotheses informed by observations made in human subjects. As an example, research identifying patterns of brain activity associated with psychedelic-induced improvement in mental function in human subjects can enable studies investigating the molecular, cellular, and circuit-level processes underlying drug effects using parallel brain measures in a preclinical species. Additionally, animal research aiming to identify mechanistic links between psychedelic-induced effects on neural plasticity and circuit dynamics should be guided by results from human synaptic density imaging studies that support the premise for such work.
In cases where evidence enables mechanistic hypothesis testing in animals, NIMH prioritizes studies aiming to identify relationships between clinically relevant psychedelic drug doses and 1) plasma and/or brain concentrations of the compound and any active metabolites, 2) target receptor occupancy levels, and 3) neuroplastic adaptions in molecular, cellular, and circuit-level processes relevant to mental health. Animal experimental designs should be informed by already available clinical data with respect to drug administration schedules, brain target occupancy, and drug pharmacokinetic/pharmacodynamic (PK/PD) properties. Lower priority will be given to studies using compounds and dose ranges for which the PK properties are not known across humans and the 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.
As outlined in NOT-MH-19-053, animal neurobehavioral measures should be selected based on their association with brain processes and circuits relevant to mental health and interpreted without making unsubstantiated links to human thoughts, emotions, or clinical diagnoses. Behavioral readouts that have been linked to serotonin 5HT2A receptor target engagement (e.g., head-twitch response) should be cautiously interpreted without claims that these behaviors reflect aspects of human subjective experiences (e.g., hallucinations).
The following are examples of basic and preclinical research on psychedelics in animals that are considered of low priority to NIMH:
- 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
Translational and Clinical Research
As with other investigational agents, any proposed clinical trials on psychedelics should follow all current existing NIMH guidance on exploratory experimental therapeutics. Investigators planning projects in pediatric populations should consult NOT-MH-17-039. Pediatric testing of psychedelics will require performing pediatric bridging studies. 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 following are examples of translational research on psychedelics in humans that are considered of low priority to NIMH:
- 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
Program Directors/Principal Investigators planning to submit applications involving psychedelics and/or related compounds are strongly encouraged to contact NIMH Program staff when developing their applications to determine the alignment of the proposed work with NIMH priorities.
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