Therapeutic Development of Psychoplastogenic Compounds for Substance Use Disorders (R43/R44 - Clinical Trials Not Allowed)

Substance Use Disorders (SUD) are defined as a collection of chronic disorders initiated by the misuse of legal and illicit drugs, then potentially leading to an uncontrollable drug-seeking behavior. The neuroimaging studies of SUD patients have demonstrated abnormal prefrontal cortex (PFC) function. The PFC can regulate the ability of the limbic reward circuitry, modulate attention, and can apply top-down regulation over drug-seeking behavior. Improving PFC function, including non-pharmacological interventions, has led to some success in treating SUD. A promising new drug class of psychoplastogenic compounds (PC) includes a growing class of fast-acting and long-lasting therapeutics which promote structural and functional neural plasticity that extends beyond the acute effects of the treatment. The development of PC-based treatments will help identify the fundamental mechanisms of action for efficacy and eliminate unnecessary side effects which would address the pressing need for new and improved SUD pharmacotherapies. As of 2022, there are over 60 public companies developing PC-based drugs for CNS indications. A number of them have launched multimillion-dollar initial public offerings, demonstrating that the area has matured and there is considerable investors’ interest in this drug class. Moreover, there is renewed interest in the psychedelic (PSD) related PC as treatments for psychiatric disorders, including SUD, which has warranted a better understanding of the neurobiological mechanisms underlying the effects of these substances. Consequently, there is a need to expand the chemical space, both according to the PSD and non-PSD effects of the PCs and to optimize their chemical diversity to treat SUDs. Given the PSD and non-PSD PC effects, the development of additional animal models to investigate the psychedelic behavioral pharmacology of PCs is also needed. Current PCs engage many molecular targets, and to date, the serotonin type 2A (5HT2A) receptor is the necessary molecular target that has emerged as mediating PSD-like drug effects in humans and animals. For example, the PSD PC, lysergic acid diethylamide (LSD), has agonist activity at a majority (12 out of 14) of human 5HT receptors and agonism at the adrenergic receptors and the dopamine receptors. As a result, uncertainty remains about which aspects of the 5HT2A receptor and other necessary receptor activities in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with different specificity and selectivity profiles. As PSD PC substances are nonselective agonists to other 5HT receptors; a common target is the 5HT-type 2B (5HT2B) receptor. The 5HT2B receptor is expressed in many tissues, including the heart, which raises a heart-related concern due to the chronic overstimulation by these 5HT2B target agonists that may lead to severe valvulopathy. However, there have been clinical trials of treatment-resistant depression that found the PSD compound, psilocybin, as a cardiac-safe, fast-acting, and effective treatment lasting months after a single or a few dose regimens. This efficacy was also comparable to a daily regimen of conventional serotonin reuptake inhibitor (SSRI) treatments without the common slow onset (e.g., 4-6 weeks to show efficacy), SSRI side effects, and eventual tapering off with withdrawal potential. State-of-the-art research has recently begun to close important knowledge gaps by investigating the mechanisms of action of PSD and other non-PCs. Their effects on receptor subsystems, systems-level brain activity, connectivity, and cognitive and emotional processing are being further elucidated. Advances in the chemistry of 5HT2A agonists have led to 5HT2A-specific substances exemplified by the synthetic, selective psychedelic, 2,5-Dimethoxy-4-(2-((2-methoxybenzyl)amino)ethyl)benzonitrile (25CN-NBOMe) and a new generation of non-PSD 5HT-2A agonists, such as tabernanthalog (TBG). TBG mechanism of action was demonstrated to be dependent on 5-HT2A agonism via 5HT-2A antagonists (e.g., ketanserin or AAZ-134) in either substance use or psychiatric disorder (PSY) animal models. Lisuride, a non-PSD structural analog of LSD and a 5HT-2A agonist, has been shown to have antidepressant properties in post-stroke depression patients. On one hand, functional studies of PSD-related PCs have demonstrated that changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects in human subjects. On the other hand, the investigations of non-PSD PCs provide evidence that the non-PSD agonism of 5HT-2A is effective and that the PSD-induced mystical subjective effects in human subjects may not be needed for effectiveness. In addition to the need for new specific chemical probes, PSD drugs' behavioral pharmacology produces phenotypes in the available animal models, such as the head twitch response (HTR), which are informative. In the HTR, there is a linear correlation between drug potencies for inducing HTR and the in vivo psychedelic doses in humans. As a result, the HTR is a gold standard model for studying PSD effects. This model only, however, partially captures the effects observed in humans, where the subjective perception of the experience plays significant roles in both the acute and enduring effects. Also, there are caveats to using the HTR model for PSD research; it can have either false positives with the non-PSD compounds (e.g., 5-hydroxytryptophan, tryptamine, and serotonin) or false negatives with strong PSD compounds (e.g., N, N-dimethyltryptamine (DMT)). The chemical probes to improve PC efficacy and mitigate side effects along with new model development are the key areas that this funding opportunity announcement seeks to address in the area of PC therapeutic development for SUD. Research Objectives : The National Institute on Drug Abuse (NIDA) seeks applications to validate PC-based pharmacotherapeutics or in vivo PSD behavioral model or PSD assay development or any combination of these activities in the context of SUD. Projects, proposing the development of PC therapeutics for a DSM5-defined SUD, will be considered equally responsive. Projects that focus on alcohol use disorder or pain as the primary indication will not be responsive and returned without review. Applications developing or utilizing natural or synthetic PC-based compounds entering at either target identification, target validation, assay development (AD), lead identification (LI), lead optimization (LO), or preclinical development (PCD) stages in the following areas for SUD are encouraged and may include: Target Identification and Validation Studies Investigation of bioactive natural products, related extracts, and the identification of essential active compounds for efficacy and toxicity in in vitro assays (e.g., on and off-target) and preclinical in vivo SUD models; Chemical synthesis of novel ligands as selective 5HT2A receptor agonists or other important tools for drug discovery of PC compounds (e.g., full or partial agonists, antagonists, allosteric modulators), purifying and testing synthetic PC candidates for efficacy and toxicity in in vitro assays (e.g., on and off-target) and preclinical in vivo SUD models; Drug repurposing and target deconvolution of the PC compounds including psychedelics (e.g., natural and synthetic 5HT2A agonists), non-psychedelics (e.g., 5HT2A agonists both new or known PCs {e.g., TBG, lisuride}), ketamine, and 3,4-Methylenedioxymethamphetamine (MDMA). Other potential PCs may also be considered responsive, if either preliminary data or cited publication evidence is provided (e.g., Salvinorin A, a κ-opioid receptor (KOR) agonist). Assay Development, hit-to-lead activities, and in vivo model development In vitro PSD and non-PSD assay development to identify phenotypes to triage compounds for PC drug development for subsequent in vivo research. Traditional hit confirmation and validation studies from target-based high content screens from chemical or virtual libraries. New In vivo model development (e.g., rodents, nonhuman primates) for PSD PC efficacy studies in comparison to the established models (e.g., head twitch model, drug discrimination model); new model development should include positive and negative control compounds (e.g., psychedelics and non-psychedelic drugs (e.g., lisuride, TBG) along with other controls, such as receptor antagonists (e.g., ketanserin or AAZ-134). Lead optimization (LO) studies For the LO stage, activities consisting of PC drug candidates demonstrating acceptable in vivo PK and toxicity, feasible formulation, in vivo preclinical efficacy (e.g., sufficiently powered) studies, dose range finding (DRF) pilot toxicology, process chemistry assessment of scale-up feasibility, and regulatory and marketing assessments. Preclinical (PCD) studies For the PCD stage, activities consisting of PC drug candidates demonstrating acceptable PK (with a validated bioanalytical method), absorption, distribution, metabolism, excretion (ADME) studies; demonstrating in vivo efficacy/activity, acceptable safety margin (e.g., toxicity in rodents or dogs, when appropriate), feasibility of GMP manufacture, acceptable drug interaction profile, and well-developed clinical endpoints. Words Matter Drug addiction is a chronic but treatable disorder with well-understood genetic and social contributors. NIDA encourages preferred language that accurately describes addiction and substance use in all submitted materials without perpetuating stigma and bias. Research shows that using person-first language—such as "person with a substance use disorder"—instead of "substance abuser" or "addict" can reduce negative associations and punitive attitudes among clinicians and researchers. Further, the term "substance abuse" has no clinical relevance, as it is no longer included in the DSM-5 terminology. Instead, NIDA encourages the use of "addiction" or "substance use disorders" or other specific terminology, such as "opioid use disorders," "cocaine use disorders," as included in the DSM-5. In addition to using person-first language, NIDA recommends avoiding the term "substance abuse" and its derivatives in favor of "use," "misuse," or "use disorder(s)" where appropriate. Similarly, "abuse potential" may be replaced with "addiction liability." NIDA encourages using the term "medications for opioid use disorder" (MOUD) instead of "medication-assisted treatment" (MAT) or "opioid substitution therapy" (OST) when referring to medications prescribed for the treatment of OUD. The term MOUD appropriately frames these life-saving medications as effective, frontline treatments. In contrast, the term MAT implies that medication should have a supplemental or temporary role in treatment. OST reinforces the misconception that MOUD "substitutes" one drug for another instead of supporting recovery. The terminology shift to MOUD aligns with the way other psychiatric medications are understood (e.g., antidepressants, antipsychotics) as critical tools central to a patient's treatment plan. These small but powerful substitutions may help address stigma in patients and study participants, which research shows reduces willingness to seek and accept treatment, among other adverse health outcomes. For more information on preferred language in addiction care, visit NIDAMED: https://www.drugabuse.gov/nidamed-medical-health-professionals/health-professions-education/words-matter-terms-to-use-avoid-when-talking-about-addiction.