The paucity of medications with novel mechanisms for the treatment of mental illnesses combined with the delayed response to currently available medications has led to great excitement about the potential therapeutic utility of previously demonized drugs, which offer the hope of generating rapid symptom reductions in some of the sickest patients. Within the past 2 years, the US Food and Drug Administration approved esketamine for treatment-resistant depression and 2 compounds that are still on the US Drug Enforcement Administration’s most restrictive schedule, 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin, have received breakthrough therapy designation. If these latter drugs are approved, they will require a new mental health care infrastructure that is capable of administering powerful psychoactive substances while simultaneously incorporating appropriate psychotherapeutic support. The sheer prevalence of the conditions these drugs are meant to treat (depression and posttraumatic stress disorder among other emerging indications) will mean that clinicians will have to deal with safety issues, including appropriate patient selection, substance abuse potential, and emergent psychiatric and medical crises. These considerations justify investment in elucidating the detailed neural mechanisms by which these drugs work so that we might better control their safety and efficacy while simultaneously developing better treatments with fewer adverse effects.
How best to pursue the mechanisms of action for this next generation of therapeutics? We have argued for a circuits-first approach,3 which involves using the armamentarium of modern neuroscience tools to define the circuit adaptations that contribute to a drug’s behavioral and therapeutic effects. Once critical circuit nodes are identified, single-cell gene profiling can be performed in their key cell types based on their connectivity, yielding novel molecular targets for the development of next generation drugs with greater efficacy and fewer side effects. Modeling complex human behaviors in animals is particularly valuable when the structure and function of the involved neuroanatomy is highly conserved. This is likely the case for several neuromodulatory systems that contribute to a host of behaviors of direct relevance to psychiatry such as Pavlovian and instrumental conditioning, prosocial approach, aggression, cognitive flexibility, and responses to motivationally significant stimuli.
Of course, it is also critical to define the molecular targets of these new therapeutic agents. For ketamine, this has been more challenging than originally expected, with findings4,5 suggesting a need to conceptualize its molecular mechanisms with more nuance than action at a single, broadly distributed glutamate receptor. The complexity of ketamine’s actions emphasizes the critical importance of determining where in the brain it is exerting its therapeutic circuit effects. In contrast to the confusion surrounding ketamine’s molecular targets, a prediction of preclinical studies of lysergic acid diethylamide (LSD), a drug with significant similarity to psilocybin, has been confirmed with the demonstration that LSD’s subjective effects in humans could be blocked by a 5HT2a receptor antagonist.6 Moreover, hallucinogen-induced changes in functional connectivity in human imaging studies2 suggest that reverse translation may be possible. For example, it will be advantageous to define the actions of 5HT2a receptors in the putative drug-modulated circuits in human brains in more experimentally tractable animal brains in which molecular and circuit targets can be manipulated with precision and detailed cellular level observations can be made. Identifying parallel circuitry that is influenced by classic hallucinogens in both humans and animals will be challenging. Nevertheless, the more we can define the relevance of evolutionarily conserved behavioral parameters to the efficacy of the therapeutic intervention, the higher the probability of defining the causal neural mechanisms underlying the drug’s therapeutic effects. In turn, more efficacious therapeutic interventions will follow.