EDUCATION CORNER

Science at the Border of Anesthesiology and Psychiatry

Boris D. Heifets, MD, PhD
Assistant Professor
Department of Anesthesiology, Perioperative & Pain Medicine
Stanford University School of Medicine

Boris D. Heifets, MD, PhD

When I meet a patient on the morning of surgery, I sometimes joke with them that “I promise to deliver you back to your family in at least as good a condition as I found you”. This exchange seems to put patients at ease (I think) because it addresses a common source of anxiety about the risks of anesthesia, almost irrespective of the risk of the planned surgery. As an anesthesiologist, I know the numbers are very much in my patients’ favor, and I often wonder if, perhaps, we have unwittingly set too low a bar for success. We are administering the most powerful consciousness-altering drugs in medicine, and our best-case scenario is that, after surgery, these drugs disappear from the patient without a trace? I believe we are sitting on a goldmine of untapped potential for engineering lasting therapeutic brain states through targeted physiology and pharmacology.

If the idea seems far-fetched, that a single dose of a drug can wield a years-long therapeutic effect, consider the recent renaissance of psychopharmacology in treating psychiatric disease. MDMA, psilocybin and ketamine, the first two of which are still classified as DEA Schedule 1 drugs of abuse, are quickly making their way through phase three trials for the treatment of depression and posttraumatic stress disorder (PTSD)1. Though the details of each drug differ in important ways, they share a remarkable property: highly psychoactive single doses have helped a remarkable proportion of treatment-refractory patients achieve symptomatic remission that far outlasts detectable levels of drug in the body2,3. Understanding how these drugs trigger such lasting benefits is the first step toward designing precision therapies1,4.

The best example of this “single-shot therapy” comes from clinical trials with MDMA. MDMA, or “ecstasy”, is a substituted amphetamine and well-known recreational drug that promotes feelings of euphoria, well-being, and uniquely, empathy and a profound sense of social connection5. In the 1970s, a group of pioneering psychiatrists in California began using MDMA as an adjunct to psychotherapy sessions for treating patients with a variety of psychological issues6. Spreading use in the psychiatric community spilled over into unregulated over-the-counter sale and distribution of MDMA nation-wide for recreational use, catching the attention of the DEA. In an emergency session in 1985, the DEA considered congressional testimony from physicians, scientists, and law enforcement agencies, and placed MDMA in the Schedule 1 category, reserved for drugs of abuse with no medical value. Non-profit advocacy groups took up the cause of funding, organizing, and executing randomized placebo-controlled trials for MDMA, focused on testing MDMA-assisted psychotherapy for the treatment for PTSD. By 2011, the first trial suggested an enormous effect size, wherein approximately 80% of patients with severe, debilitating PTSD no longer met criteria for PTSD at two months after their MDMA-assisted psychotherapy treatment; remarkably, this effect was maintained through a nearly four year follow up7,8. Subsequent trials have extended these promising early results, and the FDA granted MDMA-assisted psychotherapy Breakthrough Therapy designation in 2017.

MDMA-assisted psychotherapy may indeed change how PTSD is treated, but it is not an ideal therapeutic package. MDMA has obvious abuse potential, and long term use is associated with a host of neurological, psychiatric, and cardiovascular complications9. Our lab set out to determine whether the neural mechanism underlying MDMA’s therapeutic, prosocial effect could be separated from its abuse potential10. Fortunately, MDMA’s pharmacological targets and its molecular mechanism of action are reasonably well characterized – it has high affinity interactions with the serotonin (5-HT) and dopamine (DA) reuptake transporters (SERT and DAT, respectively), where it can both inhibit monoamine reuptake and drive reverse transport, resulting in supraphysiological levels of neurotransmitter release. MDMA administration can also result in release of other major neurohormones like oxytocin, which, like 5-HT and DA, have been implicated in the biology of prosocial behavior. Which among these neuromodulators and where in the brain they might act to produce MDMA’s various behavioral effects was unclear. Based on recent work in our lab11, we hypothesized that 5-HT released by MDMA, specifically into the nucleus accumbens (NAc), could account for MDMA’s prosocial effect but not its addictive properties.

We modeled the prosocial and nonsocial drug reward of MDMA in mice and investigated the mechanism of these processes using brain-region specific pharmacology, transgenic manipulations, electrophysiology, and in vivo calcium imaging. We found convergent evidence from drug microinjection experiments and studies with conditional SERT knockout mice demonstrating that MDMA acts at SERT-containing 5-HT terminals within the NAc. This interaction was both necessary and sufficient to explain MDMA’s prosocial effect, but not its nonsocial drug reward, which was instead mediated by DA signaling in the NAc. We used in vivo calcium imaging in behaving mice both to show that 5-HTergic afferents in the NAc were preferentially active in social-contexts, and that MDMA’s effect at these terminals was due to a reverse-transport mechanism via SERT.

Therapists involved with clinical trials of MDMA-assisted psychotherapy hypothesize that MDMA’s lasting benefits stem from its acute effects on patients, fostering feelings of openness and connectedness2,11. This framework points to the importance of MDMA’s acute effect in triggering long lasting neural and behavioral adaptation, provides a when for MDMA’s mechanism. Our data to this point suggested a where for that process – the NAc. We thus moved to an experimental preparation better suited for detailed electrophysiology to explore the how. We recorded synaptic currents from various NAc neuronal subtypes in mouse brain slices while electrically stimulating excitatory afferents. In this system, we found that a brief application of MDMA could induce a long-term depression (LTD) of excitatory synaptic strength, suggesting a possible synaptic analog of MDMA’s lasting therapeutic effect. We found that this LTD required activation of the 5-HT1b receptor, was mimicked by d-fenfluramine, a selective 5-HT-releasing drug, and did not require oxytocin receptor activation. These electrophysiological findings directly matched our behavioral data: MDMA-induced prosocial behavior was blocked a 5-HTR1b antagonist infused into the NAc; it was mimicked by d-fenfluramine; and, remarkably, was completely independent of oxytocin receptor signaling. Based on these data, we predict that perhaps a 5-HTR1b agonist or even d-fenfluramine, in the context of psychotherapy, could produce beneficial subjective effects similar to MDMA without the addictive potential.

These experiments are a starting point for unraveling the complex physiology that defines a therapeutic prosocial state. Moreover, MDMA is only one example of a drug that can have lasting benefits when given in controlled circumstances. Ketamine, well known to us in the operating room, has found new fame with its spreading use as a rapid-acting antidepressant and the FDA approval of esketamine as the first antidepressant with a novel mechanism in decades. Highly promising early studies suggest that other drugs in our drawers (and ventilators) may have rapid-acting and durable therapeutic effects for psychiatric disease, including N2O12, isoflurane13, and propofol14. Animal models and carefully constructed clinical experiments will be needed to reveal what neural physiology and pharmacology accounts for their benefits. Reproducing these physiological states with precise pharmacological tools, perhaps coupled with emerging noninvasive brain stimulation techniques, will open new realms of possibility for treating patients, and for the evolution of our field of anesthesiology.

References

1. Heifets, B. D. & Malenka, R. C. Disruptive Psychopharmacology. JAMA Psychiatry (2019) doi:10.1001/jamapsychiatry.2019.1145.
2. Mithoefer, M. C., Grob, C. S. & Brewerton, T. D. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry 3, 481–488 (2016).
3. Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000).
4. Icaza, E. E. & Mashour, G. A. Altered states: psychedelics and anesthetics. Anesthesiology 119, 1255–1260 (2013).
5. Greer, G. & Tolbert, R. Subjective Reports of the Effects of MDMA in a Clinical Setting. Journal of Psychoactive Drugs 18, 319–327 (1986).
6. Passie, T. The early use of MDMA (‘Ecstasy’) in psychotherapy (1977–1985). Drug Science, Policy and Law 4, 205032451876744 (2018).
7. Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L. & Doblin, R. The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol 25, 439–452 (2011).
8. Mithoefer, M. C. et al. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J Psychopharmacol 27, 28–39 (2013).
9. McCann, U. D. & Ricaurte, G. A. Effects of MDMA on the Human Nervous System. in The Effects of Drug Abuse on the Human Nervous System 475–497 (Elsevier, 2014). doi:10.1016/B978-0-12-418679-8.00015-0.
10. Heifets, B. D. et al. Distinct neural mechanisms for the prosocial and rewarding properties of MDMA. Sci Transl Med 11, (2019).
11. Walsh, J. J. et al. 5-HT release in nucleus accumbens rescues social deficits in mouse autism model. Nature 560, 589–594 (2018).
12. Nagele, P. et al. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biol. Psychiatry 78, 10–18 (2015).
13. Weeks, H. R. et al. Antidepressant and Neurocognitive Effects of Isoflurane Anesthesia versus Electroconvulsive Therapy in Refractory Depression. PLoS ONE 8, e69809 (2013).
14. Mickey, B. J. et al. Propofol for Treatment-Resistant Depression: A Pilot Study. Int. J. Neuropsychopharmacol. 21, 1079–1089 (2018).