Faculty Bibliography

Clinical trials in depression lack objective measures. Speech latencies are an objective measure of psychomotor slowing with face validity and empirical support. 'Turn latency' is the response time between speakers. Retrospective analysis was carried-out on the utility of turn latencies as an enrichment tool in a clinical trial of bipolar I depression. Speech data was obtained from 274 participants during 1,352 Montgomery-Åsberg Depression Rating Scale (MADRS) recordings in a randomized, placebo controlled, 6-week clinical trial of SEP-4199 (200 mg or 400 mg). Post-randomization turn latencies were compared between patients with moderate to severe depression and patients whose depression had remitted. A cutoff was determined and applied to turn latencies pre-randomization to classify individuals into two groups: Speech Latencies Slow (SL-Slow) and Speech Latencies Normal (SL-Normal). At week 6, SL-Slow (N = 172) showed significant separation in MADRS scores between placebo and treatment arms. SL-Normal (N = 102) showed larger MADRS improvements and no significant separation between placebo and treatment arms. Excluding SL-Normal increased primary outcome effect size by 52 % and 100 % for the treatment arms. Turn latencies are an objective measure available from standard clinical assessments and may assess the severity of symptoms more accurately and screen out placebo responders.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials^1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus^5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

1The relationship between the acute effects of psychedelics and their persisting neurobiological and psychological effects is poorly understood. Here, we tracked brain changes with longitudinal precision functional mapping in healthy adults before, during, and for up to 3 weeks after oral psilocybin and methylphenidate (17 MRI visits per participant) and again 6+ months later. Psilocybin disrupted connectivity across cortical networks and subcortical structures, producing more than 3-fold greater acute changes in functional networks than methylphenidate. These changes were driven by desynchronization of brain activity across spatial scales (area, network, whole brain). Psilocybin-driven desynchronization was observed across association cortex but strongest in the default mode network (DMN), which is connected to the anterior hippocampus and thought to create our sense of self. Performing a perceptual task reduced psilocybin-induced network changes, suggesting a neurobiological basis for grounding, connecting with physical reality during psychedelic therapy. The acute brain effects of psilocybin are consistent with distortions of space-time and the self. Psilocybin induced persistent decrease in functional connectivity between the anterior hippocampus and cortex (and DMN in particular), lasting for weeks but normalizing after 6 months. Persistent suppression of hippocampal-DMN connectivity represents a candidate neuroanatomical and mechanistic correlate for psilocybin's pro-plasticity and anti-depressant effects.

IMPORTANCE:Psychedelic drugs are becoming accessible in the US through a patchwork of state legislative reforms. This shift necessitates consensus on treatment models, education and guidance for health care professionals, and planning for implementation and regulation. OBJECTIVE:To assess trends in psychedelics legislative reform and legalization in the US to provide guidance to health care professionals, policy makers, and the public. EVIDENCE REVIEW:Data were compiled from legislative databases (BillTrack50, LexisNexis, and Ballotpedia) from January 1, 2019, to September 28, 2022. Legislation was identified by searching for terms related to psychedelics (eg, psilocybin, MDMA, peyote, mescaline, ibogaine, LSD, ayahuasca, and DMT). Bills were coded by an attorney along 2 axes: which psychedelic drugs would be affected and in what ways (eg, decriminalization, funding for medical research, and right to try). To explore drivers and rates of legislative reform, data were compared with other state indices including 2020 presidential voting margins and marijuana legislative reform. FINDINGS:Twenty-five states have considered 74 bills (69 legislative initiatives, 5 ballot measures); 10 bills were enacted, and 32 were still active. The number of psychedelic reform bills introduced during each calendar year increased steadily from 5 in 2019 to 6 in 2020, 27 in 2021, and 36 in 2022. Nearly all bills specified psilocybin (67 [90%]), and many also included MDMA (3,4-methylenedioxy-methamphetamine; 27 [36%]). While bills varied in their framework, most (43 [58%]) proposed decriminalization, of which few delineated medical oversight (10 of 43 [23%]) or training and/or licensure requirements (15 of 43 [35%]). In general, bills contained less regulatory guidance than the enacted Oregon Measure 109. While early legislative efforts occurred in liberal states, the margin between liberal and conservative states has decreased over time (although the difference was not significant), suggesting that psychedelic drug reform is becoming a bipartisan issue. In addition, an analytic model based on marijuana legalization projected that a majority of states will legalize psychedelics by 2034 to 2037. CONCLUSIONS AND RELEVANCE:Legislative reform for psychedelic drugs has been proceeding in a rapid, patchwork fashion in the US. Further consideration should be given to key health care issues such as establishing (1) standards for drugs procured outside the medical establishment, (2) licensure criteria for prescribers and therapists, (3) clinical and billing infrastructure, (4) potential contraindications, and (5) use in special populations like youths, older adults, and pregnant individuals.

The 21^st century has brought novel therapies and new therapeutic targets for major depressive disorder (MDD). Until recently all antidepressant medications targeted monoamines-serotonin, norepinephrine, and dopamine- and their regulatory systems. But growing evidence has suggested that individuals who fail to respond to a monoaminergic treatment are likely to fail to respond to other monoaminergic options. The emergence in recent years of treatment targets beyond the monoaminergic systems (e.g. κ-opioid antagonists, ketamine and other NMDA modulators, neurosteroids) has cultivated hopes for not only greater efficacy in treating depression, but also improved precision in targeting specific phenotypes and symptoms. Concurrently, an expanding repertoire of diagnostic and assessment tools-such as smartphone-based experience sampling and brain imaging-is moving the field toward more reliable and symptom-specific measurement with greater descriptive and prescriptive power. Taken together, these diagnostic tools and treatment options herald a new era of "precision psychiatry"-the selection and implementation of an optimal treatment for an individual patient's particular needs. Anhedonia offers an example of the new precision psychiatry. Anhedonia has moved from merely one among several criteria for depression to a transdiagnostic psychopathology which can be understood neurobiologically, assessed quantitatively, and centered as a primary target in research and development of novel pharmacotherapies. We describe functional testing of reward circuits in the development of kappa-opioid antagonists for anhedonia. This offers a lens for understanding how and under what circumstances other novel treatments, such as psychedelics, might find a place in the future landscape of precision psychiatric care.

Understanding the relationships between brain organization and behavior is a central goal of neuroscience. Traditional teaching emphasizes that the human cerebrum includes many distinct areas for which damage or dysfunction would lead to a unique and specific behavioral syndrome. This teaching implies that brain areas correspond to encapsulated modules that are specialized for specific cognitive operations. However, empirically, local damage from stroke more often produces one of a small number of clusters of deficits and disrupts brain-wide connectivity in a small number of predictable ways (relative to the vast complexity of behavior and brain connectivity). Behaviors that involve shared operations show correlated deficits following a stroke, consistent with a low-dimensional behavioral space. Because of the networked organization of the brain, local damage from a stroke can result in widespread functional abnormalities, matching the low dimensionality of behavioral deficit. In alignment with this, neurological disease, psychiatric disease, and altered brain states produce behavioral changes that are highly correlated across a range of behaviors. We discuss how known structural and functional network priors in addition to graph theoretical concepts such as modularity and entropy have provided inroads to understanding this more complex relationship between brain and behavior. This model for brain disease has important implications for normal brain-behavior relationships and the treatment of neurological and psychiatric diseases.

The striatum and cerebral cortex are interconnected via multiple recurrent loops that play a major role in many neuropsychiatric conditions. Primate corticostriatal connections can be precisely mapped using invasive tract-tracing. However, noninvasive human research has not mapped these connections with anatomical precision, limited in part by the practice of averaging neuroimaging data across individuals. Here we utilized highly sampled resting-state functional connectivity MRI for individual-specific precision functional mapping (PFM) of corticostriatal connections. We identified ten individual-specific subnetworks linking cortex-predominately frontal cortex-to striatum, most of which converged with nonhuman primate tract-tracing work. These included separable connections between nucleus accumbens core/shell and orbitofrontal/medial frontal gyrus; between anterior striatum and dorsomedial prefrontal cortex; between dorsal caudate and lateral prefrontal cortex; and between middle/posterior putamen and supplementary motor/primary motor cortex. Two subnetworks that did not converge with nonhuman primates were connected to cortical regions associated with human language function. Thus, precision subnetworks identify detailed, individual-specific, neurobiologically plausible corticostriatal connectivity that includes human-specific language networks.

There is a serious need for novel therapies that treat individuals with depression, including major depressive disorder (MDD) and treatment-resistant depression (TRD). An emerging body of research has demonstrated that psychedelic drugs such as psilocybin, combined with supportive psychotherapy, exert rapid and sustained antidepressant effects. The use of psychedelics is not new: they have a rich history with evidence of their use in ritual and medical settings. However, due to political, social, and cultural pressures, their use was limited until modern clinical trials began to emerge in the 2010s. This review provides a comprehensive look at the potential use of psilocybin in the treatment of depression and TRD. It includes an overview of the history, pharmacology, and proposed mechanism of psilocybin, and describes several published studies in the last decade which have provided evidence of the efficacy and safety of psilocybin-assisted psychotherapy for individuals with depression. It also includes a discussion of the limitations and barriers of current research on psychedelics. The results of these studies are contextualized within the current treatment landscape through an overview of the pathophysiology of depression and the treatments currently in use, as well as the clinical needs these novel therapies have the promise to fulfill.