Johns Hopkins School of Medicine

Neuropsychopharmacology of Psychoactive Drugs

I work at the intersection of cognitive neuroscience and behavioral pharmacology to better understand the psychological, cognitive, and neurobiological basis of the acute and enduring effects of psychoactive drugs in both healthy and patient human populations. My primary interests are in the acute and enduring effects of classic (serotonergic) psychedelic drugs (such as psilocybin and LSD), and we consider these in comparison to similar effects of atypical hallucinogens (such as the NMDA-antagonist dextromethorphan and the kappa opioid agonist salvinorin A) and other psychoactive compounds (such as stimulants and cannabinoids). In collaboration with colleagues across the institution, we apply psychometrically validated questionnaire instruments, computerized cognitive testing, peripheral and central electrophysiological measurements, magnetic resonance imaging methods (functional, structural, and spectroscopic), and molecular imaging methods to these questions.

We have published a comprehensive review of leading circuit models of acute psychedelic drug effects in the brain (Doss et al., 2022), while also providing primary empirical evidence for psilocybin effects on some of these circuits. We demonstrate effects of psilocybin on a cortico-striatal-thalamic-cortical circuit (Gaddis et al., 2022). We have also published first-in-human and first-ever evidence for an effect of psilocybin on the claustrum and cortico-claustro-cortical circuits (Barrett et al., 2020a; Madden et al., 2022). We have demonstrated separable and differentially dissociable acute effects of classic psychedelic drugs compared to atypical hallucinogens on working and episodic memory, executive function, and associative learning (Barrett et al., 2017)., and of the atypical hallucinogen salvinorin A on human brain network activity and connectivity (Doss et al. 2020). These effects may be in part explained by acute effects of psychedelics on thalamic and claustral circuits.

We are also leading the way in understanding the enduring effects of psychedelics on brain and behavior in both healthy individuals and patients suffering from mood and substance use disorders. We were the first to demonstrate enduring effects of psilocybin administration (1 week and 1 month after administration) on human affect and brain function (Barrett et al., 2020b). We also the first to conduct a randomized controlled trial demonstrating an antidepressant effect of psilocybin in patients with major depressive disorder (Davis et al., 2020). We have also provided evidence for enduring effects of psilocybin on psychological (Davis, Barrett & Griffiths, 2020) as well as cognitive and neural flexibility (Doss et al., 2021), with enduring neural effect of psilocybin being shown in brain regions and circuits in which we have separately demonstrated, using [11C] MDL 100907 molecular positron emission tomography, high levels of regional occupancy by psilocybin of the molecular and psychoactive target of psychedelic drugs, the serotonin 2A receptor (Barrett et al., 2022). With these findings, we have proposed a new theoretical framework suggesting that psychedelics may adjust an individual’s balance of cognitive stability and flexibility, which may explain effects of psychedelics not only in enduring therapeutic response in patients with mood and substance use disorders, but also in the domain of creativity (Sayali & Barrett, 2023). 

We have also established and validated instruments for the assessment of subjective effects of psychedelic drugs that have gained world-wide acceptance and application (Barrett et al., 2015, 2016), and we have shown that the subjective states described in this manner may be useful predictors of therapeutic outcomes of psychedelic experiences (Nikolaidis et al., 2023). We are moving further to try to understand the impact of set (or expectancy) and setting (or context) in helping to shape acute psychedelic experience and potentially determine enduring effects of these experiences. While much anecdotal attention is given to set and setting in psychelic experiences, little is known empirically (Golden et al., 2022), except that music may be a powerful modulator of subjective experiences (Barrett, Preller, & Kaelen, 2018). Better understanding set and setting may help us to optimize the delivery of current psychedelic therapies, and advance the development of novel treatments and compounds in the future. Given these findings as well as the peculiar subjective effects of psychedelic drugs, my work advancing our understanding of the potential of psychedelics to modify negative affect, cognitive control, and associated neural circuitry may expand not only our understanding of the development, maintenance, and treatment of mood disorders and substance use disorders, but also the neural basis of consciousness and subjective experiences more broadly.

Computational Modeling of Music Cognition

Humans may be a uniquely musical species. Music as an auditory stimulus is both spatially and temporally complex, evolving over time and relying on continually developing violation and resolution of expectancy in complex auditory objects in tonal space. I have helped to develop and refine a computational model of music cognition in tonal space that can be used to quantify and subsequently interrogate both behavior and brain function assessed during and in response to music listening (Collins et al., 2014). This model is comprised of binning and smoothing of a projection of auditory waveforms through a computational model of cochlear nerve response. This timecourse is then fed through a neural network trained to organize sound in tonal centers arranged as movement on the surface of a torus. This toroidal representation can then be utilized to generate predictions of behavior for ratings of tonal expectancy violation and resolution during music listening. The representation can also be decomposed into regressors that are used to predict behavior and interrogate brain activity measured during music listening.

We have demonstrated that different networks of brain areas track the moment-to-moment movement of music through tonal space depending on the psychological context of music listening (e.g. listening to music that evokes a memory, or music that evokes a particular emotional experience; Barrett & Janata, 2016). We have also demonstrated that these networks are further modified during the acute effects of lysergic acid diethylamide (LSD), such that brain regions involved in autobiographical memory and self-referential processing show enhanced tonality tracking, and this tonality tracking is somewhat dependent upon stimulation of the serotonin 2A receptor (Barrett et al., 2018).