Dr. MANESH GIRN
Research

Neurodegeneration represents one of the most urgent and difficult challenges in modern medicine. Conditions like Parkinson’s and Alzheimer’s disease are characterized by the progressive destabilization of neural circuits — processes for which current treatments offer symptomatic relief at best.

A growing body of preclinical and clinical evidence suggests that psychedelic-inspired compounds hold significant promise here: by engaging serotonergic pathways that regulate synaptic plasticity, neuroinflammation, and circuit function, these molecules offer a mechanistically novel approach to slowing or partially reversing the neural dysfunction that drives disease progression.

My current work in this area is translational and company-building in nature. As Co-Founder and CEO of Five Discovery, I am leading the preclinical development of non-hallucinogenic neuroplastogens for neurodegenerative disease — compounds designed to capture the neurobiological benefits of psychedelic molecules without the psychedelic experience. Our lead program targets Levodopa-Induced Dyskinesia (LID), a debilitating and undertreated motor complication affecting a substantial proportion of Parkinson’s patients on long-term dopaminergic therapy. Beyond LID, our pipeline vision encompasses Parkinson’s disease itself and other neurodegenerative conditions including Alzheimer’s disease,

This work builds directly on my academic research into the serotonergic and network-level mechanisms of psychedelics, and represents what I see as one of the field’s most consequential and underinvested frontiers.

Scientific and public interest in psychedelics has surged in recent years, spearheaded by promising clinical trials supporting their significant potential in the treatment of several mental health conditions, including depression, end-of-life anxiety, and substance use disorders. This interest, coupled with the emergence of a multi-billion dollar psychedelic industry, has necessitated a deeper understanding of how these drugs work.

My primary research focus is in applying the tools and frameworks of modern neuroscience – and functional neuroimaging in particular – towards an understanding of psychedelic brain effects in humans. Through a combination of state-of-the-art statistical and methodological approaches, as well as psychological and behavioral paradigms, I endeavor to uncover the various ways in which brain activity relates to the acute psychedelic experience and its lasting effects. I am also engaged in the development and refinement of theoretical frameworks that synthesize disparate findings and which can inform approaches to and understanding of psychedelic-assisted psychotherapy.

Relevant publications:

Girn, M., Rosas, F. E., Daws, R. E., Gallen, C. L., Gazzaley, A., & Carhart-Harris, R. L. (2023). A complex systems perspective on psychedelic brain action. Trends in Cognitive Sciences.

Girn, M., Mills, C., Roseman, L., Carhart-Harris, R. L., & Christoff, K. (2020). Updating the dynamic framework of thought: Creativity and psychedelics. Neuroimage

Girn, M., Roseman, L., Bernhardt, B., Smallwood, J., Carhart-Harris, R., & Spreng, R. N. (2022). Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex. NeuroImage

Carhart-Harris, R. L., Chandaria, S., Erritzoe, D. E., Gazzaley, A., Girn, M., Kettner, H., … & Friston, K. J. (2022). Canalization and plasticity in psychopathology. Neuropharmacology

Timmermann, C., Roseman, L., Haridas, S., Rosas, F.E., Luan, L., Kettner, H., Martell, J., Erritzoe, D., Tagliazucchi, E., Pallavicini, C., Girn, M. … & Carhart-Harris, R. L. (2023). Human brain effects of DMT assessed via EEG-fMRI. Proceedings of the National Academy of Sciences

As the Scientific Director of
The Center for MINDS
, I am leading efforts to explore how psychedelics and other consciousness-expanding tools can unlock humanity’s creative potential. The Center for MINDS is a nonprofit organization dedicated to advancing research into tools and practices that catalyze breakthrough insights and innovation. Through research, public education, and community development, our work investigates how altered states of consciousness can drive creativity and problem-solving in real-world contexts. By integrating science with actionable solutions, we aim to transform the way humanity approaches global challenges, paving the way for a more innovative, sustainable, and interconnected future.

A core aspect of the human experience is our sense of being someone that is distinct from others and our environment. Cognitive scientists and philosophers call this our ‘sense of self’, and often separate it into two main components. The first is our ‘minimal’ or ‘bodily’ sense of self: our sense of having a first-person perspective that is rooted in our body and a particular location in space. The other – which I am more interested in – is our ‘autobiographical’ or ‘narrative’ sense of self.

Our autobiographical self is our sense of identity that is rooted in memories and concepts. It is composed of the various beliefs we have about ourselves, the traits and characteristics we identify with, and our sense of who we’ve been in the past and the person we’re becoming. This aspect of self is encoded within the narratives and stories we have about ourselves and gives us a sense of continuity in time. Critically, our autobiographical self – and, in particular, our self-beliefs – play a central role in our mental health and well-being. Negatively biased and inaccurate beliefs are found across most, if not all, mental health conditions – and can have far-reaching effects on how we understand and emotionally respond to life events and how we navigate relationships.

I am very interested in understanding how psychedelic drugs alter our self-beliefs and how we process positive and negative self-related information. Towards this end, at UCSF – under the supervision of Dr. Robin Carhart-Harris – I will be conducting investigations on the psychological and neural underpinnings of changes in self-beliefs and self-related processing induced by psilocybin. In alignment with one of my most passionate interests, this research will directly inform our scientific understanding of the mechanisms underlying healing and personal transformation.

Relevant publications:

Girn, M., & Christoff, K. (2018). Expanding the scientific study of self-experience with psychedelics. Journal of Consciousness Studies

Mosurinjohn, S., Roseman, L., & Girn, M. Psychedelic-Induced Mystical Experiences: An Interdisciplinary Discussion and Critique. Frontiers in Psychiatry

Carhart-Harris, R. L., Chandaria, S., Erritzoe, D. E., Gazzaley, A., Girn, M., Kettner, H., … & Friston, K. J. (2022). Canalization and plasticity in psychopathology. Neuropharmacology,

The default mode network is an interconnected set of brain regions that have a variety of unique qualities and which mediate a variety of complex and human-defining cognitive processes. These processes include escaping the here-and-now and thinking about the past or imagining the future, processing information related to the self, thinking about the minds of others, conceptual thinking and meaning-making, and interpreting narratives. Strikingly, the regions which compose this network are the most expanded in humans relative to other primates, are among the most interconnected and metabolically expensive brain regions, are considered to be the apex of the brain’s processing hierarchy, and are highly dense in 5-HT2A receptors – the receptors most important for psychedelic drug effects.

A core part of my PhD research, and broader research program, is understanding this network in more detail. In particular, I have ongoing and completed studies investigating (i) the ways in which this network contributes to complex cognitive processes and behaviors, (2) whether certain subcortical and limbic regions can be seen as part of this network, and (3) how psychedelics alter this network and its relationship to the rest of the brain. In terms of cognitive processes, I am particularly interested in how the default mode network contributes to how we perceive, interact with, give meaning to, and interpret events in the external world.

Relevant publications:

Dixon, M. L., Andrews-Hanna, J. R., Spreng, R. N., Irving, Z. C., Mills, C., Girn, M., & Christoff, K. (2017). Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states. Neuroimage, 147, 632-649.

Dixon, M. L., Girn, M., & Christoff, K. (2020). Brain network organization during mindful acceptance of emotions. BioRxiv PrePrint

Dixon, M. L., Andrews-Hanna, J. R., Spreng, R. N., Irving, Z. C., Mills, C., Girn, M., & Christoff, K. (2017). Interactions between the default network and dorsal attention network vary across default subsystems, time, and cognitive states. Neuroimage

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