Tryp Therapeuatics (TRYPF) Coverage Report

Exhibit 9: Neurotransmitter receptor binding affinities by brain region, per hallucinogenic & word association The leading factor underlying hallucinogenic experiences is compatible with the phenomenon of ego dissolution. Shows the statistically strongest pattern of how binding affinities of neurotransmitter receptors were cross-linked with usages of >14,000 words in thousands of real-world hallucinogenic sessions. Left: Experiential terms together make apparent the semantic context that was consistent across drugs with diverging pharmacological mechanisms of action. Bigger words had relatively higher ranking in the factor. Right: Synaptic receptor density proxies that were most associated with the experiential theme of factor 1. Blue bars correspond to the blue word-values on the left, while red bars correspond to red words. Middle: Shows how much each examined drug is associated with the receptor gene profiles of factor 1. Blue bars correspond to the blue word-values on the left, while red bars correspond to red words. Brain renderings highlight those among the 200 anatomical regions where the local co-expression of receptor genes was most tightly linked with factor 1. Sagittal, coronal, and axial brain slices are shown at x=+5, y=-14, and z=+15, (per Montreal Neurological Institute (MNI) templates). The colors of these renderings demonstrate the density of the weighted receptor gene expression for each region and correspond to the poles of the factor: blue words and bars correspond to blue/green brain regions (green>blue intensity) while red words and bars correspond to red/yellow brain regions (yellow>red intensity). Source: bioRxiv preprint doi : https://doi.org/10.1101/2021.07.13.452263 In line with others, we believe, the SUNY researchers theorized that psychedelics would generate a cortex-wide distribution of receptor-experience, but they also found evidence in anatomical regions across the deepest and shallowest neural network layers. Each of the 6,850 subjective drug experiences were modeled as a specific combination of the brain- behaviors to deconstruct the changes of conscious awareness that were triggered by hallucinogenic drugs. They found smooth transitions of expression strength between neighboring brain regions. Brain-behavior effects were often found to be mirrored in homologous brain regions in the left and right hemisphere. The researchers used a pattern-learning algorithm which identified eight factors to link psychedelics to receptor affinities and experiential terms from the testimonials. Ultimately, the researchers found, “…a wider group of receptors may individually or collectively underpin the process of self-disintegration that is thought to be critical for the success of psychedelics-assisted psychotherapy.” To us, this is not terribly surprising, given the tendency in drug discovery to clinch to a mechanism (in this case, to 5HT2A), while other factors are at play. We agree with the researchers that psychedelics may come to, “…serve as a tool to study the mechanistic receptor basis of how the higher association cortex orchestrates its subordinate large-scale circuits to impose structure on sensory perception”, but given the challenges of studying the human brain may benefit post hoc from all the clinical trials underway and expected in the near-term years ahead. Michael Higgins 212.409.2074 Tryp Therapeutics, Inc. (TRYPF) Page 17