PDP-17: [Funding] Regulation of Endogenous DMT Biosynthesis

Applicants: Dr. Andrew R. Gallimore, Prof. Carl H. Smith, Dr. Chris McCurdy Deal Shepherds: Tyler Quigley & Warren Winter

Overview

DMT is one of the most potent psychedelic compounds known. It is endogenously produced in mammals, including humans. DMT activates multiple receptor subtypes, notably 5HT2A and sigma-1, which are thought to contribute to its pronounced neuroplastogenic effects. Through these mechanisms, DMT has been proposed as a treatment candidate for conditions such as ischemic stroke, neurodegeneration, depression, and chronic pain, as well as a potential tool to support psychotherapeutic and cognitive enhancement applications.

This project aims to uncover how endogenous dimethyltryptamine (DMT) is regulated in the mammalian brain. The applicants suspect that an uncharacterized enzymatic “off switch” regulates DMT production by inhibiting the enzyme indole N-methyltransferase (INMT). Though first described decades ago, such an enzyme has never been fully identified.

By isolating and sequencing these enzymes, this study lays critical groundwork for understanding how the body modulates DMT levels, and whether it might one day be possible to safely activate endogenous DMT production for extended periods of time (i.e.,“endo-DMTx”) without external DMT dosing.

Clarifying how DMT is regulated endogenously may:

• Reveal new pathways to understand if/why DMT levels fluctuate in normal waking life and during certain activities.
• Establish the scientific basis for protocols to induce sustained DMT states via internal pathways (endogenous, extended state DMT).
• Enable new therapeutic levers targeting neuroprotection, learning, and mood. This project is the first systematic effort to characterize the endogenous inhibitors believed to control DMT biosynthesis in the brain.

Experimental Plan

This project will isolate and characterize endogenous peptide inhibitors of INMT, the enzyme responsible for DMT biosynthesis.

1. Sample Preparation

• Prepare homogenates from rabbit brain and lung tissues; obtain human CSF samples.

2. Inhibitory Activity Confirmation

• Replicate prior dialysis experiments demonstrating increased INMT activity after removal of endogenous inhibitors.

3. Fractionation and Purification

• Use size-exclusion chromatography to isolate active inhibitory fractions.

4. Enzyme Assays

• Assess INMT activity in vitro via non-radiometric methods and fluorometric methyltransferase assays.

5. Molecular Characterization

• Estimate inhibitor molecular weight using calibrated columns; evaluate protease sensitivity to confirm peptide nature.

6. Sequencing

• Perform MALDI-TOF MS, de novo sequencing, and Edman degradation to identify amino acid sequences.

Budget

This proposal requests an initial tranche of funding to launch the first milestone of the study.

• Total project budget: $429,506
• Project sponsor: Noonautics, on behalf of the principal investigators.
• Research institution: University of Florida, Dr. McCurdy’s laboratory.

Financing and PsyDAO Terms

Funding requested from PsyDAO: $107,000 Upon successful completion of this milestone, additional funding may be derived from proceeds from tokenization to progress the remaining project aims. In return for PsyDAO’s support, Noonautics will:

• Enter into a Memorandum of Understanding (MoU) granting PsyDAO the right to tokenize this project as an IPT.
• Provide PsyDAO the right of first refusal to partner on any future intellectual property-producing research arising from this work.
• Share regular progress updates and milestone reports with the PsyDAO community.

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Please visit the following link to view the full proposal details: https://docs.google.com/document/d/1-HyXUeQVl-RbVkMGKouAM1cskqAC5UtFZdo0ZvOP6C4/edit?usp=sharing