Defining Endogenous DMT Brain Biotypes: A Multi-Modal Neuroimaging Study

Principal Investigator: Faye McKenna, PhD

The McKenna Lab and research team at the Magnetic Resonance Research Center

1. Overview

Despite researchers documenting endogenous DMT as early as the mid 1900’s in mammals there is still a lack of understanding of its underlying neurobiolocal mechanisms (1). Endogenous DMT is of great current interest as there is a rise in the use of psychedelics for the treatment of neuropsychiatric disorders, such as depression, anxiety, post-traumatic stress and multiple sclerosis, particularly those individuals who are currently treatment-resistant (2,3). Our study aims to delineate DMT biotypes based on advanced neuroimaging methods, peripheral biomarkers and cognitive measures across in a large cohort (N = 1,100) of healthy individuals and those with neuropsychiatric disorders. We believe new therapies could be designed to treat DMT biotypes. We will delineate DMT biotypes by applying a novel in vivo multi-modal magnetic resonance imaging (MRI) technique that combines complementary DMT neuroimaging markers (PET, diffusion and resting-state MRI) and see if those biotypes are associated with clinical features as so to better understand their phenotypic presentation. Additionally, we will test if peripheral blood markers of DMT processes (tryptophan, cortisol, 5-HT polymorphisms) support the value of the proposed metrics in detecting DMT biotypes. The aims of this proposal are to: (a) test a novel multi-modal neuroimaging method for measuring in vivo DMT processes for the first time, (b) examine if in vivo MRI DMT measures can delineate two DMT biotypes, and (c) test whether DMT biotypes are associated with distinct clinical features and peripheral DMT markers, with our ultimate goal being to identify DMT biotypes that have clinical treatment potential. All parts of the study will be conducted at the Albert Einstein College of Medicine, which is an excellent institution for biomedical imaging and psychiatry. This fellowship would be instrumental to the primary investigator’s career and research and, moreover, would further the science of neuroimaging, endogenous DMT and its efficacious impact on improving mental health.

2. Introduction

Recent discoveries have revealed that DMT occurs naturally in the human brain and is as abundant as classical monoamine (MAO) neurotransmitters (4). While DMT’s specific endogenous function is still not clear, both previous and ongoing research suggests that it can be used therapeutically to improve mood (5,6), neuroplasticity (7) and decrease inflammation and oxidative stress (8). Although endogenous DMT has great therapeutic potential, there is still a lack of understanding of DMT’s neurological underpinnings in humans. This is likely due to previous unspecific quantification methods and its changing neurological concentration (9) due to physiological, biological and lifestyle factors (i.e. stress (1), hypoxia (10), sleep (11), genetics (12) and psychological state (13)).

What has been shown is that DMT has a physiologically relevant binding affinity with various serotonergic receptors involved in regulating anxiety, depression, social interaction, neuroplasticity and mitochondrial function (14). In addition to this specific serotonergic binding profile, DMT can modulate the GABAAergic neurotransmitter system (15), reduce neuroinflammation (16) and reduce top-down global default mode network (DMN) brain functioning (17).

The Center for Integrated Molecular Brain Imaging (Cimbi) has collected over 1000 high-resolution Positron Emission Tomography (PET) scans, along with structural T1 MRI for anatomical segmentation, resting-state functional MRI (fMRI) and diffusion MRI (dMRI) scans, blood, saliva, clinical, cognitive and genetic data on healthy individuals and those with several of the most common psychological disorders (i.e. depression, anxiety, substance abuse) as part of an open-source data sharing initiative (18). The PET scans they obtain supply critical information of serotonergic whole brain receptors systems involved in endogenous DMT activity, namely 5-HT1A, 5-HT1B and 5-HT2A.

Table 1. Neuroimaging methods collected for N = 1,100 participants as part of Cimbi that can measure aspects of endogenous DMT in the brain and will help detect a DMT biotypes.

Neuroimaging Modality	DMT-specific Method	Neurobiological basis
PET	5-HT1A receptors [¹¹C]CUMI-101 ligand	DMT is an agonist at this receptor- anxiolytic, antidepressant, reduces impulsive action, improves social interaction, passive coping properties (19) oppositive effect to 5HT-2A
PET	5-HT1B receptors [¹¹C]AZ10419369 ligand	DMT is an agonist at this receptor- regulates neurotransmitter release, mood, anxiety and aggression
PET	5-HT2A receptors [¹⁸F]Altanserin and [¹¹C]Cimbi-36 ligand	DMT antagonist at this receptor- anxiolytic, antidepressant, neuroplasticity, psychedelic, active coping, mitochondrial biogenesis properties (20)
PET	GABAA receptors [¹¹C]flumazenil ligand	DMT alters GABAergic inhibition leads to a heightened state of neural excitability (21).
fMRI	Resting-state connectivity of the DMN	Decreased DMN activation is related to increased mindfulness, decreased depression and anxiety and has been noted as a result of those on DMT (11,17).
dMRI	Free water imaging (FWI)	Decreased free water (FW) is associated with a reduction in neuroinflammation and its processes found associated with DMT, i.e. microglia influx, edema (16,22,23).

While substances other than DMT activate these same serotonergic receptors bind sites, for example cannabinoids, melatonin and dopamine, by incorporating several other DMT-specific neurobiological characteristics (increased GABA, decreased DMN activity, a DMT-specific atlas and decreased neuroinflammation) we believe it will be possible to create DMT biotypes where individuals’ neurobiology is consistent with what we would expect of someone with high or low endogenous DMT rather than other binding substances. Anazing maps of 5-HTT and 5-HT4 binding, serotonergic receptors unrelated to DMT (14), will also help control for non-DMT binding serotonergic substance types.

These DMT biotypes can be used further to explore which lifestyle, genetic, cognitive and clinic attributes are most characteristic and phenotypical of these individuals to help build therapeutic agents. Most pertinent to DMT, the Cimbi database contains biometrics on cortisol, tryptophan, genetic polymorphisms related to 5-HT and cognitive functioning and measures on sleep, physical activity, socialization, mood and personality (18).

Specifically, lifestyle factors that have been most associated with psychological states similar to those experienced on therapeutic levels of DMT, i.e. reduced anxiety and depression and increased feelings of well-being and connection, are physical activity (24), healthy sleep patterns (25), socializing (26) and mindfulness (27).

Hypothesis: Our overarching hypothesis is that there is are significantly distinct endogenous DMT biotypes with a high DMT biotype with increased levels of DMT-specific serotonin receptor binding, GABA and decreased DMN activity and neuroinflammation, which can be quantified using a multi-modal approach that includes PET, fMRI and FWI dMRI techniques in a data set of 1,100 individuals. We additionally propose to test that DMT biotypes have unique clinical, cognitive and peripheral markers of well-being indicative of whole-body endogenous DMT.

Impact: If confirmed, these hypotheses will a) establish DMT biotypes which can be measured using neuroimaging techniques in vivo; b) propose DMT phenotypes based on associated clinical and cognitive data profiles which can help devise treatment targets.

Aim 1: To examine if in vivo neuroimaging DMT measures can delineate two DMT biotypes within a large transdiagnostic cohort. Endogenous DMT has been shown to vary across populations and extend into various neuropsychiatric disorders (1,19). Previous research has suggested that there is at least one high endogenous DMT biotype (19), with specific neurobiological characteristics. We will use hierarchical clustering of all participants based on the PET, fMRI and FWI measures to identify DMT biotypes within a transdiagnostic sample.

Aim 2: To test if in vivo DMT MRI neurobiological measures alongside peripheral blood and saliva markers and clinical features can delineate two DMT biotypes with phenotype attributes. Increased endogenous DMT has been shown to occur more in those with low stress, certain 5-HT polymorphisms, increased tryptophan and BDNF markers and has been linked to an elevated mood, healthy sleep, exercise and socialization (1). Additionally, high endogenous DMT likely increases general cognitive functioning (11). Therefore, we hypothesize that hierarchical clustering using these additional metrics will result in at least two DMT subgroups, one with increased neural and peripheral DMT markers, decreased stress, and increased mood, cognition and a healthy lifestyle.

3. Methods

Aim 1: will examine if in vivo MRI DMT measures can delineate two DMT biotypes within a transdiagnostic sample. It is clear that endogenous DMT heterogeneity exists across and within the population. We will perform agglomerative hierarchical clustering using the DMT measures (PET markers, FW and rs-fMRI of the DMN) in the regions most related to DMT delineated by previous DMT research (17,19) as the input to partition the sample into clusters that are internally homogenous (minimal within subgroup variation) and externally heterogeneous (substantial variation between subgroups) in terms of the imaging markers of DMT. Various partitions will be considered by setting the number of clusters at 2, as is consistent with our stated objective, and by setting the number of clusters at values identified as optimal according to each of the Silhouette and Dunn cluster validation indices. This analysis will investigate heterogeneity and patterns of in vivo neurobiological DMT metrics in order to isolate biotypes that may be suitable for promising new therapies. The clinical validity of the resultant clusters as biotypes will be assessed in Aim 2, wherein the clusters will additionally be partitioned based on clinical features and blood biomarkers.

Aim 2: will test if in vivo MRI DMT measures alongside peripheral DMT markers and clinical features can delineate two DMT biotypes with additional attributes. We will repeat the procedure outlined in Aim 1 of agglomerative hierarchical clustering of DMT metrics but also incorporate cortisol, BDNF, tryptophan and 5-HT polymorphisms blood and saliva markers along with lifestyle, mood, sleep and cognitive functioning measures of clinical phenotype as input to partition the sample into clusters. Adding measures of peripheral DMT attributes and clinical presentation into the clustering of DMT biotypes should support the distinctiveness and value of the proposed neuroimaging metrics in detecting endogenous DMT. The clustering procedure will follow the same steps outlined in Aim 1 where various partitions will first be considered by setting the number of clusters at 2, then subsequently testing the number of clusters at values identified as optimal according to each of the Silhouette and Dunn cluster validation indices. We hypothesize that clustering will result in isolating a high DMT biotype with increased neural and peripheral markers of DMT, decreased stress, increased cognition and lifestyle health and particular 5-HT polymorphisms.

Factors such as time of day, age, sex, stress and medication can affect DMT levels and therefore will be controlled for in all analyses.

Facilities and Ethics Approvals: The project requests $165,000 USD for essential personnel, supplies, and overhead. Our MRI research center at the Albert Einstein College of Medicine are well-equipped to perform the proposed research with high-powered computing clusters, and the principal investigator is currently approved for the proposed experimental procedures working with deidentified human data and to take on new graduate students to work on this project for the upcoming year.

Estimated Timeline: This project is designed for completion within 12 months.

5. Budget

Personnel: $120,000 (Includes partial salaries/benefits for postdoctoral researchers/graduate students/principal investigators)

Supplies/Overhead: $45,000

Total: $165,000

6. References

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17. Gattuso JJ, Perkins D, Ruffell S, Lawrence AJ, Hoyer D, Jacobson LH, et al. Default Mode Network Modulation by Psychedelics: A Systematic Review. Vol. 26, International Journal of Neuropsychopharmacology. 2023.

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Funding

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Defining Endogenous DMT Brain Biotypes: A Multi-Modal Neuroimaging Study

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Funding Progress

Nonprofit Recipient

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Defining Endogenous DMT Brain Biotypes: A Multi-Modal Neuroimaging Study

Funding Progress

Nonprofit Recipient

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DOI