N, N-Dimethyltryptamine (DMT), a naturally occurring psychedelic compound found in various plant and animal species, including humans, has garnered increasing interest for its therapeutic potential. While other classical psychedelics like lysergic acid diethylamide (LSD) and psilocybin have been extensively studied for their therapeutic effects, DMT remains relatively underexplored. However, preliminary clinical evidence suggests that DMT and ayahuasca, a psychoactive brew containing DMT, exhibit antidepressant, anxiolytic, and antiaddictive properties.
Fig. 1 Structure of N, N-dimethyltryptamine (DMT) (Barker S. A. 2018).
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Synthesis of Endogenous DMT
Endogenous DMT is synthesized from the essential amino acid tryptophan. Tryptophan is first decarboxylated to tryptamine, which is then transmethylated by the enzyme indolethylamine-N-methyltransferase (INMT) using S-adenosyl methionine as a substrate. This process produces N-methyltryptamine (NMT) and DMT. INMT is expressed widely in peripheral tissues, such as the lungs, thyroid, and adrenal gland, and in the brain's uncus, medulla, amygdala, frontal cortex, and other areas.
INMT activity is regulated by endogenous inhibitors, and DMT production increases under stress in rodents. However, only a small fraction of synthesized DMT is released into the blood due to rapid metabolism. DMT's primary metabolic route is via monoamine oxidase A (MAO-A), leading to the formation of indoleacetic acid (IAA).
Mechanisms Modulating Neurochemical Systems
Cortical Glutamate Modulation via 5-HT Receptors
DMT primarily exerts its effects by activating serotonin (5-HT) receptor 2A (5-HT2A), a Gq/11 G protein-coupled receptor highly expressed in cortical layer V pyramidal neurons. Activation of 5-HT2A enhances membrane excitability and facilitates the release of glutamate (Glu), a key excitatory neurotransmitter. Interestingly, psychedelics like DMT induce an unusual late and prolonged excitatory postsynaptic current component due to the activation of extrasynaptic N-methyl-D-aspartate (NMDA) receptors.
In addition to 5-HT2A, DMT also interacts with 5-HT1A, an inhibitory receptor, and 5-HT2C, another excitatory receptor found in cortical GABAergic interneurons. The complex interplay between these receptors leads to a nuanced modulation of cortical excitability, which can simultaneously promote and reduce Glu release. This glutamatergic modulation is significant, as fast-acting antidepressants like ketamine, an NMDA antagonist, have shown efficacy in treating depressive disorders.
Modulation of Monoaminergic Systems
DMT is an endogenous monoamine and binds to several receptors within the serotoninergic, dopaminergic, and adrenergic systems. It interacts with serotonin, dopamine (DA), and norepinephrine (NA) transporters, as well as monoamine oxidase (MAO) and trace amine-associated receptor 1 (TAAR1). These interactions influence dopaminergic transmission and the overall levels of monoamines in the brain.
Monoamine Transporter Binding and Substrate Release
DMT binds to serotonin, dopamine, and norepinephrine transporters, increasing synaptic monoamine levels through competitive inhibition or reverse transport. This mechanism shares similarities with some first-line antidepressants, highlighting DMT's potential as a therapeutic agent.
MAO and TAAR1
MAO rapidly metabolizes DMT, rendering it inactive when ingested unless combined with MAO inhibitors (MAOIs), as in ayahuasca. DMT's interaction with TAAR1, particularly in rodents, suggests potential anxiolytic effects, although further research is needed to confirm this in humans.
Dopaminergic Transmission
While DMT binds to DA receptors and exhibits MAOI properties at high doses, it does not directly modulate dopaminergic activity. However, DMT's ability to promote DA release at high doses suggests potential therapeutic applications for substance use disorders, given DA's central role in addiction.
Mechanisms Promoting Neuroplasticity
DMT promotes neuroplasticity through various molecular pathways, primarily involving 5-HT2A activation. It induces the expression of early growth response proteins, which are key players in neural plasticity. DMT also activates phospholipase A2 and subsequent mitogen-activated protein kinases (MAPKs), leading to dendritic growth and synaptogenesis in cortical neurons.
In addition to cortical plasticity, DMT facilitates neurogenesis and gliogenesis in the hippocampus, enhancing spatial learning and memory. This process is mediated by sigma-1 receptors (σ1) and is independent of 5-HT1A/2A antagonists. These neuroplasticity-promoting effects underpin the therapeutic potential of DMT in treating neurodegenerative diseases and mental health disorders.
Therapeutic Potential and Risks
Antidepressant Effects
DMT shows promise as a rapid-acting antidepressant, similar to ketamine. Clinical trials have demonstrated its safety and efficacy in treating major depressive disorder, with DMT-assisted therapy undergoing phase II trials. Ayahuasca, containing DMT, has also shown significant antidepressive effects in open-label and randomized controlled trials.
Anxiolytic and Antiaddictive Properties
DMT and ayahuasca have demonstrated anxiolytic properties, with studies reporting reductions in anxiety and improvements in mood. Furthermore, observational studies suggest that ritual ayahuasca use may lead to remissions of substance-use disorders, indicating DMT's potential as an antiaddictive treatment.
Neurodegenerative Diseases
DMT's ability to promote neuroplasticity and activate σ1, which drives anti-inflammatory and tissue-protective processes, makes it a promising candidate for research into neurodegenerative diseases. However, more extensive clinical studies are needed to confirm these potential benefits.
Conclusion
DMT is a potent psychedelic with significant neuromodulatory effects that span multiple neurochemical systems. Its ability to modulate cortical excitability, influence monoaminergic transmission, and promote neuroplasticity underlies its therapeutic potential. Preliminary clinical evidence supports DMT's efficacy in treating depression, anxiety, and addiction, and its neuroplasticity-promoting effects suggest potential applications in neurodegenerative diseases.
However, the current body of research on DMT is limited compared to other psychedelics. Further studies are needed to elucidate the mechanisms underlying DMT's neuromodulatory effects and to establish its safety and efficacy in larger, more diverse populations. As interest in psychedelic therapy continues to grow, DMT represents a promising avenue for future research and clinical applications.
References
- Barker S. A. N, N-dimethyltryptamine (DMT), an endogenous hallucinogen: past, present, and future research to determine its role and function. Frontiers in Neuroscience. 2018, 12: 318716.
- Jiménez J. H. Neuromodulatory mechanisms of N, N-dimethyltryptamine: a narrative review. Brain Network and Modulation. 2023, 2 (3): 53-62.
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