Psychedelic Substance 5-MeO-DMT May Help Treat Mental Health Conditions By Inducing Neural Plasticity

A new animal model study has recently revealed the potential of the psychedelic compound 5-MeO-DMT to modify the brain’s neuroplasticity. By creating new neuron connections, the substance can boost the brain’s adaptability and responses to new experiences. Despite being relatively understudied, 5-MeO-DMT shows antidepressant qualities, offering promising therapeutic benefits for some patients diagnosed with mental health conditions.

Origins and uses of 5-MeO-DMT

5-Methoxy-N, N-dimethyltryptamine, or 5-MeO-DMT, is a natural psychedelic compound found in some plant species but primarily has high amounts in the venom of the Colorado River Toad. It is a derivative of DMT with an additional methoxy group which causes it to interact with the brain differently. Individuals who take 5-MeO-DMT have reported feelings of unity, out-of-body experiences, and a life-altering perspective change.

Indigenous cultures in Central and South America have used the substance for centuries, primarily for spiritual purposes. Many shamans would use 5-MeO-DMT in rituals and ceremonies to alter their consciousness to obtain new wisdom and spiritual insight. It became more widely populated in the 1960s and 70s during the rise of psychedelic interest and has recently gained more attention for its therapeutic potential.

Potential therapeutic applications

5-MeO-DMT is in the tryptamine class of psychoactive drugs, just like psilocybin and ayahuasca, and it impacts the brain in similar ways (1). When taken, 5-MeO-DMT mimics serotonin and interacts with serotonin receptors in the brain called 5-HT1A and 5-HT2A. The 1A receptors can regulate mood, anxiety, and perception, while the activation of 2A receptors contributes to the psychedelic effects typically associated with these substances (2).

Though serotonergic psychedelics like psilocybin have shown promise as treatments for mental health conditions, patients who undergo treatment must be closely watched since the mind-altering effects can last several hours. 5-MeO-DMT is a potential alternative that can have the same impact but works much faster, and the effects don’t last as long. As a result, it is a less expensive option for facilitated treatment since appointments can be finished in shorter periods of time with similar results.

Compared to other psychedelic drugs, 5-MeO-DMT is limited to anecdotal reports and observational studies instead of controlled tests, which does not conclude the efficacy of the substance as a treatment for various psychiatric disorders (3). Furthermore, there are currently no published, placebo-controlled clinical trials done on 5-MeO-DMT. However, several instances of therapeutic evidence still show promise for 5-MeO-DMT being an effective drug.

Current research findings

In one study, the majority of the 515 respondents of a web-based survey reported a moderate to intense mystical-type experience. Many of those diagnosed with psychiatric disorders like PTSD, depression, and substance use disorders reported an improvement in their symptoms following the use of 5-MeO-DMT. The study found that the substance has a low potential for addiction and has potential psychotherapeutic effects (4).

Another study by Johns Hopkins researchers examined the self-reported improvements in individuals with depression and anxiety following a dose of 5-MeO-DMT in a group setting with structured procedures that guided the dose and administration of the substance. The survey, which consisted of 362 adults, found that 80% of reporting individuals saw an improvement in their depression symptoms, while 79% saw improvements in their anxiety. These improvements were associated with a greater intensity of a mystical experience from the substance (5).

5-MeO-DMT’s impact on behavioral activity

This new study focused on the behavioral effects of 5-MeO-DMT on certain parts of the brain linked to depression. Previous research has shown that chronic stress can alter this area of the brain, but certain hallucinogens like psilocybin have shown promise in clinical studies in reversing these changes. The researchers of the study wanted to see if 5-MeO-DMT could achieve similar effects despite its shorter duration of effects.

Using animal models, they measured both the behavior and brain structure changes of mice given a concentrated form of 5-MeO-DMT in a saline solution. Multiple experiments were conducted to measure their response to the substance. Researchers analyzed different behavioral feedback to see how mice reacted to 5-MeO-DMT, such as head-twitch response and social ultrasonic vocalization (USV).

The head-twitch response test is a behavioral marker that indicates the activation of the 5-HT2A receptor. It is often used to show the presence of hallucinations and whether or not a substance has psychedelic properties in humans (6). 

USVs are high-frequency sounds emitted by mice, typically done in the presence of other mice of the opposite sex. They generally indicate the subject’s behavioral and emotional state and any changes they may experience while on 5-MeO-DMT. The study found that the effects of the substance did not last as long compared to psilocybin, similar to the results of human studies. Both substances significantly reduced the amount of social USVs and altered the mice’s vocalization patterns.

For some of these tests, the mice were examined with a special microscope to observe small changes in their bodies. Data from these images were analyzed with a software that allowed them to measure the changes in the mice’s bodies over time (7).

5-MeO-DMT’s ability to alter brain structure

To study how 5-MeO-DMT directly impacts the brain and its cell structure, the researchers used two-photon microscopy imaging to observe tiny structures on nerve cells called dendritic spines. This imaging was carried out several times before and after giving the mice 5-MeO-DMT or a placebo.

The researchers followed the same dendritic spines over time to see how many remained unchanged, how many new ones formed, and how many were eliminated. They examined almost 900 spines in total from 10 different mice. Their analysis found that a single dose of 5-MeO-DMT quickly increased the number of dendritic spines, and this effect could still be observed a month later. The rate of new spine formation increased after giving the mice 5-MeO-DMT. Still, the effect was temporary, suggesting that a temporary increase in the rate of new spine formation caused a long-lasting increase in the number of dendritic spines (Jefferson et al., 2023). 

The formation of dendritic spines is key to neural plasticity, which allows the brain to reorganize itself by forming new neural connections. As a result, neural networks are strengthened, boosting cognitive abilities such as learning and memory. The enhancement of these functions can also support therapeutic processes regarding mental health conditions, allowing patients to learn new ways of thinking and behavior. This can also help redirect harmful thought patterns or behaviors associated with several mental health conditions (8). 

The future of 5-MeO-DMT in mental health therapy

Though the results of this study show positive results for how  5-MeO-DMT can alter the brain, these tests have yet to be done on human subjects. While animal studies can be constructive in our understanding of psychedelic substances, they cannot capture the full range of effects and emotions that a human may experience. More research will be needed to fully establish the safety and effectiveness of 5-MeO-DMT on human subjects. However, its short duration of effects and apparent capacity to enhance neuroplasticity assert its potential in mental health therapies. 

“Research has shown that psychedelics given alongside psychotherapy help people with depression and anxiety. However, psychedelic sessions usually require 7 – 8 hours per session because psychedelics typically have a long duration of action,” according to Alan K. Davis, Ph.D., a researcher from Johns Hopkins. “Because 5-MeO-DMT is short-acting and lasts approximately 30-90 minutes, it could be much easier to use as an adjunct to therapy because current therapies usually involve a 60 – 90 minute session.”

Understanding the practicality of 5-MeO-DMT’s shorter acting time can revolutionalize how we approach psychedelic mental health treatment. This form of therapy would no longer be bound by time-consuming sessions required by traditional psychedelic treatments, allowing therapists to use 5-MeO-DMT for similar results more efficiently and economically. To bring about this shift, continued research is critical.  

“My lab started research on psychiatric drugs like ketamine and psychedelics about 10 years ago. We were motivated by how basic science and clinical research can together powerfully move a drug forward to become medicine. Specifically, I believe there is a lot of potential for psychedelics as therapeutics, and that drives our interest in this topic”, says Alex Kwanan, study author and associate professor at the Meinig School of Biomedical Engineering at Cornell University.

As the body of knowledge surrounding 5-MeO-DMT continues to grow, continued research efforts will contribute to a deeper understanding of the compound, allowing for a more evidence-based approach to utilizing  5-MeO-DMT in therapeutic settings.  

References

1. Santos, Rafael G. dos, Flávia L. Osório, José Alexandre S. Crippa, Jordi Riba, Antônio W. Zuardi, and Jaime E. C. Hallak. 2016. “Antidepressive, Anxiolytic, and Antiaddictive Effects of Ayahuasca, Psilocybin and Lysergic Acid Diethylamide (LSD): A Systematic Review of Clinical Trials Published in the Last 25 Years.” Therapeutic Advances in Psychopharmacology 6 (3): 193–213. https://doi.org/10.1177/2045125316638008.
2. Shen, Hong-Wu, Xi-Ling Jiang, Jerrold C. Winter, and Ai-Ming Yu. 2010. “Psychedelic 5-Methoxy-N,N-Dimethyltryptamine: Metabolism, Pharmacokinetics, Drug Interactions, and Pharmacological Actions.” Current Drug Metabolism 11 (8): 659–66. https://doi.org/10.2174/138920010794233495.
3. Reckweg, J. T., M. V. Uthaug, A. Szabo, A. K. Davis, R. Lancelotta, N. L. Mason, and J. G. Ramaekers. 2022. “The Clinical Pharmacology and Potential Therapeutic Applications of 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT).” Journal of Neurochemistry 162 (1). https://doi.org/10.1111/jnc.15587.
4. Davis, Alan K, Joseph P Barsuglia, Rafael Lancelotta, Robert M Grant, and Elise Renn. 2018. “The Epidemiology of 5-Methoxy-N, N-Dimethyltryptamine (5-MeO-DMT) Use: Benefits, Consequences, Patterns of Use, Subjective Effects, and Reasons for Consumption.” Journal of Psychopharmacology 32 (7): 779–92. https://doi.org/10.1177/0269881118769063.
5. Davis, Alan K., Sara So, Rafael Lancelotta, Joseph P. Barsuglia, and Roland R. Griffiths. 2019. “5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Used in a Naturalistic Group Setting Is Associated with Unintended Improvements in Depression and Anxiety.” The American Journal of Drug and Alcohol Abuse 45 (2): 161–69. https://doi.org/10.1080/00952990.2018.1545024.
6. Halberstadt, Adam L., and Geyer, M. A. 2013. “Characterization of the Head-Twitch Response Induced by Hallucinogens in Mice.” Psychopharmacology 227 (4): 727–39. https://doi.org/10.1007/s00213-013-3006-z.
7. Jefferson, Sarah J., Ian Gregg, Mark Dibbs, Clara Liao, Hao Wu, Pasha A. Davoudian, Samuel C. Woodburn, et al. 2023. “5-MeO-DMT Modifies Innate Behaviors and Promotes Structural Neural Plasticity in Mice.” Neuropharmacology. April, 1–10. https://doi.org/10.1038/s41386-023-01572-w.
8. Uhlhaas, Peter J. 2015. “Neural Dynamics in Mental Disorders.” World Psychiatry 14 (2): 116–18. https://doi.org/10.1002/wps.20203.