OPEN Foundation

DMT

DMT alters cortical travelling waves

Abstract

Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.

Alamia, A., Timmermann, C., Nutt, D. J., VanRullen, R., & Carhart-Harris, R. L. (2020). DMT alters cortical travelling waves. eLife, 9, e59784. https://doi.org/10.7554/eLife.59784

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N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

Abstract

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Morales-Garcia, J. A., Calleja-Conde, J., Lopez-Moreno, J. A., Alonso-Gil, S., Sanz-SanCristobal, M., Riba, J., & Perez-Castillo, A. (2020). N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo. Translational psychiatry, 10(1), 331. https://doi.org/10.1038/s41398-020-01011-0

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DMT and near-death experiences

Being one of the most powerful psychedelics we know, it is not strange that DMT has become the subject of numerous speculations over the years. Theories linking this molecule to near-death experiences have circulated persistently among users and researchers – yet the scientific evidence just doesn’t seem to be there. 
Enzo Tagliazucchi is a neuroscientist and professor at the University of Buenos Aires. He will be speaking at ICPR 2020 about his research and the first neuroimagery study of DMT in naturalistic settings.
This is the final part of a three-part interview series with Prof. Enzo Tagliazucchi
Part one: The Science and Folklore of DMT
Part two: Psychedelics: key to consciousness
Part three: DMT and near-death experiences
Enzo, you have experience researching NDEs. How is this phenomenon approached from a scientific perspective?
NDEs are really fun to investigate because they are simultaneously a very strange phenomenon, and something that does indeed happen to people in robust and reproducible ways.
There are several things that are common features to most reported NDEs, such as the feeling of floating around, feelings of extreme bliss and transcendence, life review, and the sensation that you are about to cross a visible or invisible threshold, among others. It seems that different cultural backgrounds are not a huge factor determining the specific contents of NDEs. This is somewhat controversial, but apparently at least some of these features could be, in a certain sense, universal.
Then comes the question of why this is happening, and this has been the source of a lot of bullshit, unfortunately. Some insist that everything that happens during NDEs is the manifestation of your soul leaving your body and entering into the afterlife or other realms of existence, which is something that many people would love to believe. Researchers have tested this experimentally: for instance, they have hidden an object in a room and then have somebody experience an out-of-body experience (a defining feature of NDEs) and float around. Needless to say, they never find the object, and they don’t find it simply because they are not floating around in any meaningful interpretation of those words.
People do not even know whether some NDEs happen in the moment someone flatlines, or before or after the event. It could happen moments before you wake up: there is simply no known way of proving that NDEs take place when you are sort of dead for a moment. Even worse than that, people can report NDEs when they think they are going to die but they aren’t really at risk. For example, if you fall from a chair, you might report a flash experience that is indistinguishable from a NDE, but you weren’t even unconscious for a moment.
What are the main explanatory theories of NDEs and how would you assess Strassman’s DMT hypothesis?
Nobody knows for certain why NDEs occur. And maybe there is not simply just one answer, it could be several different factors. But as scientists like to have simple explanations, they have tried to come up with one factor underlying all the different aspects of NDEs.
Perhaps the most attractive one-factor theories are related to the potential presence of endogenous chemicals. Some came to believe that there is a kind of chemical imbalance during NDEs that can lead to the experience, and here Strassman proposed that a massive release of DMT when you are close to death is what is behind the strange phenomenology of NDEs.
As an alternative, Karl Jansen proposed that there is some ketamine-like compound in the brain that blocks NMDA receptors in a similar way to ketamine, a substance whose acute effects can lead to NDE-like phenomenology. At some point in the last couple years, I started to read Jansen and Strassman, became interested in this discussion, and eventually published a paper in which I tried to put their hypotheses to test for the first time.
Using computational semantic analysis, we compared drug reports from Erowid to the narratives of patients who had NDEs, and we confirmed that ketamine was actually way above in similarity to those experiences compared to DMT. Actually, if you think of what the DMT experience is like, it is not this solemn-going-to-the-light-in-bliss but rather a confusing but festive colourful state. People do not really report these things in NDEs at all. And if you have been in the K-hole you already know that it is probably the closest to feeling dead, whatever that means. But that is not the point… this is science and I try to be scientific about it, haha!
In the last paper I read by Strassman, he conceded that there might be some release of a ketamine-like substance when you are close to dying, but the question remains: Why does this substance lead to this strange state of consciousness? Whatever the function of this molecule, why can’t it just shut off your consciousness instead of giving rise to NDEs?
The answer given by Jansen is that a ketamine-like compound could have neuroprotective effects. If there is a massive release of glutamate, an excitatory neurotransmitter that makes neurons fire at a high rate, neurons might die because they are basically too activated, a phenomenon known as excitotoxicity. So if ketamine or a related compound blocks that process, it can extend the life of neurons and increase the likelihood of survival. It sounds reasonable that you have that kind of process built into your brain as a mechanism to cope when you are close to death.
But at this point, Strassman argued something like: OK, but why has evolution given us this very strange experience that happens when we block the glutamate receptor? Why can’t the brain just block the glutamate receptors and protect itself with no experience at all? He concluded that maybe it is not that these receptors get blocked and then you have this experience. It is something different, something like you have a soul and the moment your soul starts to leave your body, the receptors get blocked.
For me that is very difficult to swallow. I am a physicist, and I cling to a scientific worldview. At some point I think Strassman lost that worldview and I actually haven’t read much of his theories since then. I respect him nevertheless, he is a pioneer in this field of research.
So what happened in the search of an endogenous chemical behind these experiences? Again, not conclusive. My guess is that it is a combination of several factors, and that people are really misled when they believe something related to the proximity of death is behind all these experiences.
What about other non-ordinary phenomena such as mystical experiences?
Mystical-type experiences, on the other hand, you can investigate more easily, because you can induce these experiences in safe and reproducible ways. That is what the Johns Hopkins group has been showing over the last years, focusing on psilocybin as an induction agent.
Griffiths’ group repeated the famous Good Friday experiment by Panhke, but under more controlled and rigorous conditions, and they showed that you can induce these experiences with psilocybin combined with the proper set and setting in 60% of the participants. The likelihood of induction is dose-dependent, so the higher the dose the higher the chances of having this kind of experience. They also showed that if you are undergoing treatment for tobacco cessation or if you are an oncological patient with anxiety related to the end of life and you are treated with psilocybin, the likelihood that you are going to get better increases if you have a mystical-type experience. In other words, the potential therapeutic properties of the psychedelic experience are apparently tied to mystical-type experiences. I believe these findings are really interesting from a clinical perspective and, again, in contrast to NDEs this is something that you can induce reliably in a controlled setting.

The Science and Folklore of DMT

Being one of the most powerful psychedelics we know, it is not strange that DMT has become the subject of numerous speculations over the years. Theories linking this molecule to the pineal gland, to dreams or near-death experiences have circulated persistently among users and researchers – yet the scientific evidence just doesn’t seem to be there. 

It has been established that DMT occurs in many organisms endogenously, like plants, animals and humans. Besides that, much has yet to become established science in the academic world. Is DMT synthesized in the pineal gland? If so, what is its function? Is it involved in generating dreams or normal consciousness? Is it behind so-called near-death experiences?

We approached researcher Enzo Tagliazucchi to help us bring some clarity and a scientific perspective to these questions. Tagliazucchi is a neuroscientist and professor at the University of Buenos Aires. He will be speaking about his research and the first Electroencephalography (EEG) study of DMT in naturalistic settings at ICPR 2020.

This is the first part of a three-part interview series with Prof. Enzo Tagliazucchi

OPEN Foundation: Twenty years ago, Rick Strassman popularized DMT as the “Spirit Molecule”. In his popular book, he made the claim that this psychedelic compound is endogenously synthesized in the human pineal gland. What led him to this hypothesis?

Enzo Tagliazucchi: It would not be strange if DMT would actually be synthesized in the pineal gland because melatonin, a molecule that is pretty similar in its structure compared to DMT, is released there. All the necessary enzymes in the corresponding metabolic pathway are present in the pineal gland. You have all these coincidences that seem to suggest that it is a natural process that is creating the molecule, and that this process can take place in the pineal gland.

Strassman was, in fact,  interested in melatonin research at first and then came across DMT. From there, he started to convince himself that it was synthesized in the pineal gland and started wondering about its function. People have been trying to find a role for DMT from the moment it became obvious that it is an endogenous molecule, for instance, some have the hypothesis that DMT is actually a neurotransmitter still without a known receptor (the sigma receptor was considered as a candidate for some time but eventually it was abandoned). Of course, whatever the function was, they conjectured, it had to be something related to the phenomenology of the psychedelic state.

In his investigations, Strassman came across these really strange experiences reported by his research participants, which he actually describes as a kind of shock for him. Confronted with this bizarre information, he hypothesized that DMT is present in the brain to signal certain important moments in life, and that these moments are experienced as strange DMT-like experiences, such as birth and death. This is why he coined the popular phrase “the spirit molecule” in reference to DMT.

Last year, a research team from the University of Michigan led by Jimo Borjigin reported concentrations of DMT in rats’ brains to be similar to that of other neurotransmitters like serotonin during induced experimental cardiac arrest. What are the implications of these findings and what do we know about the endogenous levels of DMT in the human brain?

Recently there was some controversy because of this paper, in which Strassman was actually co-author, showing in an animal model that you can find large amounts of DMT produced near the moment of death.

David Nichols tried to refute this hypothesis years ago arguing that even if DMT is actually synthesized in the pineal gland, you will never get sufficiently high concentrations of endogenous DMT to ever produce a psychedelic-like experience. That was the end for a while, and then came this article which Strassman and others took as evidence to support his theory.

David Nichols again published a rebuttal arguing that the finding of high amounts of DMT is not really conclusive because at that critical moment you get a massive release of several neurotransmitters. If you have twice the usual concentration of DMT, then you also have twice the usual concentration of serotonin. And since serotonin is competing with DMT and it has a higher affinity for all serotonin receptor sub-types, then why would you get an endogenous DMT trip considering these difficulties in binding to serotonin receptors?

I think if I had to bet money, I would say that there is DMT in the pineal gland. It is a very simple tryptamine and you have a lot of different possible pathways to get it. All the chemicals you need for the synthesis of DMT can be found in the pineal gland. I would even bet that when you have hypoxia or if there is a critical injury in the brain, there is a spike in DMT concentration. But at such a moment, you have spikes of several neurotransmitters. However, if somebody finds a high spike of DMT alone, that would be a remarkable finding.

I think that more research is needed because it is really strange that DMT is in the brain. People should keep doing this research and should keep asking: Why is DMT there? What does it do? What receptors does it bind to? What is its role? These questions are important, even if the findings so far have been, for the most part, negative.

We don’t really have any proof at all that Strassman’s theories are more than attractive hypotheses. Something valuable about Strassman’s work is that it made a lot of people think for the first time about the possibility of endogenously triggered altered states of consciousness. Unfortunately, I think there is yet nothing to the claim that DMT is behind these experiences.

It seems that Borjigin’s research has been welcomed by DMT enthusiasts who link this molecule to dreams and normal consciousness. If it is present in the human brain at significant levels, could DMT be considered a neurotransmitter playing a role in generating ordinary consciousness or in dreaming, as it has been claimed?

The challenge is to find DMT in a sufficiently high concentration to produce such effects. You would need around 25 mg of DMT being produced in a short period of time for something like that to happen in your consciousness and, apparently, there is no way that can happen. The endogenous concentrations are in the microgram range, below the active levels by orders of magnitude. The reason why it can’t happen is not only because researchers have not found such high levels, it is because essentially the metabolic pathways do not seem to be able to support that massive biosynthesis.

Similarly, it does not seem that DMT is produced with a sufficiently high concentration to be involved in dreaming, and so on. I do not think it is even needed to explain the phenomenology of dreaming. We understand more or less the neurochemistry of dreaming and serotonin, in fact, tends to be blocked during REM sleep. So the neurochemistry does not seem to suggest at all that 5-HT2A receptor activation by any molecule, let alone one in such small quantities, is responsible for dreaming. This does not preclude, of course, that the phenomenology of dreaming and psychedelic states are very similar. You might get to the same effect following different routes.

If it is in the concentrations it is suspected to be in, there is no way it can influence consciousness. That is the current state of knowledge.

See Enzo’s talk titled The neural and psychological correlates of inhaled N,N-dimethyltryptamine (DMT) in natural and ceremonial settings at ICPR2020.

Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans

U.S. Special Operations Forces Veterans are at increased risk for a variety of mental health problems and cognitive impairment associated with military service. Current treatments are lacking in effectiveness and adherence. Therefore, this study examined psychedelic treatment with ibogaine and 5-methoxy-N,N-dimethyltryptamine for trauma-related psychological and cognitive impairment among U.S. Special Operations Forces Veterans.

We conducted a survey of Veterans who completed a specific psychedelic clinical program in Mexico between 2017 and 2019. Questions probed retrospective reports of mental health and cognitive functioning during the 30 days before and 30 days after treatment. A total of 65 people completed treatment during this time frame and were eligible for contact. Of these, 51 (78%) completed the survey and were included in data analyses (mean age = 40; male = 96%; married = 55%; Caucasian/White = 92%; Operation Enduring Freedom/Operation Iraqi Freedom Service = 96%).

Results indicated significant and very large reductions in retrospective report of suicidal ideation (p < .001; d = −1.9), cognitive impairment (p < .001; d = −2.8), and symptoms of posttraumatic stress disorder (p < .001; d = −3.6), depression (p < .001; d = −3.7), and anxiety (p < .001; d = −3.1). Results also showed a significant and large increase in retrospective report of psychological flexibility (p < .001; d = 2.9) from before-to-after the psychedelic treatment. Increases in the retrospective report of psychological flexibility were strongly associated with retrospective report of reductions in cognitive impairment, and symptoms of posttraumatic stress disorder, depression, and anxiety (rs range −0.61 to −0.75; p < .001). Additionally, most participants rated the psychedelic experiences as one of the top five personally meaningful (84%), spiritually significant (88%), and psychologically insightful (86%) experiences of their lives.
Limitations: Several limitations should be considered including the retrospective, self-report, survey design of the study, and the lack of randomization and blinding, thus making these finding preliminary.

U.S. Special Operations Forces Veterans may have unique treatment needs because of the sequela of problems associated with repeated trauma exposure and the nature of the exposure. Psychedelic-assisted therapy with these under-researched psychedelics may hold unique promise for this population. However, controlled studies are needed to determine whether this treatment is efficacious in relieving mental health and cognitive impairment among U.S. Special Operations Forces Veterans.

Davis, A. K., Averill, L. A., Sepeda, N. D., Barsuglia, J. P., & Amoroso, T. (2020). Psychedelic Treatment for Trauma-Related Psychological and Cognitive Impairment Among US Special Operations Forces Veterans. Chronic Stress4, 2470547020939564; 10.1177/2470547020939564
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Synthesis and characterization of high-purity N,N-dimethyltryptamine hemifumarate for human clinical trials

Abstract

Since 2006, there has been a resurgent interest in the pharmacology and therapeutics of psychedelic drugs. Psilocybin, the 4-phosphoryl ester of N,N-dimethyltryptamine (DMT), has been studied most often, but DMT itself is also appealing because of its brief but profound psychological effects and its presence as an endogenous substance in mammalian brain. Although there have been a few studies of ayahuasca, a DMT-containing water infusion, only one human study with pure DMT has been reported since the early 2000s. Newly planned clinical trials to assess the safety and efficacy of DMT in humans with major depressive disorders require high-purity water-soluble DMT for intravenous administration. Accordingly, we synthesized and characterized DMT hemifumarate for these upcoming studies. The synthetic approach of Speeter and Anthony was slightly modified to gain some efficiency in time. In particular, this is the first known report to use aluminum hydride, generated in situ from lithium aluminum hydride, to reduce the intermediate 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide to DMT. A quench protocol was developed to produce a good yield of exceptionally pure free base DMT upon workup, which was then converted to the hemifumarate salt. Analysis of the final product included differential scanning calorimetry, thermogravimetric analysis, gas chromatography-mass spectrometry (GC-MS), 1 H and 13 C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, residual solvent analysis by GC headspace sampling, X-ray powder diffraction analysis, and residual lithium analysis by inductively coupled plasma-mass spectrometry. The DMT hemifumarate was minimally 99.9% pure, with no significant impurities or residual solvents, thus meeting regulatory standards for administration to humans.

Cozzi, N. V., & Daley, P. F. (2020). Synthesis and characterization of high‐purity N, N‐dimethyltryptamine hemifumarate for human clinical trials. Drug Testing and Analysis12(10), 1483-1493.; 10.1002/dta.2889

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Spotlight commentary: REBUS and the anarchic brain

Abstract

In ‘REBUS and the Anarchic Brain: Towards a Unified Model of the Brain Action of Psychedelics’, Carhart-Harris and Friston offer an important analysis of what the predictive processing framework has to offer our understanding of psychedelic experiences, providing an invaluable ground for psychedelic psychiatry. While applauding this, we encourage paying greater attention to contextual factors shaping extreme experiences and their sequalae, and suggest that the authors’ comparisons with certain non-psychedelic altered states may overlook more informative parallels that can be drawn elsewhere. Addressing both points will prove fruitful, ultimately, in identifying the mechanisms of action of greatest interest in psychedelic experiences.
Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics. Pharmacological reviews71(3), 316-344., https://doi.org/10.1093/nc/niaa007
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A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

Abstract

After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions – post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.
Luoma, J. B., Chwyl, C., Bathje, G. J., Davis, A. K., & Lancelotta, R. (2020). A Meta-analysis of Placebo-controlled Trials of Psychedelic-assisted Therapy. Journal of Psychoactive Drugs, 1-11., https://doi.org/10.1080/02791072.2020.1769878
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Mystical Experiences in Retrospective Reports of First Times Using a Psychedelic in Finland

Abstract

Despite their acutely inebriating and sometimes unpleasant effects, some people report positive changes in life satisfaction, well-being, or mental health after taking psychedelic drugs. One explanation may be the ability of psychedelics to trigger mystical-type experiences. We examined the validity, reliability, and factor structure of a novel Finnish translation of the Revised Mystical Experiences Questionnaire (MEQ30) among 288 people retrospectively reporting on their first time using a psychedelic. We found evidence for internal consistency reliability and preliminary evidence for criterion and discriminant validity of the Finnish MEQ30. A four-factor structure with factors for mystical qualities, positive mood, transcendence, and ineffability had the best, fair to reasonable fit to the data. MEQ30 scores and having a full mystical experience were highly associated with describing the experience as mystical, spiritual, or religious, and as personally significant, and somewhat associated with the experience being sad or difficult. Mystical experiences were especially associated with positive changes in relationships with nature and oneself and in creativity. Mystical experiences were more common with larger doses. Increasing research suggests mystical-type experiences to relate to positive changes after taking psychedelics. The Finnish MEQ30 is able to tap into relevant information about this aspect of people’s psychedelic experiences.
Kangaslampi, S., Hausen, A., & Rauteenmaa, T. (2020). Mystical Experiences in Retrospective Reports of First Times Using a Psychedelic in Finland. Journal of Psychoactive Drugs, 1-10. https://doi.org/10.1080/02791072.2020.1767321
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Ayahuasca – potential therapeutic properties in psychiatry. Research review

Abstract

Ayahuasca, also known as “the liana of the soul” and “the vine of the soul” is a ritual psychedelic traditionally administered in the form of plant decoction, used by the indigenous people of South America for centuries, and in the last 25 years also in Europe, Asia, Africa, Australia, Canada, and the United States. Its biological activity results from the content of N,N-dimethyltryptamine (DMT), acting mainly as a non-selective agonist of serotonin receptors and beta-carboline alkaloids, which are strong and short-acting monoamine oxidase type A(MAOI-A) inhibitors. For many years there have been reports of both the anti-anxiety and antidepressant effects of ayahuasca, as well as indications of the possibility of its use in the treatment of addictions. The results of studies of its effectiveness in drug-resistant depression seem to be promising, comparable in the opinion of some authors with the effect of therapeutic action of ketamine. In the article, we try to explain the complex profile of action and the resulting potential benefits, but also the risk of interaction and adverse effects associated with the taking of ayahuasca, which is important given the high variability of herbal mixtures used to produce the decoction.

Barabasz-Gembczyk, A., & Kucia, K. (2020). Ayahuasca–potential therapeutic properties in psychiatry. Research review. Psychiatr. Pol.. Pol54(2), 381-389., https://doi.org/10.12740/PP/103364
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21 March - Ketamine Discussion with Celia Morgan, Filip Tylš & Will Barone

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