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Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process

April 5, 2018 / Anxiety Disorders / PTSD, Ayahuasca, DMT, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Ayahuasca ingestion modulates brain activity, neurotransmission, gene expression and epigenetic regulation. N,N-Dimethyltryptamine (DMT, one of the alkaloids in Ayahuasca) activates sigma 1 receptor (SIGMAR1) and others. SIGMAR1 is a multi-faceted stress-responsive receptor which promotes cell survival, neuroprotection, neuroplasticity, and neuroimmunomodulation. Simultaneously, monoamine oxidase inhibitors (MAOIs) also present in Ayahuasca prevent the degradation of DMT. One peculiarity of SIGMAR1 activation and MAOI activity is the reversal of mnemonic deficits in pre-clinical models. Since traumatic memories in post-traumatic stress disorder (PTSD) are often characterised by “repression” and PTSD patients ingesting Ayahuasca report the retrieval of such memories, it cannot be excluded that DMT-mediated SIGMAR1 activation and the concomitant MAOIs effects during Ayahuasca ingestion might mediate such “anti-amnesic” process. Here I hypothesise that Ayahuasca, via hyperactivation of trauma and emotional memory-related centres, and via its concomitant SIGMAR1- and MAOIs- induced anti-amnesic effects, facilitates the retrieval of traumatic memories, in turn making them labile (destabilised). As Ayahuasca alkaloids enhance synaptic plasticity, increase neurogenesis and boost dopaminergic neurotransmission, and those processes are involved in memory reconsolidation and fear extinction, the fear response triggered by the memory can be reprogramed and/or extinguished. Subsequently, the memory is stored with this updated significance. To date, it is unclear if new memories replace, co-exist with or bypass old ones. Although the mechanisms involved in memory are still debated, they seem to require the involvement of cellular and molecular events, such as reorganisation of homo and heteroreceptor complexes at the synapse, synaptic plasticity, and epigenetic re-modulation of gene expression. Since SIGMAR1 mobilises synaptic receptor, boosts synaptic plasticity and modulates epigenetic processes, such effects might be involved in the reported healing of traumatic memories in PTSD patients. If this theory proves to be true, Ayahuasca could come to represent the only standing pharmacological treatment which targets traumatic memories in PTSD. Lastly, since SIGMAR1 activation triggers both epigenetic and immunomodulatory programmes, the mechanism here presented could help understanding and treating other conditions in which the cellular memory is dysregulated, such as cancer, diabetes, autoimmune and neurodegenerative pathologies and substance addiction.
Inserra, A. (2018). Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process. Frontiers in pharmacology, 9, 330. 10.3389/fphar.2018.00330
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Influence of Environmental Factors and Cultural Methods on the Content of N,N‑Dimethyltryptamine in Psychotria viridis (Rubiaceae)

December 6, 2017 / Ayahuasca, Biology & Ethnobotany, DMT, Papers, Pharmacology & Chemistry, Publications / By / , , , , , ,

Abstract

Psychotria viridis is one of the species that produces N,N-dimethyltryptamine. Its decoction together with other species, such as Banisteriopsis caapi, produces ayahuasca, a beverage used for ritualistic and medicinal purposes. The goal of this study was to understand how environmental factors and cultivation methods influenced the content of N,N-dimethyltryptamine in P. viridis. Over all four seasons, leaf samples were collected from 25 different locations in 14 Brazilian states, and Federal District. Environmental parameters, micro and macronutrients, plant characteristics, information on farming methods were correlated with N,N-dimethyltryptamine content, determined by gas chromatography coupled to mass spectrometry (GC-MS). Greatest effects on the N,N-dimethyltryptamine amount were associated with seasonality, altitude, latitude and biome type. A positive correlation between N and Mg content and N,N-dimethyltryptamine levels was statistically established. By regression analysis, the adequate foliar nutrient levels that would result in the concentration of N,N-dimethyltryptamine in cultivated plants similar to that of Amazonian P. viridis were equated.

Cavalcante, A. D., Cardoso, G. A., de Oliveira, F. L., Bearzoti, E., Okuma, A. A., Duartee, L. P., & Vieira-Filhof, S. A. Influence of Environmental Factors and Cultural Methods on the Content of N, N‑Dimethyltryptamine in Psychotria viridis (Rubiaceae).
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Studies with psychedelic drugs in human volunteers

November 18, 2017 / DMT, Ketamine, MDMA, Papers, Psychology, Publications / By / , ,

Abstract

Scientific curiosity and fascination have played a key role in human research with psychedelics along with the hope that perceptual alterations and heightened insight could benefit well-being and play a role in the treatment of various neuropsychiatric disorders. These motivations need to be tempered by a realistic assessment of the hurdles to be cleared for therapeutic use. Development of a psychedelic drug for treatment of a serious psychiatric disorder presents substantial although not insurmountable challenges. While the varied psychedelic agents described in this chapter share some properties, they have a range of pharmacologic effects that are reflected in the gradation in intensity of hallucinogenic effects from the classical agents to DMT, MDMA, ketamine, dextromethorphan and new drugs with activity in the serotonergic system. The common link seems to be serotonergic effects modulated by NMDA and other neurotransmitter effects. The range of hallucinogens suggest that they are distinct pharmacologic agents and will not be equally safe or effective in therapeutic targets. Newly synthesized specific and selective agents modeled on the legacy agents may be worth considering. Defining therapeutic targets that represent unmet medical need, addressing market and commercial issues, and finding treatment settings to safely test and use such drugs make the human testing of psychedelics not only interesting but also very challenging.
Sellers, E. M., Romach, M. K., & Leiderman, D. B. (2017). Studies with psychedelic drugs in human volunteers. Neuropharmacology. 10.1016/j.neuropharm.2017.11.029
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Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT

October 9, 2017 / DMT, Papers, Psychiatry & Medicine, Publications / By / , , , , , ,

Abstract

Dimethyltryptamines are entheogenic serotonin-like molecules present in traditional Amerindian medicine recently associated with cognitive gains, antidepressant effects, and changes in brain areas related to attention. Legal restrictions and the lack of adequate experimental models have limited the understanding of how such substances impact human brain metabolism. Here we used shotgun mass spectrometry to explore proteomic differences induced by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) on human cerebral organoids. Out of the 6,728 identified proteins, 934 were found differentially expressed in 5-MeO-DMT-treated cerebral organoids. In silico analysis reinforced previously reported anti-inflammatory actions of 5-MeO-DMT and revealed modulatory effects on proteins associated with long-term potentiation, the formation of dendritic spines, including those involved in cellular protrusion formation, microtubule dynamics, and cytoskeletal reorganization. Our data offer the first insight about molecular alterations caused by 5-MeO-DMT in human cerebral organoids.
Dakic, V., Nascimento, J. M., Sartore, R. C., de Moraes Maciel, R., Araujo, D. B., Ribeiro, S., … & Rehen, S. K. (2017). Short term changes in the proteome of human cerebral organoids induced by 5-MeO-DMT. Scientific Reports, 7(1), 12863. 10.1038/s41598-017-12779-5
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N,N-dimethyltryptamine and the pineal gland: Separating fact from myth

October 1, 2017 / DMT, Neuroscience, Papers, Psychology, Publications / By /

Abstract

The pineal gland has a romantic history, from pharaonic Egypt, where it was equated with the eye of Horus, through various religious traditions, where it was considered the seat of the soul, the third eye, etc. Recent incarnations of these notions have suggested that N,N-dimethyltryptamine is secreted by the pineal gland at birth, during dreaming, and at near death to produce out of body experiences. Scientific evidence, however, is not consistent with these ideas. The adult pineal gland weighs less than 0.2 g, and its principal function is to produce about 30 µg per day of melatonin, a hormone that regulates circadian rhythm through very high affinity interactions with melatonin receptors. It is clear that very minute concentrations of N,N-dimethyltryptamine have been detected in the brain, but they are not sufficient to produce psychoactive effects. Alternative explanations are presented to explain how stress and near death can produce altered states of consciousness without invoking the intermediacy of N,N-dimethyltryptamine.
Nichols, D. E. (2017). N, N-dimethyltryptamine and the pineal gland: Separating fact from myth. Journal of Psychopharmacology, 0269881117736919.
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Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

August 18, 2017 / DMT, Ketamine, Papers, Publications / By / , , , , , ,

Abstract

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug’s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine (“Kratom”), synthetic cannabinoids (e.g., “Spice”), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.
Hassan, Z., Bosch, O. G., Singh, D., Narayanan, S., Kasinather, B. V., Seifritz, E., … & Müller, C. P. (2017). Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs. Frontiers in psychiatry, 8, 152. 10.3389/fpsyt.2017.00152
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A Systematic Review Of Research On N,N-Dimethyltryptamine

August 1, 2017 / DMT, Neuroscience, Papers, Psychology / By / ,

Abstract

Introduction: The effects of the endogenous hallucinogen N,N-dimethyltryptamine are poorly understood and its medical significance is widely unknown. A small number of  studies regarding its biochemical, pharmaceutical and physiological role have been conducted and the efficacy of its therapeutic potential is presently disregarded. How can scientists proceed in gaining insight into DMT and discovering possible medical uses of this substance?
Materials and Methods: Published articles from  1964 to the present year have been reviewed and the outcome of the studies summarized. The results of drug action,  therapeutic use and potential were investigated . Studies that appeared to have little medical purpose or those, which focus on the use of  Ayahuasca, a South American ritual drink containing N,N-dimethyltryptamine and a monoamine oxidase (MAO)  inhibitor of plant origin, have been excluded.
Results: The research conducted between 1964 and 1987 seems to be an approach to understanding general chemical and biochemical properties of the substance (e.g. metabolites, tolerance, distribution, toxicity, etc.). Rick Strassman, who conducted a broad study from 1990 till 1994 has initiated a recurring interest in the field of psychopharmacology towards DMT. Thus, in the following years, the research was focused on the therapeutic gain of N,N-dimethyltryptamine but resulted mostly inconclusively leading to suggestions of further research. The findings have shown contradictions of already established knowledge, especially for receptors like the sigma-1 receptor, the only direct agonist of which is found to be N,N-dimethyltryptamie.
Conclusion: The studies that now need to be conducted should analyze the correlations between psychiatric diseases (e.g. schizophrenia), purpose of the normal endogenous production and exact action, and the already suggested in various studies therapeutic importance. The low amount of knowledge about the drug action (in case of pharmaceutical use), its targets and drug effect should motivate researchers to gain more insight.
Hristova, D., & Zhelyazkova-Savova, M. (2017). A SYSTEMATIC REVIEW OF RESEARCH ON N, N-DIMETHYLTRYPTAMINE. Scripta Scientifica Vox Studentium, 1(1).
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Psychedelic drug use in healthy individuals: A review of benefits, costs, and implications for drug policy

July 26, 2017 / Ayahuasca, DMT, LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / By /

Abstract

The potential of psychedelic drugs in the treatment of mental health problems is increasingly being recognized. However, relatively little thrust has been given to the suggestion that individuals without any mental health problems may benefit from using psychedelic drugs, and that they may have a right to do so. This review considers contemporary research into the use of psychedelic drugs in healthy individuals, including neurobiological and subjective effects. In line with findings suggesting positive effects in the treatment of mental health problems, such research highlights the potential of psychedelic drugs for the enhancement of wellbeing even in healthy individuals. The relatively low risk associated with usage does not appear to align with stringent drug laws that impose heavy penalties for their use. Some policy implications, and suggestions for future research, are considered.
Elsey, J. W. (2017). Psychedelic drug use in healthy individuals: A review of benefits, costs, and implications for drug policy. Drug Science, Policy and Law, 3, 2050324517723232.
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A Physician’s Attempt to Self-Medicate Bipolar Depression with N,N-Dimethyltryptamine (DMT)

July 7, 2017 / Depressive Disorders, DMT, Papers, Psychology / By / , , , ,

Abstract

N,N-dimethyltryptamine (DMT) is a psychoactive substance that has been gaining popularity in therapeutic and recreational use. This is a case of a physician who chronically took DMT augmented with phenelzine in an attempt to self-medicate refractory bipolar depression. His presentation of altered mental status, mania, and psychosis is examined in regards to his DMT use. This case discusses DMT, the possible uses of DMT, and the theorized mechanism of DMT in psychosis and treatment of depression, particularly involving its agonist activity at 5-HT1A, 5-HT2A, and 5-HT2C. It is also important to recognize the dangers of self-medication, particularly amongst physicians.
Brown, T., Shao, W., Ayub, S., Chong, D., Cornelius, C. A Physician’s Attempt to Self-Medicate Bipolar Depression with N,N-Dimethyltryptamine (DMT). Journal of Psychoactive Drugs. 10.1080/02791072.2017.1344898
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A Physician's Attempt to Self-Medicate Bipolar Depression with N,N-Dimethyltryptamine (DMT)

July 7, 2017 / Depressive Disorders, DMT, Papers, Psychology / By / , , , ,

Abstract

N,N-dimethyltryptamine (DMT) is a psychoactive substance that has been gaining popularity in therapeutic and recreational use. This is a case of a physician who chronically took DMT augmented with phenelzine in an attempt to self-medicate refractory bipolar depression. His presentation of altered mental status, mania, and psychosis is examined in regards to his DMT use. This case discusses DMT, the possible uses of DMT, and the theorized mechanism of DMT in psychosis and treatment of depression, particularly involving its agonist activity at 5-HT1A, 5-HT2A, and 5-HT2C. It is also important to recognize the dangers of self-medication, particularly amongst physicians.
Brown, T., Shao, W., Ayub, S., Chong, D., Cornelius, C. A Physician’s Attempt to Self-Medicate Bipolar Depression with N,N-Dimethyltryptamine (DMT). Journal of Psychoactive Drugs. 10.1080/02791072.2017.1344898
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