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.
Highlights
Ayahuasca is a psychoactive plant brew containing N,Ndimethyltryptamine (DMT) and β-carboline alkaloids traditionally used in the Amazon basin for therapeutic and spiritual purposes (Schultes et al, 1979; Frecska et al, 2016)
The hallucinogenic tryptamine DMT is obtained from Psychotria viridis and it binds to Sigma 1 receptor (SIGMAR1), the serotonin receptors (5HTR) 1A/1D/1E/2A/2B/2C/5A/6/7, the serotonin transporter, the dopamine receptor D1 (D1R), the adrenergic receptors alpha 1A/1B/2A/2B/2C, the imidazoline 1 receptor and the trace amine associated receptor (Deliganis et al, 1991; Smith et al, 1998; Bunzow et al, 2001; Fontanilla et al, 2009; Ray, 2010). β-carbolines are obtained from Banisteriopsis caapi and function as monoamine oxidase inhibitors (MAOIs) to render DMT orally active (Riba et al, 2003)
The deep changes in perception and cognition elicited by Ayahuasca ingestion are underlined by a profound activation of limbic, paralimbic and neocortical brain areas, which are Abbreviations: 5HT, Serotonin; brain-derived neurotrophic factor (BDNF), Brain-derived neurotrophic factor; cannabinoid receptor 1 (CB1), Cannabinoid receptor 1; default mode network (DMN), Default mode network; DMT, N,NDimethyltryptamine; GABA, Gamma-aminobutyric acid; histone deacetylase (HDAC), Histone deacetylase; inferior frontal gyrus (IFG), Inferior frontal gyrus; LVGCC, L-type voltage-gated calcium channels; MAOI, Monoamine oxidase inhibitor; MDMA, 3,4methylenedioxy-methamphetamine; nuclear factor kappa-B (NFKB), Nuclear factor kappa-B; NMDA, N-methyl-D-aspartate; post-traumatic stress disorder (PTSD), Post-traumatic stress disorder; SIGMAR1, Sigma 1 receptor
Summary
Ayahuasca is a psychoactive plant brew containing N,Ndimethyltryptamine (DMT) and β-carboline alkaloids (harmine, harmaline, and tetrahydroharmine) traditionally used in the Amazon basin for therapeutic and spiritual purposes (Schultes et al, 1979; Frecska et al, 2016). Β-carbolines are obtained from Banisteriopsis caapi and function as monoamine oxidase inhibitors (MAOIs) to render DMT orally active (Riba et al, 2003). No pre-clinical or clinical studies to date have investigated this possibility. In this work, based on converging layers of evidence from in-vitro, pre-clinical and clinical studies, I postulate a mechanism involving the activation of discrete brain areas and receptor systems which triggers the recall of traumatic memories and their reconsolidation (and potentially fear extinction learning) hypothetically via modifying the epigenetic signatures of the memory
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