The following is a detailed functional analysis:
“DMT binds to the sigma-1 receptor, which provides new opportunities for understanding how ayahuasca may produce its marked effects on the body and mind and what might be the role of endogenous DMT and how ayahuasca may have effects on cancer.
The human sigma-1 receptor has been cloned and shows no homology with other mammalian proteins. Single-photon emission tomography (SPET) analysis in humans revealed that these receptors are present in organs such as the lung and liver and most concentrated in the brain. Sigma-1 receptor activity has been implicated in a variety of diseases, including cancer, depression, and anxiety. Sigma-1 receptors are found in high densities in many human cancer cell lines, including lung, prostate, colon, ovaries, breast, and brain; thus, sigma ligands are regarded as potential novel antineoplastic tools.”
“DMT binds sigma-1 receptors with moderate affinity (KD = 14.75 µM, approximately half the affinity for 5-HT1A and 5-HT2A receptors) and, at high concentrations, is also capable of inhibiting voltage-gated sodium channels. Thus, DMT may exert two types of effects through sigma-1 receptors: at low concentrations, it regulates calcium flow from the ER to the mitochondria, whereas at higher concentrations, it exerts diverse effects at the plasma membrane region. The effect on calcium influx into the mitochondria may be extremely important for cancer treatment given that an energetic imbalance between excessive cytosolic aerobic glycolysis and reduced mitochondrial oxidative phosphorylation (the Warburg effect) was recently suggested as the seventh hallmark of cancer. This metabolic profile of cancer cells is accompanied by a hyperpolarization of the mitochondrial membrane potential that may be reduced by the calcium influx triggered by DMT binding to the sigma-1 receptor at the MAM. This effect may facilitate the electrochemical processes at the electron transport chain inside the mitochondria, thus increasing the production of reactive oxygen species (ROS) and leading these cells to apoptotic pathways. When high DMT concentrations induce sigma-1 receptor translocation to the plasma membrane, many cellular effects would occur due to the receptor’s interaction with different ion channels. At high concentrations of DMT, a calcium influx and mitochondrial membrane depolarization might be enough to also activate the permeability transition pore (PTP), inducing mitochondria swelling, rupture, and apoptosis.
For all these effects to help explain the available case reports of ayahuasca on cancer treatment, DMT’s physiological degradation by enteric monoamine oxidase (primarily MAO-A) after oral consumption should be inhibited, thus allowing the DMT to pass into circulation. The pharmacological activity of β-carbolines (primarily harmine) in ayahuasca inhibits MAO, with a high affinity for MAO-A. Therefore, the specific effects of ayahuasca on the different types of cancer could also vary depending on the predominant MAO subtype, given that the ratio of MAO-A to MAO-B varies, for example, from 1:3 in the brain to 4:1 in the intestine, and the placenta has only MAO-A and blood platelets have only MAO-B. Another consequence of inhibiting MAO in different tissues is interference with apoptotic pathways, thus strengthening the synergistic action of β-carbolines and DMT.
In addition to allowing DMT to exert its effects on cancer tissues and cells, β-carbolines may have other important roles. It was recently demonstrated that harmine activates pathways of apoptosis in B16F-10 melanoma cells; it inhibits tumor-specific neo-vessel formation, both in vitro and in vivo in mice, through a series of mechanisms involving decreased serum levels of pro-angiogenic factors and an increase in antitumor factors and displays an inhibitory effect on cell proliferation against human carcinoma cells. Harmine and harmaline were also shown to reduce cell proliferation in the human leukemia cell line HL60. Harmine was also shown to induce apoptosis in the human hepatocellular carcinoma cell line HepG2. Harmine may also be beneficial in cancer treatment due to its inhibitory effect on the DYRK1A kinase. This kinase is implicated in the resistance of many cancerous tissues to pro-apoptotic stimuli and the enhancement of proliferation, migration, and reduced cell death. Another pharmacological effect of harmine that may be important in brain cancer is its role on the EAAT2 glial glutamate reuptake transporter. Harmine was identified as one the most efficient molecules to upregulate this transporter in glial cells among a library of 1040 Food and Drug Administration (FDA)-approved substances. This fact may be of importance because most brain tumors are of glial origin and involve excessive glutamate release, causing neurotoxicity. Also important for gliomas may be the binding of harmine to imidazoline I2 receptors. These receptors are highly expressed in gliomas, and their density increases with malignancy in human cells. However, their physiological role in these tissues remains unclear.
A recent study has shown that DMT inhibits the indoleamine 2,3 dioxygenase enzyme. This enzyme, when upregulated, is associated with malignant cells escaping immune surveillance, and thus DMT may help increase immune functions against malignant cells.”
In summary, it is hypothesized that the combined actions of β-carbolines and DMT present in ayahuasca may diminish tumor blood supply, activate apoptotic pathways, diminish cell proliferation, and change the energetic metabolic imbalance of cancer cells, which is known as the Warburg effect. Therefore, ayahuasca may act on cancer hallmarks such as angiogenesis, apoptosis, and cell metabolism.”
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