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DMT (2-(1H-Indol-3-yl)-N, N-dimethylethanamine); N, N-Dimethyltryptamine; N, N-DMTl; «Dmitry», «The Glory»; «The Spirit Molecule»; jim; jam; aya; jungle spice; spice; changa; god molecule - a psychoactive substance belonging to the group of substituted tryptamines and characterized by extremely powerful psychedelic effects and short-term action, belongs to the class of entheogens. The origins of the use of ayahuasca in the Amazon Basin are lost in the mists of prehistory. No one can say for certain where the practice may have originated, and about all that can be stated with certainty is that it was already spread among numerous indigenous tribes throughout the Amazon Basin by the time ayahuasca came to the attention of Western ethnographers in the mid-nineteenth century. This fact alone argues for its antiquity; beyond that, little is known. Plutarco Naranjo, the Equatorian ethnograper, has summarized what little information is available on the prehistory of ayahuasca (Naranjo 1979, 1986). There is abundant archeological evidence, in the form of pottery vessels, anthropomorphic figurines, snuffing trays and tubes, etc., that plant hallucinogen use was well established in the Ecuadorian Amazon by 1500–2000 B.C. Unfortunately, most of the specific evidence, in the form of vegetable powders, snuff trays, and pipes, is related to the use of psychoactive plants other than ayahuasca, such as coca, tobacco, and the hallucinogenic snuff derived from Anadenanthera species and known as vilka and various other names. There is nothing in the form of iconographic materials or preserved botanical remains that would unequivocally establish the prehistoric use of ayahuasca, although it is probable that these pre-Colombian cultures, sophisticated as they were in the use of a variety of psychotropic plants, were also familiar with ayahuasca and its preparation. The lack of data is frustrating, however, particularly in respect to a question that has fascinated ethnopharmacologists since the late 1960s, when its importance was first brought to light through the work of Richard Schultes and his students. As mentioned above, ayahuasca is unique among plant hallucinogens in that it is prepared from a combination of two plants: the bark or stems of Banisteriopsis species, together with the leaves of Psychotria species or other DMT-containing admixtures. The beverage depends on this unique combination for its activity. There seems small likelihood of accidentally combining the two plants to obtain an active preparation when neither is particularly active alone, yet we know that at some point in prehistory, this fortuitous combination was discovered. At that point, ayahuasca was “invented.” Just how this discovery was made, and who was responsible, we may never know, though there are several charming myths that address the topic. Mestizo ayahuasqueros in Peru will, to this day, tell you that this knowledge comes directly from the “plant teachers” (Luna 1984), while the mestres of the Brazilian syncretic cult, the UDV, will tell you with equal conviction that the knowledge came from “the first scientist,” King Solomon, who imparted the technology to the Inca king during a little publicized visit to the New World in antiquity. In the absence of data, these explanations are all that we have. All that we can say with confidence is that the knowledge of the techniques for preparing ayahuasca, including knowledge of the appropriate admixture plants, had diffused throughout the Amazon by the time the use of ayahuasca came to the attention of any modern researcher.
Over the past several hundred years, the use of ayahuasca spread into Peru,
Fiedler et al. studied motives for use among Santo Daime members, and found that reasons were consistently religious or spiritual, as well as selftreatment. Travelling in search of a transformative hallucinogenic experience is referred to in the literature as drug tourism, spiritual tourism, or modern shamanic tourism. Ayahuasca tourism is growing in popularity, and most often this involves non-indigenous tourists going on all-inclusive trips to the Amazon to partake in a shaman-led ayahuasca ceremony. One article analyzes the internet’s role in the evolution of ayahuasca tourism, specifically by examining the website of one such tour company, Blue Morpho Tours, and suggests that such experiences represent the quest for ‘the authentic, ethnic Other”. Modern shamanic tourism is discussed in a dissertation by Fotiou and in articles by Winkelman and Arrevalo, both of whom collected data showing that motivations to participate in such an experience are usually not excuses for drug experimentation, but are genuinely sought out as spiritual pilgrimages. Kavenska and Simonova examined the motivations, perceptions, and personality traits of 77 study participants who had gone to South America to use ayahuasca. Motivations included "curiosity, desire to treat mental health problems, need for self-knowledge, interest in psychedelic medicine, spiritual development, and finding direction in life". Reported benefits included self-knowledge, improved interpersonal relations, and gaining new perspectives on life. Participants scored significantly above average on the PSSI scales of "intuition, optimism, ambition, charm, and helpfulness and significantly lower on the scales of distrust and quietness". While most experiences of this variety with ayahuasca are relatively safe, Arrevalo warns against inexperienced or false shamans using toxic plants as additives to the ayahuasca preparation. Balikova reports on a “meditation session” in Prague in 2001 (named “releasing autohypnosis of forest medicine men”) that ended with many of its participants hypotensive, hyperthermic, with some even requiring mechanical ventilation. This was attributed to a synergistic effect between harmine and two anticholinergics, atropine and scopolamine, found in the brew allegedly made from plants named “Ikitos” or “Toe”. However, these anticholinergics are not found in ayahuasca. Alexander Shulgin synthesized and personally tried hundreds of psychoactive substances. He and his wife, Ann Shulgin, wrote the book TIKHAL (Tryptamines I have known and loved), which contains a fictionalized autobiography and essays, along with a synthesis manual for 55 substituted tryptamines, and dosing suggestions and accounts of the subjective experience of taking these substances. Research into ayahuasca really took off in 1993, when a multidisciplinary team began a comprehensive investigation into the immediate physiologic and psychological effects as well as the pharmacology of ayahuasca use in 15 male long-term (greater than 10 years) adult members of the União do Vegetal church (UDV) called the Hoasca Project, which was conducted by an international team of researchers in the city of Manaus, Brazil. It was an observational study that compared these users with 15 matched
DMT is classified as a Schedule I drug under the United Nations 1971 Convention on Psychotropic Substances. However, this action did not regulate natural substances containing DMT, such as
In Canada, the Controlled Drugs and Substances Act is the federal law enacted in 1996 that regulates a great variety of illicit psychoactive substances, including opioids, hallucinogens, cannabis, and cocaine in accordance with international laws. Interestingly, there is a
DMT comes in various forms, which are suitable for different methods of consumption and will alter the duration of the experience. Pure DMT is a white crystalline powder or solid, but it is more commonly found as a yellow-pink powder or solid. It can also be found in herbal mixtures called ‘changa’. It is a common misconception that DMT is consumed successfully by smoking. A direct open flame will cause it to burn and become inactive. DMT comes in many shapes and sizes, and it is usually pale yellow-orange to pure white crystals when extracted. Oxidation, oils, and other
In its freebase form (commonly used for inhalation), DMT can be seen as clear or white crystals. It has a melting point (Mp) of 44.6 °C to 46.8 °C, and a pKa value of 8.68, being only soluble in diluted acetic acid and diluted mineral acid. DMT hydrochloride is a white crystalline powder soluble in water; it has a Mp of 165 °C to 168 °C, a pKa of 8.7, and a LogP of 1.9. DMT fumarate (MW of 304.34 g/mol) is a water‐soluble salt form of DMT, commonly used for drug administration by injection, and it is more stable for long‐term storage than the freebase. In solution, DMT has a fast degradation rate and should be stored at −20 °C, protected from air and light. Additionally, under certain conditions, i.e., elevated heat, it can have explosive potential. Smoked (DMT): DMT powder can be smoked in a pipe or bong, or vaporized, including through the use of vape pens. Freebase DMT is typically associated with smoking. Smoked (Changa): changa is a herb mixture containing both a DMT-containing extract and monoamine oxidase inhibitor (MAOI)-containing extract from plants. The combination of DMT and a MAOI is built upon the chemical principle of ayahuasca, whereby the addition of a MAOI will prolong the trip. Changa can be smoked in a joint, pipe, bong or vaporized with a vape pen. Injected: DMT must be injected in its salt form (DMT fumarate). Ingested/Orally: Consumed orally in the form of ayahuasca. Vaporized DMT must be in its freebase form, as there are theories that the salts release toxic compounds once heated. A common misconception surrounding vaporized DMT is that it is consumed successfully by smoking it with a direct open flame. Applying a direct open flame to freebase DMT causes it to burn and become inactive. Instead, DMT becomes active when vaporized at a temperature around 160 degrees celsius (320 °F). Effects of vaporized DMT can be prolonged by mixing it in a smoking blend called changa, which typically contains plants that have MAOI or to which an MAOI has been added. Users can also choose to snort it, which is much easier in its salt form, such as fumarate, citrate, or acetate, for better absorption through mucous membranes. Typically, Ayahuasca brews use Banisteriopsis caapi vines to provide MAOIs to the brew and another plant to provide the DMT. Recently, cultivators developed so-called psychotria nexus more adapted to live in colder climates as an alternative to B. caapi. Another option is using plants like Acacia confusa or Mimosa hostilis (Jurema) to provide the DMT and witheganum harmala (Syrian rue) for the MAOI. A common alternative to pure DMT is 5-MeO-DMT. It produces a similar short-lasting intense psychedelic experience with only minor differences. 5-HO-DMT also produces a short-lasting psychedelic experience but has been associated with more negative effects such as tightness in the chest and throat, nausea, and numbness. Other chemicals such as psilocybin, psilocin, and 4-AcO-DMT also contain the DMT molecule within their chemical structure. However, these substances produce a significantly different psychedelic experience that can last upwards of 8 hours. The difference will be in the taste and potency. There are some anecdotal reports that suggest that if DMT is a bit oily, it is actually stronger since it can also contain other alkaloids. The community often refers to some of these “stronger forms” of DMT as Jimjam and Jungle spice. Jungle spice contains small amounts of DMT, but higher amounts of other alkaloids from mimosa hostilis.
The DMT in ayahuasca is from the Psychotria viridis or Diplopterys cabrerana vines, and ranges in concentration from 0.1% to 0.66% of the dry weight. The beta-carbolines come from Banisteriopsis caapi. These compounds represent 0.05% to 1.95% of the dry weight, and are much more concentrated in the seeds and roots than in stems and leaves. DMT, a hallucinogen, can be smoked, ingested orally, given IV, or even insufflated. However, when consumed orally, essential for DMT to exert its effects is that it be consumed mixed with an MAOI to prevent degradation of the DMT by gut and liver MAOs and lengthen its action in the CNS. When ayahuasca is consumed, the DMT is taken in combination with beta-carbolines which act as reversible inhibitors of monoamine oxidase A (MAO-A), protecting the DMT from degradation. Wang found two new beta-carboline alkaloidal glycosides (Banisteride A and B) and their acetates, four known beta-carbolines (harmine, harmaline, tetrahydroharmine, and harmol), a new beta-carboline (tetrahydronorharmine), two proanthocyanides [(-)-epicatechin and (-)-procyanidin B2)] and their acetates, a new dissacharide (β-d-fructofuranosyl-(2→5)- fructopyranose) and its acetate, known saccharose and acetate, and β-D-glucose. Several studies found similar chemical profiles. Two quinazoline alkaloids, peganine and deoxypeganine, have also been isolated in a P. harmala seed infusion. The toxic dose of ayahuasca would be approximately 7.8 litres for a 75 kg person, and given its highly unpleasant taste, it is unlikely anyone would ever reach this dose. In addition, vomiting and diarrhea occur long before this limit is reached. DMT is usually present and stored as a crystallized powder. It is usually pale yellow-orange to pure white and as the molecules oxidize, the powder starts to yellow. DMT is a very stable molecule, so its potency is unlikely to degrade quickly. But it can degrade into DMT-B-oxide when exposed to air and high temperatures. DMT is a salt powder when combined with citrate, acetate, fumarate, and hydrochloride. But DMT can also come in its freebase form, which is more reactive. Generally, storing DMT as a salt is more stable and will last longer. As with most things, a cool, dark, and dry place is the best way to store DMT. The best way to store DMT is in an airtight, small glass jar. DMT can be oxidized by air, so keeping it in a sealed jar is the most important part of storage. An amber glass jar (a brown glass jar) is suggested to keep the DMT away from both air and light. But unlike LSD, DMT is not reactive to light, so it isn’t necessary to store in tin foil. As it also comes as a powder and not a tab, storing DMT in tin foil can be messy. While the community doesn’t agree if DMT will react with the aluminum foil, the safest bet is to avoid tinfoil for any storage except for short periods. Some say the freebase form of DMT will attack the metal and cause problems. It is best not to store DMT in plastic or plastic wrap for long periods. The chemicals in the plastic can leach into the DMT (or any substances for that matter) and be ingested with the DMT. Plastic wrap becomes gooey after long exposure to DMT. DMT should be stored under 77 degrees. So, unless you live in a hot or humid climate, storing at room temperature is fine. If you do decide to store it in the fridge or freezer, remember to let the DMT and jar come up to room temperature before opening the jar.
DMT is pricey due to its rarity, as well as the unique and potent psychedelic journey it provides. A handful of cities has decriminalized DMT derived from natural materials. These include Santa Cruz, CA; Oakland, CA; and Ann Arbor, MI. DMT is still considered a Schedule I substance and is illegal under state and federal law. Parts of the United States still treat the discovery and bust of an individual making DMT similarly to that of someone at a meth lab, according to officials. These outdated, extreme protocols are largely due to ignorance and lack of information. Because processing DMT comes with such high-risk circumstances, this drives up the high price point and lays the ground for a lack of quality control of DMT on the black market. For many, purchasing a large quantity of DMT might feel a little extreme. But if the funds are available, the price point can drop dramatically. One ounce of DMT usually costs $2,800.00, almost $100 per gram (or more). Purchasing a quarter pound of DMT (4 ounces) can bring the price point down to around $75 per gram, or about $8,400.
Although the plants discussed below contain the highly controlled compound DMT, the plants themselves are legal to purchase and possess without the intent of extracting the molecule. The most common DMT plant sources are sold widely on eBay and various ethnobotanical websites such as Waking Herbs and Mayan Magic Soaps. Since customs has been known to seize packages (especially in powder form), always buy from a source that ships domestically. With these plants, DMT extractions are done in a few days using a strong base, such as lye and a nonpolar solvent such as naphtha. They’re mostly carried out with Mimosa hostilis root bark, due to its high DMT and low-fat content. However, extractions can also be done with other DMT-containing plants, as long as the amount of the starting materials used are adjusted depending on the amount of DMT present in the plant. When purchasing DMT-containing plants, it’s important to note the percentages of DMT content can vary greatly. Factors such as the growing conditions, location, and time of harvest can all impact the amount of DMT in a given plant. When extracting, this can lead to differences in final yields, regardless of one’s precision with the extraction technique. Formerly known as Mimosa tenuiflora, Mimosa hostilis (Jurema) is a tropical perennial tree native to northeastern Brazil but also found in Mexico and several other South American countries. It is found growing at low altitudes and is identified by its green, fern-like leaves, white flowers, and dark brown bark that is reddish on the inside. In addition to various medicinal properties, the root bark has a DMT content between 1-1.7% (dry weight). The DMT in M. hostilis can be extracted fairly easily with commonly available precursors. In addition to its high DMT content, this plant is preferable for extractions because it contains almost no fat. For this reason, an extra defatting procedure during extraction is not required to remove fat or oil impurities from the final product. In addition to its use in extractions, the root bark is also used to brew ayahuasca when combined with an MAOI-containing plant such as Banasteriopsis caapi. Known commonly as chacruna, P. viridis is a flowering plant in the coffee family. It is native to the wet lowland tropical forests of South America. It grows up to 5 meters in height and is characterized by long, green leaves and small red fruits. The leaves contain between 0.1-0.61% DMT (dry weight), with the highest concentration of DMT found in the morning. The plant can be grown from seed, or more successfully, from cuttings. P. viridis has a long history of use in South and Central America as a principal ingredient used in the creation of ayahuasca brews. Shamans boil the leaves with the MAOI-containing yage (B. caapi) vine, which renders the DMT orally active. DMT and related alkaloids are found throughout the plant kingdom at varying concentrations. It has been identified in the leaves and bark of over 65 plant species found around the world. Besides Mimosa and Psychotria, some major plant genera containing DMT include Acacia, Anadenathera, Delosperma, Desmodium, Petalostylis, Phalaris, and Virola. Acacia genera contain the highest number of DMT-containing plants. Several Acacia species, such as Acacia confusa, are commonly used in extractions. For a complete listing of DMT-containing plants, consult this list.
Pharmacokinetics and pharmacodynamics.
With respect to plasma peak levels, Callaway showed an average time to reach maximum concentration (Tmax) of 107.5 + 32.5 minutes with 15 volunteers, and the half life (T1/2) was 259 minutes. dos Santos noted a median Tmax of 1.8 hours, with a range 1-4.5 hours. Riba found a median Tmax for orally consumed DMT of 1.5 hours for both high and low doses (0.6 mg/kg and 0.85 mg/kg), but showed a correlation between higher doses and a larger Tmax. This aligns with the finding of a cognitive peak between 60 and 120 minutes reported by Gable, as well as peaking along a similar timeline as EEG activity. The threshold for hallucinogenic effects for DMT was 0.2 mg/kg by IV. IV DMT administration also differs in that the effects come on more rapidly and last for a shorter time, displaying peak blood levels and subjective effects within 2 minutes; both were neglible at 30 minutes. Gable noted a median lethal dose (LD50) for DMT of 47 mg/kg intraperitoneally and 32 mg/kg IV in mice, which is similar to the IV LD50 in rodents for other compounds resembling DMT structurally (psilocin, psilocybin, bufotenin, 5-MeO-DMT). In comparing toxicities of various psychoactive drugs, ayahuasca has a safety margin similar to those of codeine, mescaline, and methadone, with the lethal dose being approximately 20 times the usual effective dose. Lanaro discussed differences between ritual oral ingestion of ayahuasca and recreational smoked DMT and noted that with smoked DMT the bioavailability and risk of overdose are much higher. DMT is catabolised mainly by oxidative deamination, as well as N-oxidation and N-demethylation. Metabolic studies showed indole-3-acetic acid (IAA) and indole-3-aceturic acid (IAA conjugated with glycine) as the main urinary metabolites of DMT in rats. Riba described urinary metabolites of oral and smoked DMT. Without the beta-carbolines found in ayahuasca, after oral ingestion of DMT, no psychoactive effects occurred; 97% of recovered compound was IAA, an MAO-dependent metabolite, and 3% was DMT-N-oxide (DMT-NO). DMT-NO does not appear to be a substrate for MAO. With smoked DMT, unmetabolized DMT and DMT-NO accounted for 10% and 28%, respectively, of recovered compounds, while IAA accounted for only 63%. N-methyltryptamine (NMT), 2-methyl-1,2,3,4-tetrahydro-beta-carboline (2-MTHBC) and 1,2,3,4-tetrahydro-beta-carboline (THBC) have also been identified as minor metabolites of DMT. A study by Callaway found Tmax values (minutes) for DMT of 107.5 ± 32.5, for harmine 102.0 + 58.3, for harmaline 145.0 + 66.9, and for tetrahydroharmine (THH) 174.0 + 39.6 after an ayahuasca infusion. Riba reported that THH peaked later in the serum than DMT and harmaline. Compared to low dose, high dose ayahuasca seemed to show slightly longer Tmax values for these constituents. They were unable to obtain sufficient measurable plasma levels of harmine, but had measurable levels of harmol (metabolite of harmine) with plasma concentration peaks at 1.5 and 2 hours after low and high doses. They were able to measure harmaline, and Tmax was at 1.5 and 2 hours for the low and high doses. In general, the studies by Riba and Callaway show a trend of Tmax increasing from DMT through harmaline to THH. In terms of toxicity, Gable found a median lethal dose/LD50 of 2 g/kg P. harmala seed beta-carboline admixture in rats.
DMT as an endogenous compound can be measured in human body fluids, including blood, urine and cerebral spinal fluid. Levels of endogenous DMT do not appear to be regulated by diet or gut bacteria. Infrequent and inadequate sampling methods used over time make it difficult to determine specific details pertaining to DMT production in the body. For example, we still do not know if DMT is produced in phasic or diurnal cycles. Measurable concentrations seem to only occur intermittently, and the exact tissue source or sources of DMT is still unclear. It is commonly thought that the adrenal gland and lungs are the most common places for the highest amount of DMT production, since this is where the highest levels of INMT have been reported. Throughout the studies, there were inconsistent sampling methods, including various of amounts of urine used in assays, and a range of techniques and analytical approaches were used. Some studies took dietary influences into consideration, but found no associations with endogenous DMT levels. Inconsistent units of measurement were also used across studies. Concentrations in urine range from 0.02 to 42.98+/-8.6 (SD) ug/24h, and from 0.16 to 19 ng/ml. Higher concentrations of DMT are extracted from whole blood compared to plasma, but there is no difference in venous and arterial blood. When concentrations were reported, not just whether it was present or not present, it ranged from 51 pg/ml (HPLC-radioimmunoassay) to 55 ng/ml (direct fluorescence assay of extracts). DMT was detected in cerebrospinal fluid in 4 studies, which tested 136 individuals (82 patients). Of those, 34 patients and 22 controls were positive for DMT. Concentrations ranged from 0.12 to 100 ng/ml. DMT can be detected as an endogenous compound in urine, blood, and cerebrospinal fluid.
Furthermore, hydroxylation at either the 4- or 5-position was shown to increase the affinity about 10-fold. Interestingly, the 5-HT2A receptor does not desensitize to DMT over time, which perhaps explains why tolerance to DMT does not develop in humans. Stimulation of 5-HT2A receptors appears to underlie the psychoplastogenic effects of DMT. Ly and coworkers demonstrated that DMT increases the complexity of cortical neuron dendritic arbors and promotes increased dendritic spine density. This DMT-mediated enhancement of structural plasticity occurs through an mTOR-dependent mechanism that involves activation of 5-HT2A receptors. Specifically, Ly and coworkers utilized the 5-HT2A antagonist ketanserin to effectively block the ability of DMT to promote cortical neuron neurite growth and spinogenesis. Neural plasticity in the prefrontal cortex is critical to the behavioral effects of fastacting antidepressants like ketamine, so it is possible that 5-HT2A receptor agonism underlies the known antidepressant effects of serotonergic psychedelics. Like the 5-HT2A receptor, the 5-HT2C receptor is coupled to Gq and increases phosphoinositide hydrolysis upon activation. DMT acts as a partial agonist of the 5-HT2C receptor 22, with a binding affinity approximately half that of the 5-HT2A receptor. However, unlike the 5-HT2A receptor, the 5-HT2C receptor desensitizes to DMT over time. Additionally, it does not seem to play a role in the interoceptive effects of DMT. In contrast to 5-HT2A and 5-HT2C receptors, 5-HT1A receptors are inhibitory G-protein coupled receptors (GPCRs) expressed on target cells localized mainly in cortical and subcortical regions. These receptors can also serve as autoreceptors found on the somas and dendrites of serotonergic neurons in the dorsal raphe. Compared to its affinity for other neuroreceptors, DMT is a good ligand for 5-HT1A receptors (183 nM), where it acts as an agonist. It has been shown that 5-HT1A agonists acutely inhibit dorsal raphe firing, likely through stimulation of these autoreceptors. Blier and colleagues elegantly demonstrated that increased activation of these autoreceptors decreases serotonin release in other brain regions. However, chronic treatment with antidepressants restores normal 5-HT neuron activity through desensitization of somatodendritic and terminal autoreceptors. It is because of this that many agonists of the 5-HT1A receptor are thought to exert anxiolytic and antidepressant properties. In the case of DMT, a 5-HT1A agonist, this mechanism may also contribute to its therapeutic effects.
DMT is one of the few known endogenous sigma-1 agonists (Kd = 15 μM), but the affinity of DMT for sigma-1 receptors is 100-fold lower than that for 5-HT2A receptors. The relatively weak affinity of DMT for sigma-1 receptors coupled with the low circulating levels of endogenous DMT make it unlikely that sigma-1 receptors play a significant role in the function of endogenous DMT. However, exogenously administered sigma-1 agonists, such as (+)-SKF and igmesine, produce behavioral responses similar to exogenously administered DMT such as a reduction in the number of entries into the open arms of an elevated plus maze and reduced immobility in the forced swim test. Moreover, sigma-1 receptor knockout mice exhibit a depressive phenotype, and sigma-1 receptors regulate the secretion of brain-derived neurotrophic factor (BDNF) and various forms of structural and functional neural plasticity. As DMT produces both antidepressant behavioral responses and promotes neural plasticity, it is reasonable to conclude that the sigma-1 receptor may play some role in the effects of exogenously administered DMT, though these hypotheses require additional experimental validation. Finally, it has been recently shown that DMT can protect human cortical neurons from oxidative stress via a sigma-1 receptor-dependent mechanism. While the authors attribute this protective effect to the sigma-1 receptor’s known influence on the ER stress response, it could also be due to the pro survival properties of BDNF secretion following sigma-1 stimulation. The main problem with the theory that DMT is an endogenous sigma-1 receptor agonist is that it requires concentrations in the micromolar range, whereas selective sigma-1R agonists such as (+)-pentazocine have affinities in the nanomolar range. Supporting the role of sigma-1 receptor is that the SSRI fluvoxamine, has sigma-1 receptor agonist properties with higher affinity than DMT. At best, sigma-1 receptors may partially mediate the subjective effects of DMT. Whether or not the sigma-1 receptor plays a significant role in the psychedelic effects of DMT, it may still play an important role in other physiological mechanisms. Sigma-1 receptors agonists are potentially neuroprotective via several mechanisms. DMT reduced inflammation ostensibly via sigma-1 receptor, and can induce neuronal plasticity, which is a long-term recuperative process that goes beyond neuroprotection. Sigma-1 receptors can regulate cell survival and proliferation, thus if DMT is an endogenous agonist, this may explain physiological relevance and importance of why DMT has a 3-step uptake process. Regulation of intracellular calcium overload, proapoptotic gene expression via Sigma-1 receptors, can result in neuroprotection during and after ischemia and acidosis. There would be further benefit through sigma-1 receptor dependent plasticity changes. Along these lines Frecska colleagues (2013) suggest that DMT may be protective during cardiac arrest, beneficial during perinatal development, immunoregulation, and aid in reducing cancer progression as explained below.
TAAR1 has also been suggested as a target of DMT. A study by Bunzow and coworkers elegantly demonstrated that DMT activates TAAR1 to increase cAMP production in a TAAR1-expressing HEK293 cell line. Like DMT, several other trace amines, psychedelics, and psychostimulants have been shown to bind to and activate TAAR1 to a greater extent than traditional neurotransmitters like serotonin, dopamine, or norepinephrine. While DMT was shown to activate TAAR1 at 1 μM, lower concentrations were not employed in these studies, and therefore, the exact EC50 value for DMT remains unknown. By analyzing binding-to-uptake ratios, Cozzi and coworkers determined that DMT acted as a substrate, rather than an inhibitor, for SERT and VMAT. This result is supported
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