DMT. Part I. General pharmacology

[Brain]

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.

In terms of Western culture, DMT was first synthesized by a Canadian chemist, Richard Manske, in 1931 but was, at the time, not assessed for human pharmacological effects. In 1946, the microbiologist Oswaldo Gonçalves de Lima discovered DMT’s natural occurrence in plants. DMT’s hallucinogenic properties were not discovered until 1956 when Stephen Szara, a pioneering Hungarian chemist and psychiatrist, extracted DMT from the Mimosa hostilis plant and administered the extract to himself intramuscularly. This sequence of events formed the link between modern science and the historical use of many DMT-containing plants as a cultural and religious ritual sacrament, their effect on the psyche and the chemical structure of N, N-dimethyltryptamine. For centuries, humans have consumed N, N-dimethyltryptamine (DMT) as a key ingredient in various tisanes and snuffs used during religious ceremonies in Central and South America. Cited as early as the 15th century, these concoctions were made from vines, roots, and shrubs native to these regions and were purportedly used by indigenous peoples to facilitate their communication with the gods. Accounts of such rituals indicate that users of these botanical concoctions were left feeling peaceful and enlightened, most likely due to the profound psychoactive effects of their chemical constituents. Today, it is thought that DMT and related alkaloids might be used to treat depression and other neuropsychiatric disorders. These compounds are produced by a wide variety of botanical sources. Ayahuasca, also known as hoasca, natema, iowaska, daime, or yage; is an Amazonian tisane that is made by boiling the bark of the Banisteriopsis caapi vine and the leaves of the Psychotria viridis plant. The former contains a variety of monoamine oxidase (MAO) inhibiting β-carbolines, such as harmine, harmaline and tetrahydroharmine, while the latter contains large amounts of DMT, the principle hallucinogenic. The use of ayahuasca dates back to the earliest aboriginal inhabitants of the Amazonian basin, where it was used by indigenous shamans for communication with spirits, magical experiences, rites of initiation, and healing rituals. Ayahuasca was held in high regard among these populations, particularly for religious and healing purposes. These were small private ceremonies where the patient and the shaman, and perhaps 1 or 2 others, would consume ayahuasca. Shortly after consumption, vomiting and often intense diarrhea occur. But after this, visions begin to appear, and the nature of the disease and curative plants are revealed to the shaman and the patient.

Over the past several hundred years, the use of ayahuasca spread into Peru,

Colombia, and Ecuador among indigenous Mestizo populations where it was integrated into folk medicine. These practices evolved during the early 1930s for use as a sacrament in three Brazilian syncretic churches which combine indigenous and Christian traditions, the União do Vegetal (the largest, more meditative), the Santo Daime (the oldest, livelier, with music), and Barquinha (an Afro-Brazilian church), during twice monthly ceremonies lasting approximately four hours. Ayahuasca therapy has been used by witch doctors in treating addictions, and Lemlij describes a group therapy model where participants come as many weeks as they need and may make a voluntary monetary contribution at the end. The drink is becoming more popular in North America, Europe and beyond for religious, spiritual, and recreational use, so it is important that medical practitioners be aware of the subjective and objective effects that could affect patients they may see and understand any adverse effects, as well as explore potential medical uses. While a considerable amount of modern use of DMT and ayahuasca is for recreational purposes, Cakic found that a group of Australian users gained psychotherapeutic benefits from use. Cardenas and Gomez examined motives for modern urban use by 40 residents of Bogota, Colombia. They found that subjects used ayahuasca to achieve mental well-being and also to enhance their ability to solve personal problems; in another study, the participants cited “healing” and “equilibrium” as reasons for use. Kjellgren found similar motives among northern European users, including exploring their inner world, personal development, increasing self-awareness, examining psychological patterns, and

enhancing creativity.

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

male non-users, and revealed some interesting and surprising results. Long-term users scored slightly higher on cognitive tests than non-users, and many users reported ayahuasca and UDV membership as having a very positive impact on their lives; in fact, many reported that they were able to completely turn their lives around from previous dysfunctional behaviours such as alcoholism, violence, dishonesty and infidelity, and they lived happier, more meaningful lives. In addition, there were no signs of acute toxicity or adverse effects on health from ayahuasca use reported. At a 2010 conference organised by the Multidisciplinary Association for Psychedelic Studies, ayahuasca became one of the main topics of the conference because presenters submitted such high numbers of proposals on the topic. As ayahuasca use spreads, interest among the general public is increasing as well. Ayahuasca was the subject of a 2011 episode of David Suzuki’s “The Nature of Things” on the Canadian Broadcasting Corporation network, Araujo to provide a broad update on hallucinogens. New psychoactive substances continue to be synthesized, greater than 300 of them since the year 2000. Users are obtaining a variety of synthetic or naturally sourced substances through the internet or through specialized shops. They are often sold as "research chemicals" or «legal highs» and labelled "not for human consumption". Kowalczuk were able to purchase dried P. viridis leaves over the internet from several sources in Brazil, Peru, and Hawaii, and found that not all the specimens contained DMT. The authors concluded that proper identification and sale of P. viridis are problematic, and suggested that legislation regarding both DMT and P. viridis needs to change.

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

ayahuasca. In December 2004, the United States Supreme Court lifted a stay allowing the Brazil-based União de Vegetal (UDV) church to use a tea containing DMT for their Christmas services that year. Two years later, in Gonzales v. O Centro Espirita Beneficente Uniao do Vegetal, the court ruled that the federal government must allow the UDV to import and consume the tea for religious purposes under the 1993 Religious Freedom Restoration Act. After ruling in favor of the three Santo Daime churches, Judge Owen M. Panner issued a permanent injunction barring the government from penalizing or prohibiting the sacramental use of “Daime tea”, which contains ayahuasca. In 2020, Oregon decriminalized all illegal drugs, including DMT. Law prohibits DMT in most countries. There are some exceptions for the DMT-containing ayahuasca, often for religious and spiritual purposes. However, possession and use of ayahuasca are legal in Brazil, which is why so many ayahuasca retreats exist in Brazil. Similarly, Peru is well-known for ayahuasca use, as it is legal to use and possess. Peru also offers ayahuasca retreats. There are no specific laws regarding DMT in Colombia, though ayahuasca is considered a religious sacrament and there are retreat centers available. The same goes for Costa Rica, Uruguay, and Ecuador. In many cases, DMT remains a controlled substance, whereas DMT-containing ayahuasca is considered acceptable for use in religious settings. Although there are no laws prohibiting ayahuasca in Italy, there have been recent arrests of individuals using ayahuasca in the Santo Daime Church. Similarly to Italy, there is no specific law prohibiting ayahuasca in Spain. Despite this, arrests happen to members of the Santo Daime church for its use. All DMT-containing plants are illegal in France, and while Germany does not have specific ayahuasca laws, DMT is illegal under the German Narcotics Act. The Netherlands lists DMT as a

Schedule I prohibited substance under the Opium Law. Ayahuasca became illegal on October 1st, 2019. This ruling came to power after a woman tried importing 33 kilos worth of ayahuasca brew across the border. After the decision of the lower court that she is guilty, she took the issue to the Supreme Court on the account that this would repress the religious freedoms. The Supreme Court, however, ruled that this was an infringement on public health, making this an illegal act. It is still highly unlikely that an individual will be prosecuted for personal possession. Currently, there are no specific laws that address ayahuasca in Australia. While there have been no prosecutions for ayahuasca, Australia has other harsh laws for other drugs, including DMT.

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

clause which allows certain exemptions, called Section: “The Minister may, on such terms and conditions as the Minister deems necessary, exempt any person or class of persons or any controlled substance or precursor or any class thereof from the application of all or any of the provisions of this Act or the regulations if, in the opinion of the Minister, the exemption is necessary for a medical or scientific purpose or is otherwise in the public interest.” Interestingly, compounds found in ayahuasca are controlled substances under the Controlled Drugs and Substances Act, but the plants containing the substances are not. As an example, this is unlike cocaine, as both the plant itself, Erythroxylum coca, and the substance itself are both listed. A Canadian branch of the Brazilian Santo Daime church in Montreal, called the Céu do Montreal, sought an exemption from the Canadian Controlled Drugs and Substances Act in 2001, and in 2006, Health Canada in fact decided to authorize the church to import ayahuasca in the form of tea. Gabor Maté, a Canadian physician, researcher, speaker, and columnist in conjunction with group therapy in 2009 and 2010 at his multiple day “Working with Addiction and Stress” retreats, which included 4 days of group therapy and two expertled ayahuasca ceremonies. The team holding the retreat included ayahuasca ceremonial leaders from Peru and Canada (British Columbia), and the participants were from the general Canadian public. In this small study, data indicated reduced alcohol, tobacco and cocaine use from 6 months followup self-reports, but not for marijuana or opioids. As well, various validated scales pointed towards statistically significant improvements in hopefulness, empowerment, mindfulness, and quality of life. In November 2011, Health Canada determined that Dr. Maté should discontinue his retreats, and in October 2012, the Health Minister determined that ayahuasca use, even ceremonial, was not in the best interest of the public. Indeed, more and more people are feeling compelled to speak up on behalf of religious and ceremonial use of ayahuasca and to speak out against government drug policies that hinder scientific research of hallucinogenic substances, just as scientists did in a 1951 “Statement on Peyote” regarding the use of peyote by the Native American Church. In their “Statement on ayahuasca,” Anderson argue that current policies are not based on scientific evaluations and add that sensationalized media portrayals of ayahuasca as a street drug have not aided the cause.

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

tryptamines such as NMT can cause yellowing. The most common forms of DMT include: fumarate, freebase, citrate, acetate, hydrochloride. All of these forms are a crystallized compound, with different acids or bases used to bind the molecules together. Citrade, acetate, and hydrochloride are all DMT salts with a different acid used to produce the salt. These different forms require different methods of consumption. Deriving from decarboxylation of the biosynthetic precursor tryptophan via the aromatic L‐amino acid decarboxylase, tryptamine is subsequently N, N‐demethylated by indolethylamine‐N‐methyltransferase, S-adenosylmethionine serving as the methyl donor, ultimately leading to N‐ methyltryptamine (NMT) and DMT. DMT is structurally similar to melatonin and the neurotransmitter 5‐HT, the latter playing a pivotal role in the modulation of human mood and behaviour. While sharing the tryptamine core, DMT bears a particular feature, i.e., the N, N‐dimethyl moiety. The structural backbone is also similar to that of the triptan class of vasoconstrictors, clinically used to treat migraines and cluster headaches. Such structural similarity suggests that slight modifications to the DMT molecule can enable the development of synthetic analogues lacking hallucinogenic properties, but with potential therapeutic utility. On the other hand, minor modifications and/or substitutions frequently maintain a psychedelic ability as demonstrated by several serotonergic psychedelics, such as the 4‐substituted psilocybin and psilocin, 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeO‐DMT) and 5‐methoxy‐N,N‐diisopropyltryptamine (5‐MeO‐DIPT). DMT is a lipophilic molecule (logP 2.573) with a rather small structural backbone [molecular weight (MW) 188.27

g/mol].

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.

The metabolism and pharmacokinetics of DMT play a prominent role in how it is typically administered, as well as why it produces a qualitatively different experience than other psychedelics. First, the subjective effects of DMT administered to humans via IV injection are rapid and transient, peaking at 5 min and ceasing after 30 min. Similar effects are observed when DMT is smoked. Furthermore, only 1.8 and 0.16% of an injected dose of DMT can be measured in the blood and urine of humans, respectively, at any given time. A high brain: plasma ratio (ca. 2−6) is rapidly established following administration of DMT. In rats, the accumulation of DMT appears to be the greatest in the cortex and amygdala, brain structures that play key roles in the behavioral effects of the compound. In brain slices, DMT has been shown to accumulate via an active transport mechanism that is saturable, sensitive to metabolic inhibitors, and temperature-, glucose-, and sodium-dependent. In addition to quickly accessing brain tissue following systemic administration, DMT is rapidly metabolized by MAO-A as well as liver enzymes. The half-life of DMT in vivo is approximately 5−15 min and can be extended by treating with a MAO inhibitor. In fact, DMT is not orally active due to rapid degradation by MAO-A in the gut and liver. In the case of ayahuasca, the tisane can be ingested because it also contains MAO-A inhibitors like harmine, enabling sufficient amounts of orally administered DMT to reach the brain. Some of the major metabolites of DMT have been identified as indoleacetic acid, DMT-N-oxide, N-methyltryptamine, 2-methyl-1,2,3,4-tetrahydro-β-carboline, tryptamine and 1,2,3,4-tetrahydro-β-carboline. Callaway studied slow versus fast metabolizers and cytochrome P4502D6 (CYP2D6) variations in humans. The main isozymes involved in O-demethylation of harmaline into harmalol are CYP1A1, CYP1A2, and CYP2D6, while CYP1A1, CYP1A2, CYP2C9, CYP2C19, and CYP2D6 catalyze the O-methylation of harmine into harmol. These metabolites are then excreted as glucuronates and sulphates. Harmane may break down into harmine. Only one case report attempted to quantify and compare concentrations and amounts of harmine and harmaline in an ayahuasca infusion and urine; however, it was difficult to draw any conclusions given the amount of uncertainty surrounding the preparation and ingestion. Compared to DMT from ayahuasca, smoked, IV and insufflated DMT all have a very rapid onset of activity, with peak cognitive effects lasting 3-10 minutes and episodes 5-15 minutes. Ayahuasa produced a cognitive peak between 60 and 120 minutes and effects lasting approximately four hours. Recreational DMT users describe the experience as short, intense, and pleasurable. In addition, ayahuasca has somatic effects that

appear approximately 20 minutes after consumption, including nausea, tingling, and increased body temperature.
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.

Unmetabolized DMT reaching the brain interacts with various receptors, including a large number of serotonin receptors. This method is fast, simple, and produces DMT in reasonably high yields (ca. 70%) in a single step. However, if the stoichiometry of the acid, formaldehyde, and reducing agent are not carefully controlled, byproducts such as N-methyl-N-cyanomethyltryptamine, 2-methyltetrahydro-β-carboline, and tetrahydro-β-carboline can become an issue. These latter two compounds are often found as significant byproducts under reaction conditions where the initially formed iminium ion is not rapidly reduced, as this allows Pictet−Spengler cyclization to effectively compete with the reduction. The simplicity of the reductive amination protocol for producing DMT has made it incredibly popular; however, it requires the use of tryptamine and is not amenable to making diverse analogues. A variety of harmacological and genetic experiments has shown that many of DMT’s biological effects are mediated, at least in part, by the 5-HT2A, 5-HT1A, and 5-HT2C receptors, where it acts as an agonist or partial agonist depending on the specific assay. The interoceptive and hallucinogenic effects of DMT are believed to result primarily from agonism of the 5- HT2A receptor18 and are modulated by mGlu2/3 receptors. The effects of DMT on 5-HT2A receptor signaling are the best characterized. This Gq-coupled protein is found in many mammalian brain regions including the cortex, striatum, hippocampus, and amygdala, with particularly high expression on layer V pyramidal neurons of the cortex. DMT acts as an agonist of 5-HT2A receptors, causing an increase in phosphoinositide hydrolysis. Furthermore, DMT increases both the frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs) in layer V cortical pyramidal neurons, a phenomenon previously observed by Aghajanian and Marek upon stimulation of 5-HT2A receptors with serotonin. Structure−activity relationship (SAR) studies have demonstrated that the relatively small methyl groups of DMT are critical for achieving high affinity for the

5-HT2A receptor, as N-substituents larger than isopropyl drastically reduced 5-HT2A receptor affinity.

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

by an additional study demonstrating that DMT accumulates in brain slices via an active-transport mechanism. The binding affinity of DMT for dopamine receptors is quite low (Ki ≈ 5 μM) compared to ergolines such as LSD (Ki ≈ 20 nM). Furthermore, DMT does not stimulate dopamine sensitive adenylyl cyclase systems. At high doses of DMT (10 and 20 mg/kg) rats with unilateral 6-hydroxydopamine lesions engage in a weak ipsilateral turning behavior reminiscent of dopamine agonism, and at least one report has suggested that DMT increases dopamine synthesis, but this is controversial. Finally, pretreatment with a dopamine antagonist blocked DMT-induced hyperactivity in rats, leading the authors to conclude that the dopaminergic system was involved. However, these studies were completed prior to fully understanding the pharmacology of these compounds, including their effects on the serotonergic system. It is now appreciated that haloperidol, pimozide, and methiothepin, the three antipsychotics used in this study, also have affinity for a variety of serotonin receptors (including the 5-HT2A receptor). It is possible that serotonergic antagonism is responsible for their ability to block DMT-induced effects. The effects of DMT on the cholinergic system have been poorly studied. Administration of DMT to rats had no effect on the level of acetylcholine in the cortex, but did decrease its concentration in the corpus striatum. Decreases in acetylcholine concentrations are often observed when its rate of release is enhanced. As administration of 5-hydroxytryptophan (the precursor of serotonin) and a serotonergic neurotoxin leads to reduced and increased acetylcholine levels, respectively, it is likely that DMT stimulation of the serotonergic system mediates its effects on acetylcholine levels. Through second messenger systems, DMT can affect the rate of genetic transcription, such that DMT encodes the transcription factors c-fos, egr-1 and egr-2, which are associated with synaptic plasticity. Increases in expression of brain-derived neurotrophic factor (BDNF) are also observed after DMT administration. BDNF expression is associated with synaptic plasticity, cognitive process such as memory, modulation of efficacy and plasticity of synapses. As previously mentioned, DMT interacts with a variety of ionotropic and metabotropic receptors. The subjective effects of large doses of exogenous DMT are most likely mediated primarily by 5-HT2A receptors, with 5-HT2C receptors playing little or no role. mGlu2/3 receptors have significant modulatory effects, and the interaction of serotonergic and glutaminergic receptors may play a central role. DMT does not have direct effects on DA receptors, but indirectly alters the levels of dopamine, with resulting neurochemical and behavioral effects. Similarly, DMT also alters levels of acetylcholine. Finally, DMT may be an endogenous ligand at TAAR and sigma-1 receptors, but at the least, the effects of DMT at these receptors may play important physiological roles.​

DMT. Part II. Clinical effects, doses, studies​

Synthesis of DMT from indole (experimental)​

Synthesis 5-MeO-DMT from 5-MeO-Tryptamine​

Synthesis 5-Meo-Tryptamine from Melatonin​

Synthesis of 5‐MeO-DMT via Fischer Indole​