ReviewNeuropharmacology of N,N-dimethyltryptamine
Introduction
N,N-dimethyltryptamine (DMT) is an indole alkaloid widely found in nature. It is an endogenous compound in animals (Saavedra and Axelrod, 1972, Christian et al., 1977, Hollister, 1977) and in a wide variety of plants found around the globe. Major plant genera containing DMT include Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria, but DMT has been found even in apparently innocuous sources, such as leaves of citrus plants (Servillo et al., 2012), and in the leaves, seeds, and inner bark of mimosa tenuiflora, which has become a source of livestock poisoning (Gaujac et al., 2012).
DMT has become of interest because when ingested, it causes brief, episodic visual hallucinations at high concentrations (Stoff et al., 1977, Strassman and Qualls, 1994, Strassman et al., 1994a, Strassman et al., 1994b, Shulgin and Shulgin, 1997). DMT is one of the major psychoactive compounds found in various shamanistic compounds (e.g., ayahuasca, hoasca, yagé) used in South America for centuries (Pochettino et al., 1999) and has, more recently found its way into Europe and North America as a recreational drug (Tupper, 2008).
Most hallucinogens such as lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4- methylamphetamine (DOM) cause sensory distortion, depersonalization at high doses, and at least one (N,N-diisopropyltryptamine, DiPT) causes auditory distortions, whereas some compounds such as DMT (found in ayahuasca), psilocybin (mushrooms) or mescaline (peyote) cause episodic visual effects. In the late 1990s, Rick Strassman conducted the first human research with hallucinogens in 20 years, examining the physiological effects and self-reports from people receiving DMT in carefully controlled settings (Strassman et al., 1994a, Strassman et al., 1994b, Strassman et al., 1996). A book describing these results was published in the popular press (Strassman, 2001). Strassman concluded that DMT is a powerful tool for self-discovery and understanding consciousness, which may have helped to drive interest in recreational use of DMT and related tryptamine hallucinogens. In recent years, recreational use of DMT has been increasing; for example, Cakic et al., (2010) reported that 31% of recreational DMT users endorse psychotherapeutic benefits as the main reason for consumption. Similar to ayahuasca, recreational users have made similar concoctions referred to as pharmahuasca. These are of capsules containing free-base DMT and some monoamine oxidase inhibitors (MAOI) such as synthetic harmaline (Ott, 1999) or Syrian Rue (rich in beta-carbolines; Brierley and Davidson, 2012).
It is unclear what proportion of users of hallucinogenic tryptamines has adverse events serious enough for hospitalization, but it seems that the synthetic hallucinogenic compounds, such as 25I-NBOMe may be more dangerous than the plant-derived compounds (Hill et al., 2013, Lowe et al., 2015). Databases derived from Poison Control and Emergency Department visits (via the Drug Abuse Warning Network) only sparing differentiate between hallucinogenic compounds taken and lack adequate records of DMT-specific cases. Street drugs mostly contain powdered DMT, whereas ayahuasca also contains harmine-related compounds, which limit toxic effects (Lanaro et al., 2015). However, aside from the acute cardiovascular effects there have been no consistent reports of toxic effects of long-term use of DMT in the literature. In fact, there has been a report that DMT is neuroprotective (Frecska, 2008). Without more data on the recreational use of this class of compounds, it is not possible to conclude whether the synthetic hallucinogens are indeed more toxic or whether the social context may contribute to the effects.
It is likely that most adverse effects of hallucinogens are psychological effects, such as intense fear, paranoia, anxiety, grief, and depression, that can result in putting the user or others in physical harm or danger (Carbonaro et al., submitted). Anecdotal reports describe psychologically challenging experiences with DMT and other psychedelic compounds. The rates of occurrence for these effects have not been properly accounted for. However, in the case of psilocybin, about 30% of laboratory experiences include psychologically challenging experiences (Carbonaro et al., submitted). Even though DMT may not produce physical toxicity, severe psychological adverse effects can occur.
Although widespread biological presence of DMT is acknowledged, the biological function of DMT remains a mystery. DMT is found in low concentrations in brain tissue (Saavedra and Axelrod, 1972, Christian et al., 1977, Hollister, 1977). DMT concentrations can be localized and elevated in certain instances, for example, DMT production increases in rodent brain under stress (Barker et al., 1981). Formerly, endogenous DMT was thought to exist at concentrations too low to produce pharmacological effects, but two discoveries changed that. First, trace amine-associated receptors (TAAR) are activated by DMT and other molecules (Bunzow et al., 2001) and second, DMT can be locally sequestered in neurotransmitter storage vesicles at pharmacologically relevant concentrations, thereby being able to active other pharmacological receptors, e.g. serotonin (Nagai et al., 2007, Cozzi et al., 2009). These findings suggest that DMT may have a role in normal physiological and/or psychopathology. What that role may be has not yet been established.
Although the serotonin system has been thought to be the main contributor to the psychedelic effects of DMT, other behavioral effects have been observed which do not involve the serotonin or other monoaminergic systems; such as jerking, retropulsion, and tremors (Deliganis et al., 1991, Jenner et al., 1980). In addition, molecular effects of DMT have been identified that are not mediated by serotonin receptors. For example, DMT-enhanced phosphatidylinositol production is not blocked by 5-HT2A receptor antagonists (i.e., ketanserin; Deliganis et al., 1991). More recent hypotheses for molecular roles of endogenous DMT have developed over the last decade, and include the potential involvement of TAAR (mentioned above) and sigma-1 receptors. Interactions of both TAAR and sigma-1 receptors will be discussed in detail in subsequent sections.
There has been a great deal of speculation about the role of DMT in naturally occurring altered states of consciousness, such as psychosis, dreams, creativity, imagination, religious and/or spiritual phenomena, and near-death experiences (Callaway, 1988, Strassman, 2001). Additionally, DMT may play a role in waking reality (Wallach, 2009). Waking reality is created in a similar way to altered states except that the normal state correlates with event in the “physical” world. Thus, waking reality can be thought of as a tightly regulated psychedelic experience and altered states arise when this regulation is loosened in some fashion. This model predicts that the sensory-altering effects of administered psychedelics are a result of the compound acting directly via neuropharmacological mechanisms in regions of the CNS involved in sensory perception. More simply, DMT may potentially act as a neurotransmitter to exert a signaling function in regions of the CNS, which are involved in sensory perception (Wallach, 2009).
Other theories propose that DMT may be important in psychiatric disorders. Data from early studies of DMT suggested that DMT may be a schizotoxin, and various authors hypothesized that DMT was a key factor in causing schizophrenia (Osmond and Smythies, 1952, Gillin et al., 1976, reviewed by Szára, 2007). This hypothesis is no longer accepted, but it is still thought that DMT may play a role in psychotic symptoms (Daumann et al., 2010, Warren et al., 2013). Similarly, DMT was thought to be neurotoxic, but more recent research suggests that DMT may actually be neuroprotective (Frecska et al., 2013).
More recently, Jacob and Presti (2005) proposed that endogenous DMT may have an anxiolytic role based on the reported subjective effects of DMT administered in low doses, which would result comparable concentrations and biological actions to those of endogenous DMT. Sensory alterations commonly described by people taking DMT occur only when relatively high concentrations of DMT are administered. These high concentrations are similar to those observed in the synapse when endogenous DMT is released (review, Wallach, 2009).
The putative roles of DMT will be explored in more detail in subsequent sections of this review. The review will begin by addressing the basic mechanisms of action of DMT, both pharmacokinetic and pharmacodynamic. It will then examine evidence regarding the neuropharmacological effects of DMT, from both behavioral studies of the exogenous effects of DMT, and from molecular studies of sites of action of endogenous DMT. Next, the review will turn to the use of DMT both as a model for various disorders and the use of DMT to treat some of these disorders. The review will conclude with the effects of DMT on other organ systems besides the central nervous system.
Section snippets
Pharmacokinetics of DMT
Intravenous administration of radio-labeled DMT in rabbits produces entry into the brain within 10 s and excretion via the kidneys, such that no traces of DMT or metabolite was measured in urine 24 h post administration. However, DMT could still be detected at 2 and 7 days (0.1% of initial dose) post administration (Vitale et al., 2011). In the same study, tryptamine was eliminated within 10 min. These findings show that even after complete clearance of a dose of DMT from the blood, DMT is still
Clinical effects
Oral dosing of DMT via ayahuasca produces both behavioral and neurochemical effects, such as decreases in motor activity (Pic-Taylor et al., 2015), impairment of cognitive function (Alonso et al., 2015, Bouso et al., 2013), sympathomimetic effects, increased prolactin and cortisol levels, and decreased lymphocytes increased natural killer cells (Dos Santos et al., 2011). Doses of ayahuasca 15 or 30-fold higher than commonly used ritual doses increased serotonergic neurotransmission (Pic-Taylor
DMT as a model of psychiatric disorders
There has been a revival of interest in clinical uses of hallucinogens. Among the first were a series of controlled clinical studies on DMT (Strassman et al., 1994a, Strassman et al., 1994b, Strassman et al., 1996). Those studies reported that pure DMT had rapid and extremely strong cardiovascular effects as well as profound psychological effects. The cardiovascular effects preclude the use of pure DMT; however, ayahuasca and other DMT-containing ritual beverages seem to be less toxic while
Cardiovascular system
Single doses of DMT produced rapid onset of marked sympathomimetic effects including increased heart rate and blood pressure (Strassman et al., 1994a, Strassman et al., 1994b). When a 5-HT1A antagonist, pindolol, was co-administered with DMT, the increase in heart rate was diminished whereas the increase in blood pressure was enhanced (Strassman, 1996). Tolerance to the effects of DMT was tested by administration of DMT to human volunteers four times at 30-min intervals. A progressive decrease
Summary and conclusions
DMT is a compound found widely across the plant and animal kingdoms. In mammals, the psychoactive effects produced by DMT seem to be largely mediated by the 5-HT2AR, although the complex subjective effects reported by DMT users are likely modulated by other receptor systems such as the metabotropic glutamate receptors.
The wide use of DMT in the form of ayahuasca for many years has led to a number of studies focusing on adverse health effects or potential benefits of ayahuasca use. There have
Acknowledgement
Funding was provided by the Addiction Treatment Discovery Program of the National Institute on Drug Abuse (NIH N01DA-13-8908).
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