19 fev The clinical pharmacology and potential therapeutic applications of 5‐methoxy‐N,N‐dimethyltryptamine 5‐MeO‐DMT PMC
The high levels of DMT concentration found in vesicles are needed for various pharmacological actions including activation of sigma-1 receptors and TAARs as described below. Once uptake and storage of DMT has been completed, it can remained stored in vesicles for at least 1 week and can be released under appropriate stimuli (Vitale et al., 2011). Through these three steps, peripheral synthesis of DMT, consumption of DMT-containing plant matter, or systemic administration of DMT can influence central nervous system functions (Frecska et al., 2013). The enzymatic activity of INMT is closely regulated by endogenous inhibitors (Lin, 1974; Marzullo et al., 1977).
Future DMT receptor binding studies
This being the case, there is already a significant body of work regarding DMT’s binding and effects, especially relative to effects on serotonin, acting as a serotonergic modulator. Additional work in this area, while acknowledging DMT as an endogenous ligand, will prove essential. Changes in relevant metabolomic and array profiles following DMT administration will further add to our understanding of its endogenous role. A review by Barker in 2012 assessed 69 studies that reported endogenous DMT detection and quantities reported in urine (29 studies), blood (11 studies), and cerebrospinal fluid (4 studies) from 1955 – 2010 primarily comparing detection levels within healthy controls and schizophrenic patients.
1. Clinical effects
The authors reported significant modulation of serum BDNF by a single dose of ayahuasca, which suggests a link between the previously observed antidepressant effects of the psychedelic brew (de Almeida et al., 2019). Since the primary psychoactive component of ayahuasca is DMT, a close structural analog of 5‐MeO‐DMT, it is tempting to speculate that 5‐MeO‐DMT also has potential systemic BDNF‐modulatory and neuroplasticity‐promoting effects in humans. 5‐MeO‐DMT is known to induce intense mystical‐type or “peak” experiences as well as feelings of ego dissolution (Davis et al., 2018; alcohol and acute ischemic stroke onset Metzner, 2013; Ott, 2001; Shulgin & Shulgin, 1997a; Uthaug et al., 2018; Uthaug et al., 2019; Uthaug, Lancelotta, Szabo, et al., 2020). Reports of ego dissolution are often described as a sense of oneness with the universe or the experience of relaxed boundaries between the self and the world (Uthaug et al., 2018; Uthaug et al., 2019; Uthaug, Lancelotta, Szabo, et al., 2020). The 5‐MeO‐DMT experience contrasts with the DMT experience, as the latter is known to produce particularly vivid and complex visual imagery rather than marked ego dissolution (Barker, 2018).
What is a Psychological Dependence?
Taken together, these findings do not provide support that DMT is useful for treatment of anxiety and/or aggression. It has been proposed that DMT is an endogenous anxiolytic compound through its actions at the trace amino acid receptor (Jacob and Presti, 2005). To date, this hypothesis has generated little interest and DMT has been mostly investigated for its hallucinogenic effects. One early study did examine the effects of DMT in an animal model of anxiety/aggression in which pairs of rats receive shocks while in a test chamber. The shocks produce fighting and anti-anxiety compounds reduce the shock-induced fighting. LSD increased the amount of fighting, whereas DMT suppressed fighting (Walters et al., 1978).
2. Depression
Most studies to date focus on DMT (and most classic psychedelics) as a partial agonist of serotonin (5-HT) receptors, primarily the 1A, 2A, and 2C receptor subtypes, with predominant interest at 5-HT2A receptors. DMT binds 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7 receptors with affinities ranging from 39 nM to 2.1 μM (Keiser et al., 2009). The 5-HT2A receptor is thought to be the primary target of classic serotonergic-mediated psychedelic compounds, such as LSD, DOI, psilocin, and mescaline, although 5-HT1A and 5-HT2C receptors may also play some role (Aghajaian and Marek, 1999a, 1999b; review Nichols 2004). The 5-HT2A receptor is thought to be necessary, but not sufficient for hallucinogenic effects, and 5-HT2C and 5-HT1A receptors may play important roles as well (see review by Nichols, 2004). DMT interacts with a variety of serotonin receptors, but also with ionotropic and metabotropic glutamate receptors, dopamine, acetylcholine, TAAR, and sigma-1 receptors. Current information on the roles of these receptors in mediating the effects of DMT is reviewed in the following paragraphs.
The tryptamines also exhibited an effective blocking capacity at the level of adaptive immunity by inhibiting T helper cell 1 and 17 priming by 5‐MeO‐DMT and DMT‐treated moDCs. Furthermore, 5‐MeO‐DMT appeared to be slightly more potent than DMT with regard to its immunomodulatory potential, although the differences were only trending and not statistically significant. The observed anti‐inflammatory modulation was dominantly mediated by Sig1R, and partly by other receptors, most likely by 5‐HT2A (Szabo, 2015; Szabo et al., 2014). Furthermore, these findings are in good agreement with the results of our recent report on a small cohort of healthy volunteers, where a single dose of 5‐MeO‐DMT caused a rapid decrease in salivary IL‐6 levels (Uthaug, Lancelotta, Szabo, et al., 2020). In the same study, we did not observe any effect of 5‐MeO‐DMT on salivary IL‐1β and TNF‐α, most probably because of the study design that only allowed us to probe into early acute alterations.
Outpatient mental health and behavioral health care
DMT was detected in cerebrospinal fluid in 4 studies, which tested 136 individuals (82 patients). DMT can be detected as an endogenous compound in urine, blood, and cerebrospinal fluid. Even with inconsistent detection methods, DMT does not appear to be related to the onset of schizophrenia, since it seems to be detected more so in healthy controls compared to patients.
Despite these statistically significant differences, the overall mean scores on the mystical experiences subscales indicate that most respondents experienced these subjective effects at a strong intensity. We began the survey by describing the various types of 5-MeO-DMT (i.e., chemical/synthetic, toad venom, plant extract, yopo, other). We also asked respondents to report which of these types of 5-MeO-DMT they had ever used and with which type of 5-MeO-DMT they had the most experience. The survey also included items which asked about frequency of use, dose, and motives for using 5-MeO-DMT (e.g., recreation, spiritual exploration, healing from trauma, treatment how does alcohol affect blood pressure for addiction, treatment for depression, because my friends tried it). Improvements in mood in healthy volunteers and alleviation of psychiatric symptom severity in certain clinical populations after ingestion of 5‐MeO‐DMT are similar to results of observational and clinical studies assessing the therapeutic potential of the classic psychedelics psilocybin, LSD, and ayahuasca. As reviewed elsewhere (Vollenweider & Preller, 2020; Psiuk et al., 2021; Romeo et al., 2021) there is now a wealth of research demonstrating the safety of classic psychedelics, and a growing body of clinical work demonstrating their immediate and long‐lasting therapeutic efficacy.
- We came to better understand the common human experience of pain through examining the pharmacology of administered opiates and the subsequent discovery of endogenous opioid ligands, receptors and pathways that are predominantly responsible for and regulate the experience and perception of pain.
- Alongside the development of the drug, Beckley Psytech is also co‐developing a training program for therapists who will be assisting in future 5‐MeO‐DMT clinical trials (Carpenter, 2021).
- The study also showed that INMT response was “robust and punctuate” in the pineal gland.
- However, fundamental research will also be needed to increase understanding of the neurophysiological and neural mechanisms that contribute to the potential clinical effects of 5‐MeO‐DMT and its sustainability and dissemination over time.
- Around the internet, people have described bad DMT trips that have left them shaken for days.
- It is present in cohoba, a hallucinogenic drug derived from the seeds of Piptadenia peregrina.
Increased heart rate and blood pressure can be particularly dangerous if you already have high blood pressure or any kind of heart condition. You can also reach out to addiction recovery centers that offer in-person or out-of-office treatment options to help you get your substance use disorder under control. But there is concern over the effects it might have on heart health, since it raises blood pressure. Set is how you feel before you take the drug, what expectations you have, your previous experience with mind-altering drugs, any stress or anxiety you may be feeling.
Mean subscale scores of the Challenging Experiences Questionnaire, and proportion of sample experiencing each subjective effect reported on the CEQ across the total sample and each substance specific subsample. For further authoritative information on DMT’s effects on the brain, readers can refer to the study published in the Proceedings of the National Academy of Sciences and the historical overview of DMT provided by the National Institutes of Health. Keep in mind that patient confidentiality laws will prevent them from reporting this information to law enforcement. But people no longer have to spend thousands of dollars traveling to Peru or Ecuador to experiment with DMT.
Such studies are less likely to be conducted as part of drug development programs and are more likely to rely on independent, academic initiatives. However, systematic evidence of the therapeutic utility of 5‐MeO‐DMT is currently limited to anecdotal reports and observational studies in self‐selected healthy and clinical populations, who are using the drug in a natural environment (Lancelotta & Davis, 2020). As such, the current therapeutic potential of 5‐MeO‐DMT is mainly hypothetical (Ermakova et al., 2021) and based on preliminary evidence. As reviewed above, current therapeutic evidence stems from a small number of prospective observational studies and cross‐sectional surveys on the naturalistic use of synthetic 5‐MeO‐DMT and toad secretion containing 5‐MeO‐DMT in self‐selected samples. Findings of studies in self‐described healthy volunteers suggest immediate and lasting improvements in self‐reported feelings of depression, anxiety, stress, and satisfaction with life, after a single inhalation of the substance (Uthaug, Lancelotta, Szabo, et al., 2020; Uthaug et al., 2019).
This indicates that DMT is a substrate for the SERT transporter and provides a further mechanism for the neuronal accumulation of DMT. Newer data concerning INMT in specific brain areas (Cozzi et al., 2011) and its presence in perfusates of the pineal gland of living rats (Barker fatal fix: how an opioid overdose shuts down your body et al., 2013) add additional evidence for DMT’s potential role as a neurotransmitter. At a minimum, the anatomy, pharmacology and physiology of DMT have been sufficiently characterized and demonstrated to afford DMT the classification as a putative neurotransmitter.
This has been observed in studies assessing mental health outcomes using various psychological scales. Additionally, the setting in which DMT is used, including the person who uses mindset and environment, plays a significant role in its effects. Advanced brain imaging techniques, such as EEG-fMRI, have provided insights into how DMT affects brain function. Studies indicate that DMT alters brain activity, leading to vivid visions and a sense of entering other realities, similar to near-death experiences. The interaction of DMT with serotonin receptors, particularly the 5-HT2A receptor, is believed to play a critical role in its psychedelic effects. The compound’s influence on the brain is characterized by increased neural connectivity, which could explain the complex visual hallucinations and altered perception of reality users report.
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. 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. Despite the fact that 5-MeO-DMT use is illegal in the US and elsewhere, anecdotal reports indicate that consumption continues in a variety of underground ceremonial settings as a form of spiritual exploration (Psychedelic Times, 2016). Additionally, 5-MeO-DMT use continues among individuals who might purchase 5-MeO-DMT sold on the Internet or from other sources, extract 5-MeO-DMT from natural sources, for the purpose of spiritual exploration or recreation (Reddit, 2011). Published studies of human self-experiments describe a range of subjective effects of 5-MeO-DMT that vary depending on the dose and route of administration (Ott, 2001; Shulgin & Shulgin, 1997). Such effects include auditory, visual, and time perception distortions, emotional experiences, as well as memory impairment, with peak effects between 35–40 minutes after insufflation or within seconds-to-minutes when smoked (Ott, 2001; Shulgin & Shulgin, 1997).
However, there has yet to be any clear-cut or repeatable correlation of the presence or level of DMT in peripheral body fluids with any psychiatric diagnosis. Single doses of DMT produced rapid onset of marked sympathomimetic effects including increased heart rate and blood pressure (Strassman et al., 1994). 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).
Correlation analyses between pharmacokinetic data, routes of administration, biomarker levels, and psychotherapeutic potential will help to optimize clinical treatment modalities in patient populations, as well as to unveil the underlying bio‐psychological principles that contribute to healing. Potential mechanisms underlying positive mental health changes induced by psychedelics have been attributed to both the psychological psychedelic experience (Yaden & Griffiths, 2021) as well as the underlying neurophysiological mechanisms (Olson, 2021). Both perspectives, however, are not necessarily mutually exclusive when explaining the long‐term beneficial effects of psychedelics including 5‐MeO‐DMT.
This means that the drug is unsafe, has no recognized medical use, and has a high potential for abuse and addiction. DMT isn’t addictive in the same way opioids are addictive because it doesn’t lead to physical dependence, like other substances. However, it can lead to a psychological dependence or hallucinogen use disorder (HUD) and, potentially, full-blown addiction. However, it’s important to understand that psychedelic drugs like DMT can lead to harmful risks and addiction.