Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment

Abstract

Rationale 5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce. Objectives The first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1β), as well as the acute psychedelic experience. Methods Assessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA). Results 5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment. Conclusion Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,Ndimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.

Dose–response relationships of psilocybin-induced subjective experiences in humans

“…The Mystical scale on the MEQ30 was also less dose-dependent and showed smaller effect sizes compared with our results. Similarly, studies with DMT and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) report a largely comparable pattern of responses on both versions of the ASC rating scale ( Uthaug et al, 2020 ), MEQ30 ( Barsuglia et al, 2018 ) and HRS ( Gouzoulis-Mayfrank et al, 2005 ; Strassman et al, 1994 ). Nevertheless, the comparisons are limited by the small amount of available data, so the characterization of differences requires the utilization of standardized questionnaires in future research to establish dose–response profiles, which could then serve as a general reference to compare and infer subjective experiences.…”

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

“…Although ayahuasca has been shown to rapidly relieve depression symptoms in treatment-refractory depression in controlled clinical settings (Osório et al, 2015;Palhano-Fontes et al, 2019), the use of DMT and 5-MeO-DMT in naturalistic settings is receiving considerable attention given the rapid improvements elicited in several mental health domains accompanied by longlasting decreases in drug and alcohol use and abuse (Davis et al, 2019;Uthaug et al, 2019Uthaug et al, , 2020Garcia-Romeu et al, 2020). In vitro evidence supports the notion that 5-MeO-DMT might be beneficial for drug and alcohol addiction.…”

“…Accordingly, a single inhalation of 5-MeO-DMT decreases the levels of circulating IL6 (Uthaug et al, 2020). Such fast onset of anti-inflammatory effects is of particular interest and could be harnessed in psychiatry and other areas of emergency medicine-for example, in the treatment of systemic inflammatory response syndrome, also called the "cytokine storm" (Mastronardi et al, 2007;Tisoncik et al, 2012;Szabo et al, 2014Mastronardi et al, 2015;Inserra et al, 2019;Mehta et al, 2020;Uthaug et al, 2020). Given that in psychiatric disorders there is an imbalance in immune system equilibria, which are shifted toward proinflammatory responses, therapeutic approaches with the ability to shift this balance in favor of an enhancement of immunomodulatory and anti-inflammatory responses have long been sought in psychiatry (Pulendran, 2004;Myint et al, 2005;Gola et al, 2013;Alcocer-Gómez et al, 2014).…”

“…Similarly, in hypoxic stress-challenged neuronal and microglial cultures, DMT administration enhances cell survival and hypoxic stress-related neuroprotective signaling . Accordingly, a single inhalation of 5-MeO-DMT decreases the levels of circulating IL6 (Uthaug et al, 2020). Such fast onset of anti-inflammatory effects is of particular interest and could be harnessed in psychiatry and other areas of emergency medicine-for example, in the treatment of systemic inflammatory response syndrome, also called the "cytokine storm" (Mastronardi et al, 2007;Tisoncik et al, 2012;Szabo et al, 2014Mastronardi et al, 2015;Inserra et al, 2019;Mehta et al, 2020;Uthaug et al, 2020).…”

“…A preclinical study found that ayahuasca consumption during pregnancy and lactation results in decreased anxiety and decreased the interest for social interactions in the offspring, suggesting potential neuromodulatory effects in the fetus (de Oliveira et al, 2011). Inhalation of 5-MeO-DMT has been reported to occasion mystical experiences associated with almost immediate improvements in depression and anxiety scores with enduring positive effects (Davis et al, 2019) and decreased drug use (Garcia-Romeu et al, 2020;Uthaug et al, 2020). Lastly, a study investigating platelet SERT found an upregulation in long-term ayahuasca drinkers, suggesting that long-term psychedelic use might induce plasticity mechanisms in the serotonergic system, potentially as a result of the long-term potentiation effect of ayahuasca over serotonergic neurotransmission, 5-HT levels, and SERT (Callaway et al, 1994).…”