Neurochemical and Neurophysiological Effects of Intravenous Administration of N,N-dimethyltryptamine in Rats.

N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is being investigated clinically for the treatment of psychiatric disorders. Although the neurophysiological effects of DMT in humans are well-characterized, similar studies in animal models as well as data on the neurochemical effects of DMT are generally lacking, which are critical for mechanistic understanding. In the current study, we combined behavioral analysis, high-density (32-channel) electroencephalography, and ultra-high-performance liquid chromatography-tandem mass spectrometry to simultaneously quantify changes in behavior, cortical neural dynamics, and levels of 17 neurochemicals in medial prefrontal and somatosensory cortices before, during, and after intravenous administration of three different doses of DMT (0.75 mg/kg, 3.75 mg/kg, 7.5 mg/kg) in male and female adult rats. All three doses of DMT produced head twitch response with most twitches observed after the low dose. DMT caused dose-dependent increases in serotonin and dopamine levels in both cortical sites along with a reduction in EEG spectral power in theta (4-10 Hz) and low gamma (25-55 Hz), and increase in power in delta (1-4 Hz), medium gamma (65-115), and high gamma (125-155 Hz) bands. Functional connectivity decreased in the delta band and increased across the gamma bands. In addition, we provide the first measurements of endogenous DMT in these cortical sites at levels comparable to serotonin and dopamine, which together with a previous study in occipital cortex, suggests a physiological role for endogenous DMT. This study represents one of the most comprehensive characterizations of psychedelic drug action in rats and the first to be conducted with DMT.

Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey.

Introduction: Recent research suggests that psychedelics may have potential for the treatment of various substance use disorders. However, most studies to date have been limited by small sample sizes and neglecting to include non-North American and European populations. Methods: We conducted a global, cross-sectional online survey of adults (n = 5,268, 47.2% women) self-reporting past or current psychedelic use and investigated whether psychedelic use was associated with changes in use of other substances. Results: Nearly three-quarters (70.9%; n = 3,737/5,268) reported ceasing or decreasing use of one or more non-psychedelic substances after naturalistic psychedelic use. Among those with previous use, 60.6% (n = 2,634/4,344) decreased alcohol use, 55.7% (n = 1,223/2,197) decreased antidepressant use, and 54.2% (n = 767/1,415) decreased use of cocaine/crack. Over a quarter of the sample indicated that their decrease in substance use persisted for 26 weeks or more following use of a psychedelic. Factors associated with decreased use included a motivation to either decrease one's substance use or self-treat a medical condition. Importantly, 19.8% of respondents also reported increased or initiated use of one or more other substances after psychedelic use, with illicit opioids (14.7%; n = 86/584) and cannabis (13.3%; n = 540/4,064) having the highest proportions. Factors associated with increased substance use included having a higher income and residing in Canada or the US. Discussion: Although limited by cross-sectional study design, this large observational study will help inform future studies aiming to investigate the relationship between substance use patterns and psychedelic use.

The Relationship Between Naturalistic Psychedelic Use and Clinical Care in Canada.

Naturalistic psychedelic use among Canadians is common. However, interactions about psychedelic use between patients and clinicians in Canada remain unclear. Via an anonymous survey, we assessed health outcomes and integration of psychedelic use with health care providers (HCP) among Canadian adults reporting past use of a psychedelic. The survey included 2,384 participants, and most (81.2%) never discussed psychedelic use with their HCP. While 33.7% used psychedelics to self-treat a health condition, only 4.4% used psychedelics with a therapist and 3.6% in a clinical setting. Overall, 44.8% (n = 806) of participants were aware of substance testing services, but only 42.4% ever used them. Multivariate regressions revealed that therapeutic motivation, higher likelihood of seeking therapist guidance, and non-binary gender identification were significantly associated with higher odds of discussing psychedelics with one's primary HCP. Having used a greater number of psychedelics, lower age, non-female gender, higher education, and a therapeutic motivation were significantly associated with higher odds of awareness of substance testing. We conclude that naturalistic psychedelic use in Canada often includes therapeutic goals but is poorly connected to conventional healthcare, and substance testing is uncommon. Relevant training and education for HCPs is needed, along with more visible options for substance testing.

Indolethylamine N-methyltransferase (INMT) is not essential for endogenous tryptamine-dependent methylation activity in rats.

Indolethylamine N-methyltransferase (INMT) is a transmethylation enzyme that utilizes the methyl donor S-adenosyl-L-methionine to transfer methyl groups to amino groups of small molecule acceptor compounds. INMT is best known for its role in the biosynthesis of N,N-Dimethyltryptamine (DMT), a psychedelic compound found in mammalian brain and other tissues. In mammals, biosynthesis of DMT is thought to occur via the double methylation of tryptamine, where INMT first catalyzes the biosynthesis of N-methyltryptamine (NMT) and then DMT. However, it is unknown whether INMT is necessary for the biosynthesis of endogenous DMT. To test this, we generated a novel INMT-knockout rat model and studied tryptamine methylation using radiometric enzyme assays, thin-layer chromatography, and ultra-high-performance liquid chromatography tandem mass spectrometry. We also studied tryptamine methylation in recombinant rat, rabbit, and human INMT. We report that brain and lung tissues from both wild type and INMT-knockout rats show equal levels of tryptamine-dependent activity, but that the enzymatic products are neither NMT nor DMT. In addition, rat INMT was not sufficient for NMT or DMT biosynthesis. These results suggest an alternative enzymatic pathway for DMT biosynthesis in rats. This work motivates the investigation of novel pathways for endogenous DMT biosynthesis in mammals.

An Assessment of Psychedelic Knowledge Among People Using Psychedelics Naturalistically.

Identifying gaps and strengths in psychedelic-related knowledge is key to developing effective, evidence-based education to inform appropriate use of and harm reduction practices for psychedelics in the naturalistic use landscape. The current study piloted an assessment instrument with questions on legal status, therapeutic potential, and side effects of psychedelics among people reporting current psychedelic use. We recruited participants (N = 1435) at a psychedelic advocacy event and through psychedelic interest groups on social media. Respondents completed a brief survey of psychedelic use and psychedelic knowledge. Items assessed basic knowledge of various topics surrounding psychedelics, such as legal status, active compounds, and known therapeutic efficacy based on the clinical trial literature. Respondents who had used greater numbers of different psychedelics, with higher levels of education, lower age, greater frequency of psychedelic use, identifying as male, used high doses (vs. microdosing only), identifying as Caucasian/White, and with greater annual household income answered more questions correctly. Most respondents exhibited high knowledge of psychedelics, though there is also a demonstrated need for education and outreach, especially in under-represented communities.

Naturalistic Psychedelic Use: A World Apart from Clinical Care.

Interest in and availability of psychedelics for therapeutic purposes has increased in recent decades. In a large, anonymous, online survey, we investigated patterns of communication with healthcare providers and awareness and utilization of substance testing kits or services among people using psychedelics naturalistically. The sample population included attendees of a psychedelic activism event and users of psychedelic social media forums. Among 1,435 participants, 72.5% never discussed psychedelic use with their primary care provider (PCP). Only 4.4% reported using psychedelics with a therapist and 3% in clinical settings, although 77.8% were very or extremely likely to take psychedelics with a therapist if one were legally available. While 62.6% of participants were aware of substance testing services, 42.6% of these indicated never using them. Regression analyses identified several variables associated with disclosure to PCP and utilization of substance testing services including age, gender, frequency and number of psychedelics used, and likelihood of consuming psychedelics under the guidance of a therapist if one were legally available. Further research is necessary to investigate these findings among other groups. Our findings suggest that relevant training and education for healthcare providers is needed, along with more visible options for substance identity testing.

Knowledge, Perceptions, and Use of Psychedelics among Individuals with Fibromyalgia.

Fibromyalgia (FM) is a difficult to treat chronic pain condition for which there is strong interest in alternative treatments. There is growing interest in the potential of psychedelic substances (e.g., psilocybin) in conjunction with psychotherapy to treat chronic pain. Via a cross-sectional, anonymous, online survey, we aimed to characterize knowledge, perceptions, and past use of serotonergic ("classic") and non-serotonergic psychedelics among a population of individuals with FM, and to investigate interest in psychedelic-based FM treatments. Among a North American population of 354 participants with FM, 29.9% reported past use of a psychedelic, with lysergic acid diethylamide (LSD) and psilocybin mushrooms being most commonly used. Perceptions of benefit from psychedelic use were generally neutral (59.4%) or positive (36.8%), with <3% reporting negative impacts on overall health or pain symptoms. Among 12 participants who used psychedelics with intentions of treating chronic pain, 11 reported improved symptoms. Regardless of past use, the majority of participants believed that psychedelics have potential for chronic pain treatments and would be willing to participate in a psychedelic-based clinical trial for their pain. These findings support the need for additional studies to understand the potential and effectiveness of psychedelic substances in managing FM symptoms.