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N,N -dimethyltryptamine (DMT) is a serotonergic psychedelic that is known for its short-lasting effects when administered intravenously. Several studies have investigated the administration of intravenous boluses or combinations of a bolus and a subsequent continuous infusion. However, data on dose-dependent acute effects and pharmacokinetics of continuous DMT infusions are lacking. We used a double-blind, randomized, placebo-controlled, crossover design in 22 healthy participants (11 women, 11 men) who received placebo and DMT (0.6, 1.2, 1.8, and 2.4 mg/min) over an infusion duration of 120 min. We also tested a self-guided titration scheme that allowed participants to adjust the DMT dose rate at prespecified time points to achieve their desired level of subjective effects. Outcome measures included subjective effects, autonomic effects, adverse effects, plasma hormone concentrations, and pharmacokinetics up to 3 h after starting the infusion. DMT infusions exhibited dose-proportional pharmacokinetics and rapidly induced dose-dependent subjective effects that reached a plateau after 30 min. A ceiling effect was observed for “good drug effect” at 1.8 mg/min. The 2.4 mg/min dose of DMT induced greater anxious ego dissolution than the 1.8 mg/min dose and induced significant anxiety compared with placebo. We observed moderate acute tolerance to acute effects of DMT. In the self-guided titration session, the participants opted for moderate to strong psychedelic effects, comparable in intensity to the 1.8 mg/min DMT dose rate in the randomized dosing sessions. These results may assist with dose finding for future DMT research and demonstrate that acute subjective effects of DMT can be rapidly adjusted through dose titration.

Studying transitions in and out of the altered state of consciousness caused by intravenous (IV) N,N-Dimethyltryptamine (DMT - a fast-acting tryptamine psychedelic) offers a safe and powerful means of advancing knowledge on the neurobiology of conscious states. Here we sought to investigate the effects of IV DMT on the power spectrum and signal diversity of human brain activity (6 female, 7 male) recorded via multivariate EEG, and plot relationships between subjective experience, brain activity and drug plasma concentrations across time. Compared with placebo, DMT markedly reduced oscillatory power in the alpha and beta bands and robustly increased spontaneous signal diversity. Time-referenced and neurophenomenological analyses revealed close relationships between changes in various aspects of subjective experience and changes in brain activity. Importantly, the emergence of oscillatory activity within the delta and theta frequency bands was found to correlate with the peak of the experience - particularly its eyes-closed visual component. These findings highlight marked changes in oscillatory activity and signal diversity with DMT that parallel broad and specific components of the subjective experience, thus advancing our understanding of the neurobiological underpinnings of immersive states of consciousness.

Background Tecfidera ® (dimethyl fumarate [DMF]) is an approved product for the treatment of relapsing forms of multiple sclerosis. Monomethyl fumarate (MMF) is the only active metabolite of DMF and is responsible for its therapeutic efficacy. Objective The objective of this study was to determine whether two Bafiertam™ capsules each containing 95 mg of MMF is bioequivalent to one Tecfidera ® capsule containing 240 mg of DMF, a prodrug of MMF. Methods This was a single-dose, open-label, randomized, two-way crossover study evaluating two treatments over two periods with a washout interval between treatments. Fifty healthy subjects were randomized to receive a single dose of the test drug MMF 190 mg as 2 × 95 mg delayed-release capsules or the reference drug DMF 240 mg as a 1 × 240-mg delayed-release capsule. Blood samples were obtained prior to dosing and at prespecified time points through 24 h post-dose to determine plasma concentrations of MMF. The pharmacokinetic parameters of MMF were calculated including maximum observed concentration, time to reach maximum observed concentration, apparent half-life of the drug in plasma, AUC 0– t which is the area under the plasma concentration–time curve (AUC) from time zero (dosing time) to the last time point, t , with measurable analyte concentration, and AUC 0–inf , which is AUC 0– t plus the extrapolated AUC from time t to infinity. Results The geometric least-squares mean ratios (90% confidence interval) of the test drug MMF vs the reference drug DMF were 96.80% (92.18–101.64), 96.35% (91.81–101.12), and 104.84% (95.54–115.05) for AUC 0– t , AUC 0–inf , and maximum observed concentration, respectively. Two capsules of Bafiertam™ was safe and generally well tolerated. The most common adverse event for both products was flushing, 60% and 51%, for Bafiertam™ and Tecfidera ® , respectively. Conclusions Based on the statistical analysis results of the pharmacokinetic parameters of MMF, a single oral dose of two Bafiertam™ DR 95 mg capsules is bioequivalent to a single oral dose of one Tecfidera ® DR 240 mg capsule. Clinical Trial Registration This study was retrospectively registered with ClinicalTrials.gov (NCT04570670) on 30 September, 2020.

Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT-induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e. travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.

The serotonergic psychedelic N,N‐dimethyltryptamine (DMT) presumably stimulates neuroplasticity in vitro and in vivo, by which it may exert neuroprotective effects during acute ischemic stroke. Since neuroplasticity has been implicated in the mechanism of action of rehabilitative therapy in stroke recovery, a pharmacological augmentation strategy facilitating neuroplasticity could be beneficial. To optimize this treatment strategy, a detailed understanding of the safety, pharmacokinetics, and pharmacodynamics of prolonged DMT administration is required. This randomized, double‐blind, placebo‐controlled, single ascending dose study administered three intravenous doses of DMT as a 30‐s bolus followed by a 6‐h infusion: 1.5 mg + 0.105 mg/min, 7.5 mg + 0.525 mg/min, and 5.0 mg + 0.7875 mg/min. Twelve female and seventeen male psychedelic‐experienced and naïve healthy participants, with a mean age of 27.3 (SD 10.2, range 19–57) years, were included. No serious adverse events occurred, and all adverse events were mild in intensity and self‐limiting. No significant abnormalities in vital signs or 12‐lead electrocardiography, and no suicidality or treatment‐emergent psychopathology occurred. Moderate interindividual pharmacokinetic variability was observed. Mild psychedelic effects were accompanied by decreases in sustained attention, postural stability, and occipital alpha electroencephalographic power at the highest dose, which peaked rapidly after bolus administration and remained relatively stable or decreased over time. Together, DMT administered intravenously as a 30‐s bolus followed by a 6‐h infusion and reaching maximal exposures of approximately 35 ng/mL in healthy volunteers was safe and demonstrated rapidly occurring but mild psychedelic effects, providing the basis for future proof‐of‐mechanism studies in patient populations. Trial Registration: ClinicalTrial.gov identifier: NCT05559931

Dimethyl fumarate (Tecfidera ® ) is approved for the treatment of relapsing forms of multiple sclerosis (MS). Based on evidence from the clinical trial and real-world settings, dimethyl fumarate is an effective treatment in this patient population, with benefits maintained over the longer term. In the pivotal, placebo-controlled phase III DEFINE and CONFIRM trials in adults with relapsing-remitting multiple sclerosis (RRMS), twice-daily dimethyl fumarate reduced clinical relapse and MRI measures of disease activity and improved some aspects of health-related quality of life (HR-QoL). Reduced disability progression was also observed with dimethyl fumarate in DEFINE. Results in predominantly East Asian patients (APEX trial) were reflective of those seen in DEFINE and CONFIRM. Dimethyl fumarate had an acceptable tolerability profile. The most common adverse events were flushing and gastrointestinal events, which were of mild or moderate severity and appear to be largely manageable. Thus twice-daily dimethyl fumarate remains an effective treatment option for use in patients with RRMS, with the convenience of oral administration.

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise. ClinicalTrials.gov Identifier: NCT05467631

Though clinical trials for medical applications of dimethyl sulfoxide (DMSO) reported toxicity in the 1960s, later, the FDA classified DMSO in the safest solvent category. DMSO became widely used in many biomedical fields and biological effects were overlooked. Meanwhile, biomedical science has evolved towards sensitive high-throughput techniques and new research areas, including epigenomics and microRNAs. Considering its wide use, especially for cryopreservation and in vitro assays, we evaluated biological effect of DMSO using these technological innovations. We exposed 3D cardiac and hepatic microtissues to medium with or without 0.1% DMSO and analyzed the transcriptome, proteome and DNA methylation profiles. In both tissue types, transcriptome analysis detected >2000 differentially expressed genes affecting similar biological processes, thereby indicating consistent cross-organ actions of DMSO. Furthermore, microRNA analysis revealed large-scale deregulations of cardiac microRNAs and smaller, though still massive, effects in hepatic microtissues. Genome-wide methylation patterns also revealed tissue-specificity. While hepatic microtissues demonstrated non-significant changes, findings from cardiac microtissues suggested disruption of DNA methylation mechanisms leading to genome-wide changes. The extreme changes in microRNAs and alterations in the epigenetic landscape indicate that DMSO is not inert. Its use should be reconsidered, especially for cryopreservation of embryos and oocytes, since it may impact embryonic development.

Dimethyl sulfide (DMS), dimethylsulfoniopropionate (DMSP) and dimethyl sulfoxide (DMSO) were measured at the Boknis Eck Time Series Station (BE, Eckernförde Bay, SW Baltic Sea) during the period February 2009-December 2018. Our results show considerable interannual and seasonal variabilities in the mixed-layer concentrations of DMS, total DMSP (DMSP.sub.t) and total DMSO (DMSO.sub.t). Positive correlations were found between particulate DMSP (DMSP.sub.p) and particulate DMSO (DMSO.sub.p) as well as DMSP.sub.t and DMSO.sub.t in the mixed layer, suggesting a similar source for both compounds. The decreasing long-term trends, observed for DMSP.sub.t and DMS in the mixed layer, were linked to the concurrent trend of the sum of 19.sup.' -hexanoyloxyfucoxanthin and 19.sup.' -butanoyloxy-fucoxanthin, which are the marker pigments of prymnesiophytes and chrysophytes, respectively. Major Baltic inflow (MBI) events influenced the distribution of sulfur compounds due to phytoplankton community changes, and sediment might be a potential source for DMS in the bottom layer during seasonal hypoxia/anoxia at BE. A modified algorithm based on the phytoplankton pigments reproduces the DMSP.sub.p : Chl a ratios well during this study and could be used to estimate future surface (5 m) DMSP.sub.p concentrations at BE.

Objective Neuroinflammation is an important pathogenic mechanism in amyotrophic lateral sclerosis (ALS), with regulatory T cells (Tregs) mediating a slower rate of disease progression. Dimethyl fumarate enhances Treg levels and suppresses pro‐inflammatory T cells. The present study assessed the safety and efficacy of dimethyl fumarate in ALS. Methods Phase‐2, double‐blind, placebo‐controlled randomised clinical trial recruited participants from May 1, 2018 to September 25, 2019, across six Australian sites. Participants were randomised (2:1 ratio) to dimethyl fumarate (480 mg/day) or matching placebo, completing visits at screening, baseline, weeks 12, 24 and 36. The primary efficacy endpoint was a change in Amyotrophic Lateral Sclerosis Functional Rating Scale‐Revised (ALSFRS‐R) at week 36. Secondary outcome measures included survival, neurophysiological index (NI), respiratory function, urinary neurotrophin‐receptor p75 and quality of life. Results A total of 107 participants were randomised to dimethyl fumarate (n = 72) or placebo (n = 35). ALSFRS‐R score was not significantly different at week 36 (−1.12 [−3.75 to 1.52, p = 0.41]). Dimethyl fumarate was associated with a reduced NI decline week 36 (differences in the least‐squares mean: (0.84 [−0.51 to 2.22, p = 0.22]). There were no significant differences in other secondary outcome measures. Safety profiles were comparable between groups. Interpretation Dimethyl fumarate, in combination with riluzole, was safe and well‐tolerated in ALS. There was no significant improvement in the primary endpoint. The trial provides class I evidence for safety and lack of efficacy of dimethyl fumarate in ALS.