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Our understanding of tryptamines is poor due to the lack of data globally. Tryptamines currently are not part of typical toxicology testing regimens and their contribution to drug overdoses may be underestimated. Although their prevalence was low, it is increasing. There are few published data on the many new compounds, their mechanisms of action, onset and duration of action, toxicity, signs and symptoms of intoxication and analytical methods to identify tryptamines and their metabolites. We review the published literature and worldwide databases to describe the newest tryptamines, their toxicology, chemical structures and reported overdose cases. Tryptamines are 5-HT2A receptor agonists that produce altered perceptions of reality. Currently, the most prevalent tryptamines are 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DiPT), 5-methoxy-N,N- diallyltryptamine (5-MeO-DALT) and dimethyltryptamine (DMT). From 2015 to 2020, 22 new analytical methods were developed to identify/quantify tryptamines and metabolites in biological samples, primarily by liquid chromatography tandem mass spectrometry. The morbidity accompanying tryptamine intake is considerable and it is critical for clinicians and laboratorians to be informed of the latest data on this public health threat.

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.

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.

Rationale Despite the growing scientific interest on mitragynine, the primary alkaloid in kratom ( Mitragyna Speciosa ), there is a lack of clinical trials in humans. Objectives This phase 1 study aimed to evaluate mitragynine’s safety profile and acute effects on subjective drug experience, neurocognition, and pain tolerance. Methods A placebo-controlled, single-blind, within-subjects study was conducted in two parts. In part A, eight healthy human volunteers received placebo and three doses of mitragynine (5, 10, and 20 mg) in a sequential dosing scheme, on separate days. In part B, a second group of seven volunteers received placebo and 40 mg of mitragynine. Vital signs, subjective drug experience, neurocognitive function, and pain tolerance were measured at regular intervals for 7 h after administration. Results Overall, mitragynine did not affect most of the outcome measures at any dose. Yet, the lowest dose (5 mg) of mitragynine increased subjective ratings of arousal and attention, accuracy in a sustained attention task, and motor inhibition. The highest dose (40 mg) of mitragynine increased subjective ratings of amnesia and produced mild psychopathological symptoms. Mitragynine did not significantly affect vital signs, and only mild, transient side effects were reported. Conclusion The present study suggests that low doses (5–10 mg) of mitragynine may cause subjective feelings of stimulation and enhance attention, while the highest dose (40 mg) may cause inhibitory feelings of amnesia and distress. Mitragynine doses up to 40 mg were well tolerated in this group.

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

In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT 2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N , N -dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy- N , N -dimethyltryptamine (5-MeO-DMT) and 5-methoxy- N , N -diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

The last fifteen years have seen the emergence and overflow into the drug scene of \"superpotent\" N-benzylated phenethylamines belonging to the \"NBOMe\" series, accompanied by numerous research articles. Although N-benzyl substitution of 5-methoxytryptamine is known to increase its affinity and potency at 5-HT.sub.2 receptors associated with psychedelic activity, N-benzylated tryptamines have been studied much less than their phenethylamine analogs. To further our knowledge of the activity of N-benzyltryptamines, we have synthesized a family of tryptamine derivatives and, for comparison, a few 5-methoxytryptamine analogs with many different substitution patterns on the benzyl moiety, and subjected them to in vitro affinity and functional activity assays vs. the human 5-HT.sub.2 receptor subtypes. In the binding (radioligand displacement) studies some of these compounds exhibited only modest selectivity for either 5-HT.sub.2A or 5-HT.sub.2C receptors suggesting that a few of them, with affinities in the 10-100 nanomolar range for 5-HT.sub.2A receptors, might presumably be psychedelic. Unexpectedly, their functional (calcium mobilization) assays reflected very different trends. All of these compounds proved to be 5-HT.sub.2C receptor full agonists while most of them showed low efficacy at the 5-HT.sub.2A subtype. Furthermore, several showed moderate-to-strong preferences for activation of the 5-HT.sub.2C subtype at nanomolar concentrations. Thus, although some N-benzyltryptamines might be abuse-liable, others might represent new leads for the development of therapeutics for weight loss, erectile dysfunction, drug abuse, or schizophrenia.

Adhesive Dermally-Applied Microarray (ADAM) is a device for intracutaneous drug administration consisting of a 3 cm disposable array of drug-coated titanium microprojections on an adhesive backing. It is applied using a low cost, reusable, handheld applicator. Microprojections penetrate the stratum corneum, delivering drug proximal to capillaries with limited likelihood of pain. The pharmacokinetics of zolmitriptan delivery using ADAM was evaluated in 20 healthy volunteers. Median t was <20 min, comparable to subcutaneous sumatriptan. Absorption was faster than for oral zolmitriptan, with higher exposure in the first 2 h. Most adverse events were consistent with those seen in previous triptan trials. Application site reactions were generally mild and resolved within 24 h. ADAM zolmitriptan shows a promising pharmacokinetic profile for migraine treatment.

Calcitonin gene-related peptide (CGRP) probably has a role in migraine pathophysiology, and antagonism of its receptors might provide treatment without the vasoconstrictor effects of triptans. We aimed to assess the clinical profile of MK-0974 (telcagepant), an orally bioavailable antagonist of CGRP receptor. In a randomised, parallel-treatment, placebo-controlled, double-blind, trial at 81 sites in the Europe and the USA, adults with migraine diagnosed by International Headache Society criteria treated moderate or severe attacks with either oral telcagepant 150 mg or 300 mg, zolmitriptan 5 mg, or placebo. The five co-primary endpoints were pain freedom, pain relief, or absence of photophobia, phonophobia, or nausea at 2 h after treatment. Analysis was by the full analysis set and multiplicity was controlled for with a step-down closed-testing procedure. This trial is registered with ClinicalTrials.gov, number NCT00442936. 1380 patients were randomly assigned to receive telcagepant 150 mg (n=333) or 300 mg (354), zolmitriptan (345), or placebo (348). Telcagepant 300 mg was more effective than placebo for pain freedom (95 [27%] of 353 patients vs 33 [10%] of 343 [p<0·0001]), pain relief (194 [55%] of 353 vs 95 [28%] of 343 [p<0·0001]), and absences of phonophobia (204 [58%] of 353 vs 126 [37%] of 342 [p<0·0001]), photophobia (180 [51%] of 353 vs 99 [29%] of 342 [p<0·0001]), and nausea (229 [65%] of 352 vs 189 [55%] of 342 [p=0·0061]). Efficacy of telcagepant 300 mg and zolmitriptan 5 mg were much the same, and both were more effective than telcagepant 150 mg. Adverse events were recorded for 31% taking telcagepant 150 mg, 37% taking telcagepant 300 mg, 51% taking zolmitriptan 5 mg, and 32% taking placebo. Telcagepant 300 mg is effective as an acute treatment for migraine with efficacy comparable to that of zolmitriptan 5 mg, but with fewer associated adverse effects. Merck Research Laboratories.