![A-C. The PET images and anatomical transaxial section of the same plain in the dog brain. A [liC]DMT. The PET image was obtained for 32-42 min after the injection. B 45Ti-DTPA. C Anatomical section](https://www.researchgate.net/profile/Kiichi-Ishiwata/publication/226047139/figure/fig1/AS:337155051278337@1457395436353/A-C-The-PET-images-and-anatomical-transaxial-section-of-the-same-plain-in-the-dog-brain_Q320.jpg)
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In vivo kinetics and displacement study of a carbon-11-labeled hallucinogen, N,N-[11C]dimethyltryptamine
Abstract and Figures
The endogenous hallucinogen, N,N-dimethyltryptamine (DMT), was labeled with carbon-11 and its regional distribution in rat brain studied. [11C]DMT showed higher accumulation in the cerebral cortex, caudate putamen, and amygdaloid nuclei. Studies of the subcellular distribution of [11C]DMT revealed the specific localization in the fractions enriched with serotonin receptors only when a very low dose was injected into rats. The proportions of the radioactivity in receptor-rich fractions were greatly enhanced by pretreatment with the monoamine oxidase inhibitor, pargyline. Specific binding of [11C]DMT to serotonin receptors in dog brain was demonstrated by a positron emission tomographic study in which 5-methoxy-N,N-dimethyltryptamine caused approximately 20% displacement of the radioligand from the receptors.
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... GBq/μmol. 110 3.7.2. Preclinical Studies. ...
... 90 N,N-[N-Methyl- 11 C]dimethyltryptamine accumulated in the cerebral cortex, caudate-putamen, and amygdaloid nuclei, with traces also in the cerebellum and medulla oblongata. 110 In dog brain, a displacement study with O-methylbufotenine revealed a substantial reduction in posterior cerebral cortex uptake, while a sharp decrease affected basal ganglia and frontal cortex, correlating well with the distribution and density of serotonin receptors. 110 ...
... 110 In dog brain, a displacement study with O-methylbufotenine revealed a substantial reduction in posterior cerebral cortex uptake, while a sharp decrease affected basal ganglia and frontal cortex, correlating well with the distribution and density of serotonin receptors. 110 ...
The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.
... Although we are not aware of an investigation regarding the precise mechanism by which this accomplished, it is possible that the Organic Cation Transporter (OTC) family of transporters is involved, since it can transport other closely related monoamines, such as serotonin [93]. This is corroborated to happen given the results from studies that verified the accumulation of DMT and other tryptamines in the brain after peripheral administration [91,[94][95][96]. It has been shown that DMT promptly enters the CNS and is kept there after excretion in urine has stopped (24 hours), being detected up to 7 days after administration [97]. ...
Ayahuasca is a psychoactive brew traditionally used in indigenous and religious rituals and ceremonies in South America for its therapeutic, psychedelic, and entheogenic effects. It is usually prepared by lengthy boiling of the leaves of the bush Psychotria viridis and the mashed stalks of the vine Banisteriopsis caapi in water. The former contains the classical psychedelic N,N-dimethyltryptamine (DMT), which is thought to be the main psychoactive alkaloid present in the brew. The latter serves as a source for β-carbolines, known for their monoamine oxidase-inhibiting (MAOI) properties. Recent preliminary research has provided encouraging results investigating ayahuasca’s therapeutic potential, especially regarding its antidepressant effects. On a molecular level, pre-clinical and clinical evidence points to a complex pharmacological profile conveyed by the brew, including modulation of serotoninergic, glutamatergic, dopaminergic, and endocannabinoid systems. Its substances also interact with the vesicular monoamine transporter (VMAT), trace amine-associated receptor 1 (TAAR1), and sigma-1 receptors. Furthermore, ayahuasca’s components also seem to modulate levels of inflammatory and neurotrophic factors beneficially. On a biological level, this translates into neuroprotective and neuroplastic effects. Here we review the current knowledge regarding these molecular interactions and how they relate to the possible antidepressant effects ayahuasca seems to produce.
... The suggestion that DMT predominantly achieved SD inhibition by Sig-1R activationrather than through 5-HTR binding (Yanai et al., 1986;Deliganis et al., 1991) is also substantiated by our finding that DMT counteracted the SD potentiating effect of asenapine (Fig. 3), an antagonist of multiple 5-HTRs . In other words, when 5-HTRs were occupied by asenapine, DMT still reduced SD amplitude with respect to the condition when asenapine was given alone. ...
Dimethyltryptamine (DMT), an endogenous ligand of sigma-1 receptors (Sig-1Rs), acts against systemic hypoxia, but whether DMT may prevent cerebral ischemic injury is unexplored. Here global forebrain ischemia was created in anesthetized rats and aggravated with the induction of spreading depolarizations (SDs) and subsequent short hypoxia before reperfusion. Drugs (DMT, the selective Sig-1R agonist PRE-084, the Sig-1R antagonist NE-100, or the serotonin receptor antagonist asenapine) were administered intravenously alone or in combination while physiological variables and local field potential from the cerebral cortex was recorded. Neuroprotection and the cellular localization of Sig-1R were evaluated with immunocytochemistry. Plasma and brain DMT content was measured by 2D-LC-HRMS/MS. The affinity of drugs for cerebral Sig-1R was evaluated with a radioligand binding assay. Both DMT and PRE-084 mitigated SDs, counteracted with NE-100. Further, DMT attenuated SD when co-administered with asenapine, compared to asenapine alone. DMT reduced the number of apoptotic and ferroptotic cells and supported astrocyte survival. The binding affinity of DMT to Sig-1R matched previously reported values. Sig-1Rs were associated with the perinuclear cytoplasm of neurons, astrocytes and microglia, and with glial processes. According to these data, DMT may be considered as adjuvant pharmacological therapy in the management of acute cerebral ischemia.
... 28 However, most psychoplastogens are rapidly cleared from the body (i.e., they have half-lives of several hours), 40,41 with compounds such as N,N-dimethyltryptamine (DMT) and 5-MeO-DMT having half-lives less than 15 min. 42,43 To determine the shortest period of stimulation necessary to induce neuronal growth, we treated DIV3 cortical cultures with either ketamine or LSD for varying lengths of time, removed the drug, and let the cultures mature until DIV6 ( Figure 1A). Remarkably, both drugs were able to robustly increase dendritic arbor complexity after only 15 min of stimulation ( Figure 1D), while exogenous BDNF (50 ng/mL) required a full hour to produce effects ( Figure S1A). ...
Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.
N,N-Dimethyltryptamine (DMT) is a naturally occurring amine and psychedelic compound, found in plants,animals, and humans. While initial studies reported only trace amounts of DMT in mammalian brains, recentfindings have identified alternative methylation pathways and DMT levels comparable to classical neurotrans-mitters in rodent brains, calling for a re-evaluation of its biological role and exploration of this inconsistency.This study evaluated DMT’s biosynthetic pathways, focusing on indolethylamine N-methyltransferase (INMT)and its isoforms, and possible regulatory mechanisms, including alternative routes of synthesis and how phys-iological conditions, such as stress and hypoxia influence DMT levels. This review considers the impact ofendogenous regulatory factors on DMT synthesis and degradation, particularly under conditions affectingmonoamine oxidase (MAO) efficiency and activity. We also examined DMT’s potential roles in various physio-logical processes, including neuroplasticity and neurogenesis, mitochondrial homeostasis, immunomodulation,and protection against hypoxia and oxidative stress. DMT’s lipophilic properties allow it to cross cell membranesand activate intracellular 5-HT2A receptors, contributing to its role in neuroplasticity. This suggests DMT mayact as an endogenous ligand for intracellular receptors, highlighting its broader biological significance beyondtraditional receptor pathways. The widespread evolutionary presence of DMT’s biosynthetic pathways acrossdiverse species suggests it may play essential roles in various developmental stages and cellular adaptation toenvironmental challenges, highlighting the neurobiological significance of DMT and its potential clinical ap-plications. We propose further research to explore the role of endogenous DMT, particularly as a potentialneurotransmitter.
The potent hallucinogen N,N-dimethyltryptamine (DMT) has garnered significant interest in recent years due to its profound effects on consciousness and its therapeutic psychopotential. DMT is an integral (but not exclusive) psychoactive alkaloid in the Amazonian plant-based brew ayahuasca, in which admixture of several β-carboline monoamine oxidase A (MAO-A) inhibitors potentiate the activity of oral DMT, while possibly contributing in other respects to the complex psychopharmacology of ayahuasca. Irrespective of the route of administration, DMT alters perception, mood, and cognition, presumably through agonism at serotonin (5-HT) 1A/2A/2C receptors in brain, with additional actions at other receptor types possibly contributing to its overall psychoactive effects. Due to rapid first pass metabolism, DMT is nearly inactive orally, but co-administration with β-carbolines or synthetic MAO-A inhibitors (MAOIs) greatly increase its bioavailability and duration of action. The synergistic effects of DMT and MAOIs in ayahuasca or synthetic formulations may promote neuroplasticity, which presumably underlies their promising therapeutic efficacy in clinical trials for neuropsychiatric disorders, including depression, addiction, and post-traumatic stress disorder. Advances in neuroimaging techniques are elucidating the neural correlates of DMT-induced altered states of consciousness, revealing alterations in brain activity, functional connectivity, and network dynamics. In this comprehensive narrative review, we present a synthesis of current knowledge on the pharmacology and neuroscience of DMT, β-carbolines, and ayahuasca, which should inform future research aiming to harness their full therapeutic potential.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00018-024-05353-6.
N,N-dimethyltryptamine (DMT) is a potent psychedelic naturally produced by many plants and animals, including humans. Whether or not DMT is significant to mammalian physiology, especially within the central nervous system, is a debate that started in the early 1960s and continues to this day. This review integrates historical and recent literature to clarify this issue, giving special attention to the most controversial subjects of DMT’s biosynthesis, its storage in synaptic vesicles and the activation receptors like sigma-1. Less discussed topics, like DMT’s metabolic regulation or the biased activation of serotonin receptors, are highlighted. We conclude that most of the arguments dismissing endogenous DMT’s relevance are based on obsolete data or misleading assumptions. Data strongly suggest that DMT can be relevant as a neurotransmitter, neuromodulator, hormone and immunomodulator, as well as being important to pregnancy and development. Key experiments are addressed to definitely prove what specific roles DMT plays in mammalian physiology.
Fear‐related disorders, mainly phobias and post‐traumatic stress disorder, are highly prevalent, debilitating disorders that pose a significant public health problem. They are characterized by aberrant processing of aversive experiences and dysregulated fear extinction, leading to excessive expression of fear and diminished quality of life. The gold standard for treating fear‐related disorders is extinction‐based exposure therapy (ET), shown to be ineffective for up to 35% of subjects. Moreover, ET combined with traditional pharmacological treatments for fear‐related disorders, such as selective serotonin reuptake inhibitors, offers no further advantage to patients. This prompted the search for ways to improve ET outcomes, with current research focused on pharmacological agents that can augment ET by strengthening fear extinction learning. Hallucinogenic drugs promote reprocessing of fear‐imbued memories and induce positive mood and openness, relieving anxiety and enabling the necessary emotional engagement during psychotherapeutic interventions. Mechanistically, hallucinogens induce dynamic structural and functional neuroplastic changes across the fear extinction circuitry and temper amygdala's hyperreactivity to threat‐related stimuli, effectively mitigating one of the hallmarks of fear‐related disorders. This paper provides the first comprehensive review of hallucinogens' potential to alleviate symptoms of fear‐related disorders by focusing on their effects on fear extinction and the underlying molecular mechanisms. We overview both preclinical and clinical studies and emphasize the advantages of hallucinogenic drugs over current first‐line treatments. We highlight 3,4‐methylenedioxymethamphetamine and ketamine as the most effective therapeutics for fear‐related disorders and discuss the potential molecular mechanisms responsible for their potency with implications for improving hallucinogen‐assisted psychotherapy.
The 5-HT2A receptor is thought to be the primary target for psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and other serotonergic hallucinogens (psychedelic drugs). Although a large amount of experimental work has been conducted to characterize the pharmacology of psilocybin and its dephosphorylated metabolite psilocin (4-hydroxy-N,N-dimethyltryptamine), there has been little systematic investigation of the structure–activity relationships (SAR) of 4-substituted tryptamine derivatives. In addition, structural analogs of psilocybin containing a 4-acetoxy group, such as 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), have appeared as new designer drugs, but almost nothing is known about their pharmacological effects. To address the gap of information, studies were conducted with 17 tryptamines containing a variety of symmetrical and asymmetrical N,N-dialkyl substituents and either a 4-hydroxy or 4-acetoxy group. Calcium mobilization assays were conducted to assess functional activity at human and mouse 5-HT2 subtypes. Head-twitch response (HTR) studies were conducted in C57BL/6J mice to assess 5-HT2A activation in vivo. All of the compounds acted as full or partial agonists at 5-HT2 subtypes, displaying similar potencies at 5-HT2A and 5-HT2B receptors, but some tryptamines with bulkier N-alkyl groups had lower potency at 5-HT2C receptors and higher 5-HT2B receptor efficacy. In addition, O-acetylation reduced the in vitro 5-HT2A potency of 4-hydroxy-N,N-dialkyltryptamines by about 10- to 20-fold but did not alter agonist efficacy. All of the compounds induce head twitches in mice, consistent with an LSD-like behavioral profile. In contrast to the functional data, acetylation of the 4-hydroxy group had little effect on HTR potency, suggesting that O-acetylated tryptamines may be deacetylated in vivo, acting as prodrugs. In summary, the tryptamine derivatives have psilocybin-like pharmacological properties, supporting their classification as psychedelic drugs.
Two different populations of neuroleptic receptors were found in the rat brain. Frontal cortical receptors appeared to be predominantly serotonergic whereas the striatal ones were mainly dopaminergic. Amongst the neuroleptics certain compounds showed higher affinity for the serotonergic receptors whilst others bound more preferentially to the dopaminergic receptors. The receptor populations in both regions were kinetically heterogeneous.
Five indolealkylamines (N,N-dimethyltryptamine, N-methyltryptamine, bufotenine, O-methylbufotenine, N,N,N-trimethyltryptamine iodide) were labeled with 11C by use of 11CH3I. The labeled compounds were synthesized with a radiochemical yield of 2–50% (based on trapped 11CH3I) in 20–35 min with radiochemical purities of more than 92%. The tissue distributions of these labeled compounds were investigated in rats. In all cases, the accumulations in the liver, lung and small intestine were high. [11C]DMT and [11C]OMB also accumulated to a large extent in the brain, where their accumulation was retained. Brain uptake of three other radiopharmaceuticals was low. [11C]DMT is the radiopharmaceutical of choice for the study of the serotonin action mechanism in the brain, because it has the highest radiochemical yield and the highest brain uptake of these 11C-labeled compounds.
A selective serotonin S2 receptor antagonist, ketanserin, was prepared labeled with carbon-11 by a rapid synthesis which uses no-carrier-added phosgene as the labeled precursor. The ring-closure reaction in toluene of phosgene with the substituted 2-aminobenzamide precursor gives a nearly quantitative yield of ketanserin. The 30 min procedure yields 150 mCi of HPLC purified ketanserin at a specific activity of 250 mCi/μ mol. The product's tissue distribution in mice shows a brain uptake and cerebrum to cerebellum ratio that encourages further in vivo receptor binding studies.
d-[3H]LSD binds saturably, reversibly, and with a high affinity (KD = 10nM) to rat brain membranes. The association and dissociation rates of binding are temperature dependent and fastest at 37 °C. Binding is enriched in crude microsomal (P3) membranes.d-[3H]LSD binding is stereospecific asl-LSD, the psychotropically inactive enantiomer, is 1000 times weaker thand-LSD as a displacing agent. The potencies of other LSD analogues parallel their psychotropic activity with the exception of 2-bromo-LSD (psychotropically inactive) which is as potent asd-LSD in displacing boundd-[3H]LSD. Serotonin is the only putative neurotransmitter with affinity (ED50 = 3 μM) for the LSD binding site, and psychotropically active alkylindoleamines are also potent displacing agents. Destruction of presynaptic serotonin neuronal elements by lesioning the midbrain raphe nuclei does not change the affinity or maximum number of detectablein vitrod-[3H]LSD binding sites. The regional distribution in monkey brain ofd-[3H]LSD binding and high affinity [3H]serotonin uptake, a marker for pre-synaptic serotonin nerve terminal density, shows some correlation. The most notable exceptions are cerebral cortical areas which are highest ind-[3H]LSD binding and only intermediate in [3H]serotonin uptake. Our evidence suggests thatd-[3H]LSD binds to post-synaptic serotonin receptors.
Bufotenin was found to be present in urine samples of schizophrenic patients and autistic children, but not of normal controls. The identification was based on TLC of the tertiary amine fraction using a specific o-phthalaldehyde spray, and also on GC. Unambiguous proof of the identity of bufotenin has now been provided by GC-MS analysis of the bufotenin-positive samples through its trimethylsilyl derivative.
[3H] Serotonin (5 HT) binds to membrane preparations of rat brain in a saturable fashion and with substrate specificity and regional variations consistent with its binding to the postsynaptic serotonin receptor. The dissociation constant for [3H]5 HT binding is about 8 nM, and the total number of 5 HT binding sites in the brain is 16 pmoles/g of tissue, wet wt. There is considerable structural specificity in the affinity of various tryptamines for the [3H]5 HT binding sites, with a crucial role played by the 5 hydroxy substituent. d [3H]Lysergic acid diethylamide (LSD) binding sites have substrate specificity requirements similar to the [3H]5 HT binding sites, but the 5 hydroxy substituent is less critical. 5 HT and related agonists have about 100 times more affinity for 5 HT than LSD binding sites, while classical 5 HT antagonists have 4 to 100 times greater affinity for LSD binding sites. LSD itself has a similar affinity for 5 HT and LSD binding sites. Raphe lesions which result in degeneration of 5 HT neurons do not lower [3H]5 HT binding, indicating that binding does not take place to presynaptic 5 HT neurons. Regional variations in serotonin and LSD binding are fairly similar. Highest binding occurs in the corpus striatum, hippocampus, and cerebral cortex, with lowest binding in the cerebellum. The ontogeny of 5 HT and LSD binding sites is nearly identical and does not appear to depend on functionally intact presynaptic 5 HT neuronal input.
14C-DMT accumulates in rat brain cortical slices incubated at 37 C. This process has many of the properties of an active uptake mechanism. It is temperature-sensitive, sodium-dependent, saturable, and is inhibited by metabolic inhibitors. Tryptamine derivatives were more effective than the catecholamines in competing for 14C-DMT accumulation. A number of psychotropic drugs were inhibitors of 14C-DMT accumulation. In general, irrespective of pharmacologic class, the tertiary amines were more potent than the secondary or primary amines, although there were some exceptions. Most of the accumulated 14C-DMT was associated with the cytoplasmic fraction. Of the portion associated with the crude mitochondrial fraction, 54.4% was associated with nerve-ending fraction.