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16

Journal Articles / Blockade and reversal of 5-Methoxy-N, N-Dimethyltryptamine-induced analgesia...

« on: May 01, 2017, 05:00:35 AM »

Archer T, Minor BG, Post C, 1985, 'Blockade and reversal of 5-Methoxy-N, N-Dimethyltryptamine-induced analgesia following noradrenaline depletion', Brain Research, vol. 333, no. 1, pp. 55-61, http://www.sciencedirect.com/science/article/pii/0006899385901234

Abstract

 The acute effects of the 5-hydroxytryptamine agonist, 5-Methoxy-N, N-dimethyltryptamine (5-MeO-DMT), upon pain sensitivity, using shock titration, tail-flick and hot-plate methods, in noradrenaline- and 5-hydroxytryptamine-depleted rats were examined. Noradrenaline depletion, following the systemic administration of N-2-chloroethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP4, 2 × 50 mg/kg, i.p.), caused a reversal of the analgesic effect of 5-MeO-DMT on shock-titration from hypo- to hypersensitivity, and a total blockade of the antinociceptive effect of 5-MeO-DMT upon pain responses in the hot-plate and tail-flick tests. Pretreatment with eitherp-chloroamphetamine (2 × 10 mg/kg) orp-chlorophenylalanine (200, 100, 100 mg/kg), that depletes central 5-hydroxytryptamine stores, failed to alter the analgesia caused by acute 5-MeO-DMT. Strong evidence is provided for the effect of central noradrenaline depletion upon the analgesic effect of the 5-HT agonist. These findings suggest an important tonic influence of the noradrenaline system upon the descending spinal 5-HT pathway in rats.

17

Journal Articles / Enhanced effects of amphetamine but reduced effects of 5-MeO-DMT on locomotor...

« on: May 01, 2017, 04:56:51 AM »

Van Den Buuse M, Ruimschotel E, Martin S, Risbrough VB, Halberstadt AL, 2011, 'Enhanced effects of amphetamine but reduced effects of the hallucinogen, 5-MeO-DMT, on locomotor activity in 5-HT1A receptor knockout mice: Implications for schizophrenia', Neuropharmacology, vol. 61, nos. 1–2, pp. 209-216,
http://www.sciencedirect.com/science/article/pii/S0028390811001468

Abstract

Serotonin-1A (5-HT1A) receptors may play a role in schizophrenia and the effects of certain antipsychotic drugs. However, the mechanism of interaction of 5-HT1A receptors with brain systems involved in schizophrenia, remains unclear. Here we show that 5-HT1A receptor knockout mice display enhanced locomotor hyperactivity to acute treatment with amphetamine, a widely used animal model of hyperdopaminergic mechanisms in psychosis. In contrast, the effect of MK-801 on locomotor activity, modeling NMDA receptor hypoactivity, was unchanged in the knockouts. The effect of the hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) was markedly reduced in 5-HT1A receptor knockout mice. There were no changes in apomorphine-induced disruption of PPI, a model of sensory gating deficits seen in schizophrenia. Similarly, there were no major changes in density of dopamine transporters (DAT) or dopamine D1 or D2 receptors which could explain the behavioural changes observed in 5-HT1A receptor knockout mice. These results extend our insight into the possible role of these receptors in aspects of schizophrenia. As also suggested by previous studies using agonist and antagonist drugs, 5-HT1A receptors may play an important role in hallucinations and to modulate dopaminergic activity in the brain.

18

Journal Articles / 5 Methoxy N,N dimethyltryptamine: behavioral and toxicological effects in animal

« on: May 01, 2017, 04:47:25 AM »

Gillin JC, Tinklenberg J, Stoff DM & Wyatt RJ, 1976, '5 Methoxy N,N dimethyltryptamine: behavioral and toxicological effects in animals', Biological Psychiatry, vol. 11, no. 3, pp. 355-8, https://www.researchgate.net/publication/22334810_5_Methoxy_NN_dimethyltryptamine_behavioral_and_toxicological_effects_in_animals

Abstract

These studies indicate that 5 MeO DMT has potent, rapidly appearing effects in the central nervous system. It has fatal effects in sheep at low doses, but not in monkeys, rats, or mice.

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Journal Articles / DMT and 5-MeO-DMT have different effects from mescaline on rat shuttlebox...

« on: May 01, 2017, 04:43:42 AM »

Stoff DM, Gorelick DA, Bozewicz T, Bridger WH, Gillin JC & Wyatt RJ, 1978, 'The indole hallucinogens, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), have different effects from mescaline on rat shuttlebox avoidance', Neuropharmacology, vol. 17, no. 12, pp. 1035-40,  https://www.sciencedirect.com/science/article/pii/0028390878900308

Abstract

The indole hallucinogenic drugs, N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), had a different psychopharmacological profile from mescaline on rat shuttlebox avoidance; the differences were strain and/or baseline-dependent. N,N-dimethyltryptamine and 5-MeO-DMT shared dose response disruptive effects with mescaline on avoidance behaviour in two rat strains who were performing the conditioned avoidance response at a high baseline (i.e. during acqusition in Fischer 344s—Experiment 1; on pretrained good performing hooded rats—Experiment 2). N,N-dimethyltryptamine and 5-MeO-DMT were without an effect when the baseline conditioned avoidance response was low (i.e. during acquisition in Zivic-Millers, Hoods or Roman Low Avoiders—Experiment 1; on pretrained poorly performing hooded rats—Experiment 2) but mescaline was facilitatory in these situations. There were strain-related differences in sensitivity to the drugs with Roman High Avoiders insensitive to DMT, 5-MeO-DMT and mescaline, while Fischer 344s were the most sensitive to these three drugs. The relative potency of these three hallucinogens in disrupting avoidance behavior (5-MeO-DMT > DMT > mescaline), in terms of mg/kg paralleled reports of their relative potency on central serotonergic activity. The facilitatory effect produced by mescaline, but not produced by DMT nor 5-MeO-DMT, may be related to the findings that mescaline has a stronger action on the catecholaminergic system than the indoles

20

Journal Articles / Biogenesis of 5-methoxy-N,N-dimethyltryptamine in human pineal gland

« on: May 01, 2017, 04:38:52 AM »

Guchhait RB, 1976, 'Biogenesis of 5-methoxy-N,N-dimethyltryptamine in human pineal gland', Journal of Neurochemistry, vol. 26, pp. 187-193, DOI: 10.1111/j.1471-4159.1976.tb04456.x, http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.1976.tb04456.x/full

Abstract

The present report provides further insight about the controversial role of MTHF as a methyl donor for indoleamines. Attempts are also made to demonstrate the in vitro formation of 5 MeO DMT from indoleamine precursors by the human pineal extract using SAMe as the methyl donor. The identity of this biosynthetic product is supported by thin layer chromatographic procedures and by carrier crystallization technique.

21

Journal Articles / The natural hallucinogen 5-MeO-DMT, disrupts cortical function in rats

« on: May 01, 2017, 04:34:39 AM »

Riga MS, Soria G, Tudela R, Artigas F & Celada, P 2014, 'The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs', International Journal of Neuropsychopharmacoly, vol. 17, no. 8, pp. 1269-1282. DOI: https://doi.org/10.1017/S1461145714000261

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (−31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

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Journal Articles / The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor

« on: May 01, 2017, 04:29:54 AM »

Thomson KK, Ruiz EM, Masten V, Buell M & Geyer MA, 2006, 'The Roles of 5-HT1A and 5-HT2 Receptors in the Effects of 5-MeO-DMT on Locomotor Activity and Prepulse Inhibition in Rats', Psychopharmacology, vol. 189, no. 3, pp. 319–329, https://link.springer.com/article/10.1007/s00213-006-0566-1

RATIONALE
The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm.
OBJECTIVES
A series of interaction studies using the serotonin (5-HT)1A antagonist WAY-100635 (1.0 mg/kg), the 5-HT2A antagonist M100907 (1.0 mg/kg), and the 5-HT2C antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms.
RESULTS
5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT.
CONCLUSIONS
While the prevailing view was that the activation of 5-HT2 receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT1A receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.

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Journal Articles / Modification of the effects of 5-MeO-DMT on exploratory behavior in rats by MAOI

« on: May 01, 2017, 04:22:53 AM »

Halberstadt AL, Buell MR, Masten VL, Risbrough VB & Geyer MA, 2008, 'Modification of the effects of 5-methoxy-N,N-dimethyltryptamine on exploratory behavior in rats by monoamine oxidase inhibitors', Psychopharmacology, vol. 201, no. 1, pp. 55-66, doi: 10.1007/s00213-008-1247-z, https://www.ncbi.nlm.nih.gov/pubmed/18604652

Abstract

RATIONALE:
The hallucinogenic tea known as ayahuasca is made from a combination of psychoactive plants that contribute the active components N,N-dimethyltryptamine (DMT) and 5-methoxy-DMT (5-MeO-DMT), as well as the monoamine oxidase (MAO) inhibitors (MAOIs) harmine and harmaline for oral activity.
OBJECTIVE:
The present study examined the effects of 5-MeO-DMT in combination with MAOIs in rats using the behavioral pattern monitor, which enables analyses of patterns of locomotor activity and exploration. Interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg) and the 5-HT(2A) antagonist MDL 11,939 (1.0 mg/kg) were also performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT in MAOI-treated animals.
RESULTS:
5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) decreased locomotor activity and investigatory behavior. In rats pretreated with a behaviorally inactive dose of harmaline (0.1 mg/kg), 1.0 mg/kg 5-MeO-DMT had biphasic effects on locomotor activity, initially reducing locomotion and then increasing activity as time progressed. The ability of harmaline to shift 5-MeO-DMT to a biphasic locomotor pattern was shared by the selective MAO(A) inhibitor clorgyline, whereas the selective MAO(B) inhibitor (-)-deprenyl was ineffective. The late hyperactivity induced by the combination of 1.0 mg/kg 5-MeO-DMT and 0.3 mg/kg clorgyline was blocked by pretreatment with MDL 11,939. Pretreatment with WAY-100635 failed to attenuate either the early hypoactivity or the late hyperactivity.
CONCLUSIONS:
The ability of harmaline to modify the behavioral effects of 5-MeO-DMT is mediated by the inhibition of MAO(A). Furthermore, 5-HT(2A) receptors are responsible for the late hyperactivity induced by 5-MeO-DMT in the presence of MAO(A) inhibitors.

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Journal Articles / Modification of 5-MeO-DMT-induced hyperactivity by monoamine oxidase A inhibitor

« on: May 01, 2017, 04:19:08 AM »

Jiang XL, Shen HW & Yu AM, 2016, 'Modification of 5-methoxy-N,N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor harmaline in mice and the underlying serotonergic mechanisms', Pharmacological Reports, vol. 68, no. 3, pp. 608-15, doi: 10.1016/j.pharep.2016.01.008, https://www.ncbi.nlm.nih.gov/pubmed/26977821

Abstract

BACKGROUND:
5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors.
METHODS:
Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule.
RESULTS:
High dose of harmaline (15mg/kg, ip) alone caused an early-phase (0-45min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45-180min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20mg/kg, ip) alone induced biphasic effects, an early-phase (0-45min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45-180min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI harmaline (2-15mg/kg) with a subthreshold dose of 5-MeO-DMT (2mg/kg) induced excessive hyperactivities at late phase (45-180min) that could be abolished by either WAY-100635 or MDL-100907.
CONCLUSIONS:
Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors

25

Journal Articles / Stimulus control by 5-MeO-DMT in wild-type and CYP2D6-humanized mice.

« on: May 01, 2017, 04:12:56 AM »

Winter JC, Amorosi DJ, Rice KC, Cheng K & Yu AM, 2011, 'Stimulus control by 5-methoxy-N,N-dimethyltryptamine in wild-type and CYP2D6-humanized mice', Pharmacology Biochemistry and Behavior, vol. 99, no. 3, pp. 311-5, doi: 10.1016/j.pbb.2011.05.015, https://www.ncbi.nlm.nih.gov/pubmed/21624387

Abstract

In previous studies we have observed that, in comparison with wild type mice, Tg-CYP2D6 mice have increased serum levels of bufotenine [5-hydroxy-N,N-dimethyltryptamine] following the administration of 5-MeO-DMT. Furthermore, following the injection of 5-MeO-DMT, harmaline was observed to increase serum levels of bufotenine and 5-MeO-DMT in both wild-type and Tg-CYP2D6 mice. In the present investigation, 5-MeO-DMT-induced stimulus control was established in wild-type and Tg-CYP2D6 mice. The two groups did not differ in their rate of acquisition of stimulus control. When tested with bufotenine, no 5-MeO-DMT-appropriate responding was observed. In contrast, the more lipid soluble analog of bufotenine, acetylbufotenine, was followed by an intermediate level of responding. The combination of harmaline with 5-MeO-DMT yielded a statistically significant increase in 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice; a comparable increase occurred in wild-type mice. In addition, it was noted that harmaline alone was followed by a significant degree of 5-MeO-DMT-appropriate responding in Tg-CYP2D6 mice. It is concluded that wild-type and Tg-CYPD2D6 mice do not differ in terms of acquisition of stimulus control by 5-MeO-DMT or in their response to bufotenine and acetylbufotenine. In both groups of mice, harmaline was found to enhance the stimulus effects of 5-MeO-DMT.

26

Journal Articles / Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmala

« on: May 01, 2017, 03:54:46 AM »

Jiang XL, Shen HW, Yu AM, 2015, 'Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors’, Neuropharmacology,  vol. 89, pp. 342-51, https://www.ncbi.nlm.nih.gov/pubmed/25446678

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.

27

Journal Articles / A Demand for Clarity Regarding a Case Report on the Ingestion of 5-MeO-DMT

« on: May 01, 2017, 03:47:40 AM »

Callaway JC, Grob CS, McKenna DJ, Nichols DE, Shulgin A & Tupper KW,  2006, 'A Demand for Clarity Regarding a Case Report on the Ingestion of S-Methoxy-N, N-Dimethyltryptamine (5-MeO·DMT) in an Ayahuasca Preparation'€, Journal of Analytical Toxicology, vol.30, https://www.ncbi.nlm.nih.gov/pubmed/16872575

First Sentence of Letter to Editor;

"The case report 'A Fatal Intoxication Following theIngestion of5-Methoxy-N,N-Dimethyltryptamine in an Ayahuasca Preparation' by Sklerov et al. is misleading as to the nature and toxicity of ayahuasca". 

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Journal Articles / A Fatal Intoxication Following the Ingestion of 5-MeO-DMT in an ayahuasca prep.

« on: May 01, 2017, 03:41:00 AM »

Sklerov J, Levine B, Moore KA, King T & Fowler A, 2005, 'A Fatal Intoxication Following the Ingestion of 5-Methoxy-N,N-Dimethyltryptamine in an Ayahuasca Preparation', Journal of Analytical Toxicology, vol. 29, no.8, pp. 38-41, DOI: 10.1093/jat/29.8.838, https://www.researchgate.net/publication/7414522_A_Fatal_Intoxication_Following_the_Ingestion_of_5-Methoxy-NN-Dimethyltryptamine_in_an_Ayahuasca_Preparation

Abstract

A case of a 25-year-old white male who was found dead the morning after consuming herbal extracts containing β-carbolines and hallucinogenic tryptamines is presented. No anatomic cause of death was found at autopsy. Toxicologic analysis of the heart blood identified N,N-dimethyltryptamine (0.02 mg/L), 5-methoxy-N,N-dimethyltryptamine (1.88 mg/L), tetrahydroharmine (0.38 mg/L), harmaline (0.07 mg/L), and harmine (0.17 mg/L). All substances were extracted by a single-step n-butyl chloride extraction following alkalinization with borate buffer. Detection and quantitation was performed using liquid chromatography-electrospray mass spectrometry. The medical examiner ruled that the cause of death was hallucinogenic amine intoxication, and the manner of death was undetermined.

29

Journal Articles / Human intranasal, sublingual and oral pharmacology of 5-methoxy-N,N-dmt

« on: May 01, 2017, 03:33:14 AM »

Ott J, 2011, 'Pharmepena-Psychonautics: Human Intranasal, Sublingual and Oral Pharmacology of 5-Methoxy-N, N-Dimethyl-Tryptamine', Journal
Journal of Psychoactive Drugs, vol. 33, 2001, no. 4, http://www.tandfonline.com/doi/abs/10.1080/02791072.2001.10399925

Abstract

Summarized are psychonautic bioassays (human self-experiments) of Pharmepena - crystalline 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT; O-Me-bufotenine), at times combined with crystalline b-Carboline (harmaline or harmine). These substances were administered via intranasal, sublingual and oral routes, by way of pharmacological modeling of diverse South American shamanic inebriants (principally the snuffs epena/nyakwana, prepared from barks of diverse species of Virola.) Intranasal, sublingual and oral psychoactivity of 5-MeO-DMT, and the 1967 Holmstedt-Lindgren hypothesis of the parica-effect - intranasal potentiation of tryptamines by concomitant administration of monoamine-oxidase-inhibiting (MAOI) b-Carboline from stems of Banisteriopsis caapi admixed with the snuffs - have been confirmed by some 17 psychonautic bioassays. Salient phytochemical and psychonautic literature is reviewed.

30

Journal Articles / Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline...

« on: May 01, 2017, 03:28:08 AM »

Jiang XL, Shen HW, Mager DE & Yu AM, 2013, 'Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status', Drug Metabolism and Disposition, vol. 41, no. 5, pp. 975-986, DOI: doi.org/10.1124/dmd.112.050724, http://dmd.aspetjournals.org/content/41/5/975

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name "5-MEO") is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.