Biochemical pharmacology
July 1, 2020
Kenji Hashimoto
232 citations
Ketamine, developed as an anesthetic in the 1960s, is also abused recreationally for its dissociative effects. It shows strong antidepressant effects in treatment-resistant depression. The racemic mixture contains (R)-ketamine and (S)-ketamine; (S)-ketamine nasal spray was approved by the US FDA in 2019 and in Europe later that year. Although (R)-ketamine has lower affinity for the NMDAR, it produces more potent and longer-lasting antidepressant-like effects in animal models with fewer side effects than (R,S)-ketamine or (S)-ketamine. BDNF and TrkB receptor involvement is suggested, and RNA-sequencing points to TGF-β1 in (R)-ketamine's effects. A pilot study showed rapid, sustained antidepressant effects of (R)-ketamine in treatment-resistant patients. This review covers mechanisms of ketamine enantiomers and metabolites and discusses the brain-gut-microbiota and brain-spleen axes in stress-related disorders.
Biochemical pharmacology
July 15, 1987
T D Steele, D E Nichols, G K Yim
179 citations
MDMA and related compounds block the reuptake of serotonin and norepinephrine more potently than dopamine, setting them apart from both amphetamine and the hallucinogen DOM. The S-(+) enantiomer of MDMA and MDA inhibits dopamine uptake, while the alpha-ethyl homolog MBDB does not. Both stereoisomers of MDMA, MDA, and MBDB strongly inhibit serotonin and norepinephrine uptake, whereas DOM has no effect on any monoamine uptake. These findings suggest MDMA's mechanism is closer to amphetamine than to DOM, and that serotonin and norepinephrine systems underlie its pharmacological effects.
Biochemical pharmacology
May 1, 1987
B R Sitaram, L Lockett, R Talomsin et al.
75 citations
After injection into the abdominal cavity, 5-methoxy-N,N-dimethyltryptamine and N,N-dimethyltryptamine are rapidly taken up by and cleared from all tissues examined. Live-animal experiments confirm earlier lab findings that these compounds are metabolized through oxidative deamination, N-demethylation, O-demethylation, and N-oxidation. Analysis of metabolic profiles across tissues identified N-oxides as major metabolites. Pretreating animals with iproniazid successfully inhibited and redirected metabolism away from indole acids toward the parent compounds and their structurally unique metabolites.
Biochemical pharmacology
January 15, 2007
Denis S Theobald, Hans H Maurer
59 citations
For several phenethylamine-type designer drugs (2C-series), the main metabolic step is deamination to an aldehyde. Using human enzymes expressed in cell culture, monoamine oxidase A and B (MAO-A and MAO-B) were the primary catalysts of this reaction for all compounds tested. For four of the six drugs (2C-D, 2C-E, 2C-T-2, and 2C-T-7), the cytochrome P450 enzyme CYP2D6 contributed to a very small extent. Because MAO enzymes are the major route of metabolism, these designer drugs are likely to be susceptible to drug-drug interactions with MAO inhibitors.
Biochemical pharmacology
July 1, 2010
Hong-Wu Shen, Chao Wu, Xi-Ling Jiang et al.
40 citations
The metabolism and pharmacokinetics of the natural psychoactive compound 5-MeO-DMT are strongly influenced by both CYP2D6 genetic variation and monoamine oxidase inhibitors (MAOIs). Compared to the wild-type CYP2D6.1 enzyme, the CYP2D6.2 variant showed 2.6-fold lower catalytic efficiency and CYP2D6.10 showed 40-fold lower efficiency in producing the active metabolite bufotenine. In human liver microsomes treated with the MAOI pargyline, 5-MeO-DMT O-demethylation correlated strongly with CYP2D6 activity. In mice with the human CYP2D6 gene, systemic exposure to bufotenine was 60% higher than in wild-type mice. Pretreatment with the MAOI harmaline increased systemic exposure to 5-MeO-DMT by 3.6- to 4.4-fold and to bufotenine by 6.1- to 9.9-fold, depending on mouse genotype. MAOIs substantially alter 5-MeO-DMT processing and bufotenine formation, with CYP2D6 genotype determining the extent of these effects.
Biochemical pharmacology
January 6, 1995
C A Gallagher, L B Hough, S M Keefner et al.
32 citations
A new chemical method to measure the alkaloid ibogaine in biological samples uses extraction, derivatization, and gas chromatography-mass spectrometry, with a deuterated internal standard. Standard curves for ibogaine (50-400 ng) were linear. The detection limit is about 20 ng/mL of tissue extract (180 ng/g tissue), with a coefficient of variation of 8 to 12.5%. Aqueous ibogaine solutions (1-10 mg/mL) stored at 10°C for up to 7 months showed no more than 10% loss. Measuring brain ibogaine in rats 1 and 19 hours after a 40 mg/kg dose suggests rapid drug disappearance. The method will help reveal ibogaine's pharmacokinetic properties.
Biochemical pharmacology
May 1, 1987
B R Sitaram, R Talomsin, G L Blackman et al.
23 citations
Using liquid chromatography techniques, metabolites of the psychotomimetic compounds N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine were separated and characterized after incubation with rat tissue extracts. In liver, kidney, and brain extracts, metabolic routes included oxidative deamination, N-demethylation, O-demethylation, and N-oxidation. The quantitative importance of each route was assessed using N,N-dimethyltryptamine as a substrate.
Biochemical pharmacology
October 1, 2021
Alexandra Sachkova, David Alexander Doetsch, Ole Jensen et al.
11 citations
Many psychostimulants and hallucinogens are hydrophilic and positively charged, making it unclear how they cross the blood-brain barrier (BBB). A genetically uncharacterized proton-organic cation (H+/OC) antiporter at the BBB may mediate this transport. Using hCMEC/D3 cells, uptake of methylenedioxyamphetamines, amphetamines, and dimethyltryptamine (DMT) was strongly inhibited by imipramine and diphenhydramine, while cathine was weakly inhibited and mescaline not significantly. Exchange transport after preloading with diphenhydramine left only 1.9% to 7.8% of several compounds in cells, but mescaline showed no exchange. Except for mescaline, all tested psychostimulants were substrates of the H+/OC antiporter, highlighting the need to better characterize this transporter.
Biochemical pharmacology
November 1, 2024
Tanner Magruder, Marielle Isenhart, Maximillian V Striepe et al.
8 citations
Ketamine, a sedative and dissociative anesthetic developed in the 1960s as an alternative to phencyclidine (PCP), has been used clinically for over 50 years. It causes fewer severe side effects like hallucinations than PCP, leading to its popularity in emergency medicine and surgeries requiring rapid induction and recovery. Over recent decades, ketamine has been found effective for additional conditions, including acute and chronic pain management and psychiatric disorders such as major depression. It is also a common drug of abuse sought for its hallucinogenic and sedative effects. This review explores ketamine's clinical and non-clinical uses and its impact on patient care.