Nature
June 1, 2024
Audrey L Warren, David Lankri, Michael J Cunningham et al.
74 citations
Psychedelic substances like LSD and psilocybin show potential for treating neuropsychiatric disorders, primarily acting through the serotonin 5-HT2A receptor. However, 5-HT1A also contributes to the effects of tryptamine hallucinogens, especially 5-MeO-DMT from Colorado River toad toxin. Using cryo-EM structures, medicinal chemistry, and mouse behavior, researchers mapped how 5-MeO-DMT engages 5-HT1A. They characterized molecular determinants of signaling potency, efficacy, and selectivity at both 5-HT1A and 5-HT2A. A 5-HT1A-selective analogue of 5-MeO-DMT lacked hallucinogenic effects but retained anxiolytic-like and antidepressant-like activity in socially defeated animals, uncovering molecular aspects that may aid developing new neuropsychiatric medications.
Frontiers in pharmacology
January 1, 2019
Soledad Marton, Bruno González, Sebastián Rodríguez-bottero et al.
71 citations
A single injection of ibogaine in rats increased the expression of neurotrophic factors in brain regions containing dopamine neurons, with effects depending on dose and brain area. At 24 hours, the higher dose (40 mg/kg) selectively raised GDNF in the ventral tegmental area and substantia nigra, while both doses boosted BDNF transcripts in the nucleus accumbens, substantia nigra, and prefrontal cortex. NGF mRNA increased across all regions after the higher dose. Protein levels showed GDNF rise only in the ventral tegmental area at the higher dose, and proBDNF increased in the nucleus accumbens for both doses. These changes may help explain ibogaine's reported ability to reduce drug-seeking behavior.
ACS chemical neuroscience
June 3, 2020
Paola Rodrı Guez, Jessika Urbanavicius, José Pedro Prieto et al.
44 citations
Ibogaine and its main metabolite noribogaine produce antidepressant-like effects in rats, as measured by the forced swim test. Both compounds induced a dose- and time-dependent reduction in immobility without altering locomotor activity. Noribogaine's effect was short-lived (30 minutes) and correlated with high brain concentrations (estimated >8 μM free drug), while ibogaine's effect was significant at 3 hours, when both ibogaine (~0.5 μM) and noribogaine (~2.5 μM) were present at concentrations that alone could not produce the same outcome. The findings suggest a polypharmacological mechanism underlies the antidepressant-like effects.
ACS chemical biology
January 15, 2016
Madalee M Gassaway, Teresa L Jacques, Andrew C Kruegel et al.
23 citations
A novel iboga analog, XL-008, induces release of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells. It also potentiates GDNF release induced by fibroblast growth factor 2 (FGF2), increasing potency more than 2-fold (from 7.85 ± 2.59 ng/mL to 3.31 ± 0.98 ng/mL) and efficacy more than 3-fold. The GDNF release by both XL-008 and the FGF2/XL-008 mixture is mediated through the MEK and PI3K signaling pathways but not through PLCγ. This work describes a small-molecule approach to modulating growth factor signaling in the brain, relevant to treating neuropsychiatric disorders such as depression, anxiety, and addiction.
Nature communications
September 20, 2024
Václav Havel, Andrew C Kruegel, Benjamin Bechand et al.
18 citations
A new class of iboga alkaloids, called oxa-iboga, was created by modifying the iboga molecular structure to replace a key component with a benzofuran ring. These compounds lack the heart rhythm risks (proarrhythmic effects) of ibogaine and noribogaine when tested on human heart cells. In male rats, oxa-iboga compounds were more effective than ibogaine at reducing opioid use. They act as potent kappa opioid receptor agonists but produce different behavioral effects than typical kappa agonists. A single dose or short treatment with oxa-noribogaine led to long-lasting reductions in morphine, heroin, and fentanyl intake, reversed persistent opioid-induced pain sensitivity, and suppressed drug-seeking behavior in relapse models. These compounds offer a mechanistically distinct approach to treating opioid use disorder.
Journal of the American Chemical Society
April 10, 2024
Wei-Li Lee, Xavier Westergaard, Christopher Hwu et al.
18 citations
A novel small molecule fluorescent agent called SERTlight specifically labels serotonin neurons in the mammalian brain. SERTlight is a substrate for the serotonin transporter (SERT) and accumulates inside serotonin neurons, producing a bright and selective optical signal. Unlike many other agents, SERTlight does not activate serotonin receptors or other common targets and is not released by neuronal activity or drugs like MDMA. It is compatible with other imaging tools and can label distant axonal projections while allowing simultaneous measurement of serotonin release. This new tool enables detailed study of the serotonin system in health and disease.
bioRxiv Preprint Server
March 4, 2024
Umed Boltaev, Hyun W. Park, Keaon R. Brown et al.
4 citations
preprint
Classic psychedelics are thought to work by inducing neuroplasticity, often measured as dendritic arbor growth. This study tested whether psychedelics directly activate the TrkB receptor or BDNF/TrkB signaling, and whether they cause morphological growth in primary cortical neurons. Using a multimodal screening platform, the authors found that psychedelics do not directly modulate TrkB or BDNF-TrkB signaling, and that 5-HT2A receptor expression and functional levels are low. Psychedelics did not induce dendritogenesis, unlike BDNF which did. These results challenge previous findings and highlight the need for rigorous methods in studying neuroplasticity.
Journal of pharmaceutical and biomedical analysis
June 24, 2026
Scot Mcintosh, Isabella Maldonado, Nickalus C Smith et al.
A sensitive UPLC-MS/MS method was developed and validated to quantify ibogaine, noribogaine, ibogamine, and oxa-noribogaine in rat brain microdialysate, measuring pharmacologically active, unbound drug in brain extracellular fluid rather than total tissue content. The method achieved lower limits of quantification of 0.78-1.56 ng/mL with a 6-minute run time, and calibration curves were linear over 0.78-75 ng/mL for ibogamine and 1.56-75 ng/mL for the other analytes. Accuracy and precision met acceptance criteria. Applied to rats (n=4), noribogaine in nucleus accumbens after 10 mg/kg intraperitoneal administration reached a peak unbound concentration of 292 ± 68 ng/mL at 50 minutes, demonstrating suitability for real-time neuropharmacokinetic profiling of iboga alkaloids.