Annals of the New York Academy of Sciences
September 1, 2000
D C Mash, C A Kovera, J Pablo et al.
146 citations
Ibogaine, an indole alkaloid from the Tabernanthe Iboga shrub, has been used in low doses by indigenous peoples to combat fatigue, hunger, and thirst, and in higher doses as a religious sacrament. Anecdotal reports from addict self-help groups claim a single dose eliminates opiate withdrawal symptoms and reduces drug craving for extended periods. The compound is rapidly metabolized via CYP2D6 into noribogaine, which may underlie its prolonged effects. In an inpatient detoxification setting, ibogaine significantly decreased craving for cocaine and heroin and reduced self-reported depressive symptoms, with benefits persisting 30 days after discharge. The findings suggest noribogaine's central nervous system activity may explain the lasting aftereffects on craving and mood.
Life sciences
January 1, 1995
D C Mash, J K Staley, M H Baumann et al.
108 citations
Ibogaine, a hallucinogenic indole, is thought to help treat cocaine, stimulant, and opiate abuse, possibly through a long-acting metabolite. This study reports that 12-hydroxyibogamine, a primary metabolite of ibogaine, binds with high affinity to the serotonin (5-HT) transporter and increases extracellular 5-HT levels. In binding assays, 12-hydroxyibogamine was 50-fold more potent at the 5-HT transporter than at the dopamine transporter, while ibogaine and the metabolite were equally potent at the dopamine transporter. Microdialysis showed that 12-hydroxyibogamine dose-dependently elevated extracellular 5-HT, but neither ibogaine nor its metabolite raised dopamine levels in the nucleus accumbens. The metabolite's enhancement of 5-HT transmission may improve mood and reduce drug craving, potentially explaining ibogaine's ability to interrupt drug-seeking behavior.
Psychopharmacology
September 1, 1996
J K Staley, Q Ouyang, J Pablo et al.
82 citations
Ibogaine, a treatment for drug dependence, is metabolized into 12-hydroxyibogamine (12-OH ibogamine). Both the parent drug and metabolite bind to similar molecular targets, with the highest potency at the cocaine recognition site on the serotonin transporter. The metabolite shows higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor compared to ibogaine. Micromolar concentrations of both compounds are found in rat brain. The combined actions of ibogaine and its metabolite at key pharmacological targets may alter drug-seeking behavior by modulating reward circuits.
Neuroscience letters
June 2, 1995
D C Mash, J K Staley, J P Pablo et al.
82 citations
Ibogaine and its metabolite 12-hydroxyibogamine act at the MK-801 binding site within the NMDA-receptor cation channel. Both compounds competitively displaced [3H]MK-801 binding to membranes from human caudate, cerebellum, and frog spinal cord. Ibogaine was 4-6 times more potent than its metabolite, but both were 50-1000 times less potent than MK-801. Ibogaine (100 µM) and 12-hydroxyibogamine (1 mM) blocked NMDA-induced depolarizations in frog motoneurons by 85-90%. The block was use-dependent and resembled that of MK-801. These findings suggest that ibogaine's ability to interrupt drug-seeking behavior may partly result from its action at the MK-801 binding site.
Journal of analytical toxicology
October 1, 1995
W L Hearn, J Pablo, G W Hime et al.
44 citations
A sensitive method was developed to measure ibogaine and its major metabolite, 12-hydroxy-ibogamine (noribogaine), in biological fluids and brain tissue. The metabolite was identified using gas chromatography-mass spectrometry. The procedure involves solvent extraction, derivatization with ethyl iodide, and cleanup before analysis. Detection limits were 5 ng/mL for both compounds, and quantitation limits ranged from 5 to 10 ng/mL across all tested matrices. Calibration curves were linear from 3 to 1000 ng/mL or ng/g.
Annals of the New York Academy of Sciences
September 1, 2000
M H Baumann, J P Pablo, S F Ali et al.
37 citations
Ibogaine, a plant-derived alkaloid being studied for substance use disorders, is rapidly converted in the body to its metabolite noribogaine. In rats, noribogaine reaches higher blood levels than ibogaine and persists for at least 24 hours. Noribogaine did not cause tremors or forepaw treading, unlike ibogaine, but both drugs elevated stress hormones corticosterone and prolactin, with ibogaine more potent for corticosterone. Neither drug affected dopamine levels in the nucleus accumbens, but both increased serotonin levels, with noribogaine more potent. Noribogaine is biologically active and likely contributes to ibogaine's effects but may be safer, producing fewer adverse effects like tremors and stress-axis activation.
Journal of medicinal chemistry
November 5, 1998
S M Efange, D C Mash, A B Khare et al.
33 citations
Five new compounds derived from a fragment of ibogaine were synthesized and tested for their ability to bind to brain receptors and transporters. All five showed 8 to 10 times stronger binding to the dopamine transporter than ibogaine itself. Two compounds were more potent than ibogaine at the serotonin transporter, while the others were weaker. The compounds generally had weak binding to dopamine D1 and D2 receptors, but two showed moderate binding to dopamine D3 receptors. All had weak binding to opioid receptors and NMDA receptors. These derivatives may serve as useful substitutes for ibogaine in addiction therapy.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
July 1, 1999
C Zubaran, M Shoaib, I P Stolerman et al.
31 citations
In rats trained to distinguish ibogaine from a placebo, the metabolite noribogaine produced the same discriminative effect as ibogaine but at roughly half the dose. Noribogaine was found in blood and brain tissue after either ibogaine or noribogaine was given. At doses that produced the discriminative effect, noribogaine concentrations in plasma, cerebral cortex, and striatum were similar whether ibogaine or noribogaine was administered. The findings suggest noribogaine may lack the NMDA antagonist and kappa-opioid agonist effects of ibogaine and may be primarily responsible for ibogaine's discriminative stimulus effect in rats.
Neuroreport
January 5, 1998
J P Pablo, D C Mash
27 citations
Noribogaine, a metabolite produced in the body from the natural compound ibogaine, acts as a full agonist at the mu-opioid receptor. In rat thalamic membranes, noribogaine stimulated a 170% increase above basal G-protein activation at sub-micromolar concentrations, an effect blocked by naloxone, confirming opioid receptor involvement. Its intrinsic activity matched that of the full agonists DAMGO and morphine. Ibogaine itself had no significant effect. This full mu-opioid agonist efficacy may explain ibogaine's ability to block acute opiate withdrawal and reduce morphine self-administration.
Natural product research
July 10, 2006
D Passarella, A Barilli, S M N Efange et al.
4 citations
A microwave-assisted chemical reaction was used to create a key intermediate for synthesizing ibogaine analogues. One analogue, a hydroxymethyl indolyl derivative, showed promising binding to dopamine, serotonin, and opioid receptors in lab tests and reduced withdrawal symptoms in mice. Simplifying the ibogaine molecule appears to be a useful strategy for designing new compounds to treat addiction withdrawal.