Pharmacology, biochemistry, and behavior
January 1, 2006
W E Fantegrossi, A W Harrington, C L Kiessel et al.
144 citations
5-MeO-DIPT, a hallucinogenic drug similar to DMT, produced head-twitch responses in mice, an effect blocked by a serotonin 2A receptor antagonist. In rats trained to recognize LSD, 5-MeO-DIPT partially substituted for LSD (75% generalization) and suppressed response rates in a dose-dependent way; this effect was abolished by a 5-HT2A antagonist but not by a 5-HT1A antagonist. The drug showed micromolar affinity for 5-HT2A and 5-HT2C receptors and much higher affinity for 5-HT1A receptors in rat brain tissue. The results indicate that the 5-HT2A receptor is a key site of action for 5-MeO-DIPT, despite its in vitro selectivity for the 5-HT1A receptor.
Pharmacology, biochemistry, and behavior
January 1, 2000
J C Winter, R A Filipink, D Timineri et al.
80 citations
In rats trained to recognize the effects of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or (-)-2,5-dimethoxy-4-methylamphetamine (DOM), blocking specific serotonin receptors revealed which receptors mediate each drug's effects. Blocking 5-HT1A receptors strongly reduced 5-MeO-DMT's effects, while blocking 5-HT2 receptors had little effect. Conversely, DOM's effects were blocked by a 5-HT2 antagonist but not by 5-HT1A antagonists. 5-MeO-DMT partially mimicked DOM only when given subcutaneously, and this required both 5-HT1A and 5-HT2 receptor involvement. The findings indicate that 5-MeO-DMT's effects rely mainly on 5-HT1A receptors, but it also activates 5-HT2 receptors, a component revealed in animals trained with the 5-HT2-selective drug DOM.
Pharmacology, biochemistry, and behavior
October 1, 2007
J C Winter, K C Rice, D J Amorosi et al.
73 citations
Psilocybin produces a complex internal cue in rats that depends partly, but not entirely, on the 5-HT2A serotonin receptor. Blocking the 5-HT2A receptor with M100907 only partially reduced the drug's effect, while blocking the 5-HT1A/7 receptor or the dopamine D2 receptor had no effect. Rats trained to recognize psilocybin also recognized other hallucinogens such as LSD, psilocin, and DOM, and partially recognized mescaline and 2C-T-7. LSD and MDMA partly substituted for psilocybin, and those effects were fully blocked by M100907. Unlike the related hallucinogen 5-MeO-DMT, psilocybin's effects do not involve the 5-HT1A receptor.
Pharmacology, biochemistry, and behavior
February 1, 1998
S Helsley, D Fiorella, R A Rabin et al.
35 citations
In rats trained to recognize the hallucinogen ibogaine, two other hallucinogens—LSD and DOM—partially substituted for ibogaine (63% and 66.4% of responses, respectively). This partial substitution was completely blocked by the 5-HT2A antagonist pirenpirone, indicating that LSD and DOM produce ibogaine-like effects through the 5-HT2A receptor. However, pirenpirone did not block ibogaine itself or its effects from harmaline and noribogaine. Ibogaine, noribogaine, and harmaline showed only micromolar affinity for the 5-HT2A receptor (92.5, 34.5, and 42.5 µM). Ibogaine and harmaline, but not noribogaine, protected the receptor from alkylation. The findings suggest that while ibogaine interacts with 5-HT2A receptors, these interactions are not essential for its discriminative stimulus effects.
Brain research
June 13, 1997
S Helsley, C A Dlugos, R J Pentney et al.
19 citations
Repeated administration of ibogaine to male Fischer 344 rats over 60 days did not cause loss of cerebellar Purkinje cells. The ibogaine group had an average of 243,764 Purkinje cells and the control group 230,813, a difference that was not statistically significant. This suggests that chronic ibogaine exposure at a behaviorally active dose does not damage these neurons.
European journal of pharmacology
December 5, 1996
R A Rabin, J C Winter
17 citations
Ibogaine and its metabolite noribogaine do not directly alter adenylyl cyclase activity in the rat brain, but they enhance the inhibition of this enzyme caused by morphine and serotonin. In the frontal cortex, midbrain, and striatum, both compounds amplified morphine's effect; in the hippocampus, they boosted serotonin's effect. Ibogaine was more potent than noribogaine, but both were equally effective. The compounds did not affect inhibition by the muscarinic agonist carbachol. This selective potentiation of receptor-mediated inhibition may contribute to ibogaine's pharmacological actions.
Pharmacology, biochemistry, and behavior
February 1, 1998
S Helsley, R A Filipink, W D Bowen et al.
16 citations
Ibogaine, a hallucinogen with potential for treating addiction, produces its effects through interactions with multiple brain receptors. In rats trained to recognize ibogaine, ligands targeting sigma2 and opiate receptors partially reproduced ibogaine's effects, while sigma1-selective agents did not. Morphine and kappa-selective opioids failed to substitute for ibogaine, but mixed-action opiates like (-)-SKF 10,047 and nalorphine showed intermediate generalization. Naloxone partially blocked ibogaine's effects and fully blocked those of (-)-SKF 10,047 and nalorphine. Neither PCP nor MK-801 substituted for ibogaine, indicating NMDA receptors are not involved. The findings suggest that sigma2 and opiate receptors, but not NMDA receptors, contribute to ibogaine's discriminative stimulus.
Pharmacology, biochemistry, and behavior
July 1, 1999
J C Winter, S Helsley, D Fiorella et al.
14 citations
Pretreatment with the monoamine reuptake inhibitors fluoxetine, fluvoxamine, and venlafaxine increased the discriminative stimulus effects of the hallucinogens LSD, (-)-DOM, and ibogaine in rats trained to recognize these drugs. For 5-MeO-DMT-trained rats, only fluoxetine enhanced drug-appropriate responding. The reuptake inhibitors alone sometimes produced intermediate responding, suggesting partial substitution. Further experiments with (-)-DOM showed that most combinations produced additive rather than truly potentiating effects. The findings extend earlier observations that fluoxetine augments LSD's effects to include other hallucinogens, though the mechanisms and differences between acute and chronic treatment remain unknown.
Life sciences
January 1, 1997
S Helsley, R A Rabin, J C Winter
13 citations
Rats were trained to distinguish the psychoactive drug ibogaine from water. The dose needed to produce the drug effect half the time (ED50) was 4.6 mg/kg. The drug's effect peaked at 60 minutes after injection, with 94% of responses indicating the drug was present, then declined over time; after 8 hours only 6.4% of responses were drug-appropriate. A metabolite of ibogaine, noribogaine, partially substituted for ibogaine (71.6% drug-appropriate responding), while the drug harmaline fully substituted (83.5%), suggesting shared mechanisms.
Progress in neuro-psychopharmacology & biological psychiatry
February 1, 1999
S Helsley, R A Rabin, J C Winter
9 citations
In rats trained to recognize ibogaine's effects, activating 5-HT2C receptors with MK-212 or mCPP produced ibogaine-like responses (79.6% and 76.4% of the time), and this substitution was blocked by the 5-HT2C antagonist metergoline. However, metergoline did not block ibogaine itself, indicating that while ibogaine may activate 5-HT2C receptors, this action is not necessary for its distinctive cue. Neither a 5-HT3 agonist nor antagonist, nor a 5-HT1A agonist or antagonist, substituted for ibogaine, and a 5-HT1A antagonist did not block ibogaine's effects. Thus, 5-HT1A and 5-HT3 receptors appear uninvolved in ibogaine's discriminative stimulus.
Pharmacology, biochemistry, and behavior
September 1, 1997
S Helsley, D Fiorella, R A Rabin et al.
9 citations
Ibogaine, at a potentially neurotoxic dose, did not impair rats' ability to learn or perform a maze task. In a study with 12 rats trained in an 8-arm radial maze, those given ibogaine showed similar learning and accuracy as controls but had lower response rates. When given before maze sessions, ibogaine dose-dependently slowed responding without reducing accuracy. When given after sessions, ibogaine-treated rats made fewer errors than controls. The authors conclude that ibogaine failed to produce any harmful effects on learning or task efficiency.
Brain research
August 26, 1996
R A Rabin, J C Winter
7 citations
The antiaddictive compound ibogaine and its primary metabolite noribogaine were tested for their effects on phosphoinositide hydrolysis in rat brain tissue. Ibogaine did not alter phosphoinositide turnover in striatal or hippocampal slices, but noribogaine caused a concentration-dependent increase in the generation of inositol phosphates. This increase was not due to neurotransmitter release, as it was unaffected by tetrodotoxin, cadmium, or omega-conotoxin. The results suggest that noribogaine's stimulation of phosphoinositide hydrolysis may contribute to the behavioral effects of ibogaine.
European journal of pharmacology
March 19, 1998
S Helsley, R A Rabin, J C Winter
6 citations
Rats trained to recognize ibogaine's effects were tested with several beta-carbolines to see which ones produced similar internal sensations. 6-Methoxyharmalan fully mimicked ibogaine in 86.3% of trials, while harmaline had done so in 83.5% in earlier work. Harmine, harmane, harmalol, and tetrahydro-beta-carboline produced partial substitution, but norharmane and DMCM did not. These results suggest that some beta-carbolines share ibogaine-like effects, though whether this extends to anti-addictive properties remains unknown.
The Alkaloids. Chemistry and biology
January 1, 2001
S Helsley, R A Rabin, J C Winter
4 citations
Ibogaine appears to produce its effects through selective interactions with multiple brain receptors, specifically 5-HT2A, 5-HT2C, and sigma 2 receptors, with possible involvement of opiate receptors. Sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not play a major role. The hallucinogenic effects may stem from 5-HT2A and 5-HT2C receptor interactions, while antiaddictive properties may result from sigma 2 and opiate receptor interactions. Alternatively, the hallucinogenic properties themselves could underlie the antiaddictive effects, supporting a role for 5-HT2 receptors in therapeutic actions. Many questions remain, and future research combining drug discrimination with other techniques promises to clarify ibogaine's mechanism of action.