1. 18-methoxycoronaridine A review by Jonathan Freedlander, BA

2. Introduction Synthetic iboga alkaloid congener Developed by team at Albany Medical College – Primary investigator: Stanley Glick Similar anti-addictive effects as ibogaine seen in animal research Non-tremerogenic and non-neurotoxic May not be a psychedelic

3. Effects No evidence of tremorogenic activity Does not decrease heart rate, ibogaine can No evidence of neurotoxicity at doses up to 300 mg/kg –Glick et al hypothesize that ibogaine’s putative neurotoxicity at high doses is due to its overstimulation of the olivio-cerebellar pathway, damaging Purkinje cells Attenuates self-administration of cocaine, morphine, alcohol, methamphetamine, and nicotine in rats

4. Attenuates of symptoms of morphine withdrawal (teeth chattering, wet-dog shakes, and diarrhea) Does not affect grooming behavior –Ibogaine decreases grooming behaviour (grooming behavior is another sign of morphine withdrawal in rats) Does decrease burying behavior (another withdrawal symptom) –Ibogaine does not decrease burying behavior

5. Least effective on methamphetamine, most effective on nicotine Longer lasting reduction of morphine self administration than ibogaine Approximately twice as potent in attenuation of oral nicotine self- administration as ibogaine Attenuation of morphine and cocaine self- administration lasted at least a day, and up to two weeks after repeated administration

6. Some rats responded to treatment (for morphine and cocaine) after one dose, some after two or doses, and a few did not respond at all 18-MC pretreatment enhances morphine induced locomotor activation in acute morphine treat rats, but blocks locomotor sensitization in rats having been repeatedly administered morphine –Ibogaine reduces morphine induced locomotion in acute morphine treated rats

7. Does not affect responding for a nondrug reinforcer (water) –Ibogaine has been shown to decrease responding for water Like ibogaine, attenuates and then increases cocaine and methamphetamine induced locomotion and stereotypy Like ibogaine, reduces methamphetamine induced behavioral disinhibition and novelty seeking –As measured by # of entries into the open arm of a maze

8. Pharmacology Primary mechanism of action thought to be decrease of extracellular dopamine and the DA metabolite dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (NAC) –Does not affect level of DA metabolite homovanillic acid (HVA) in the NAC –Attenuates nicotine, morphine, and cocaine induced dopamine release –May affect cocaine induced locomotion via action at some sites downstream of the midbrain dopamine neurons

9. –Does not affect basal dopamine,HVA, or DOPAC –Lack of effect on HVA shows that it may exert its dopaminergic effects by interfering with DA release mechanisms, without affecting DA synthesis Unlike ibogaine, does not cause an increase in extracellular serotonin in the nucleus accumbens –This is why it is hypothesized that 18-MC may not be psychedelic

10. Like ibogaine, acts as an antagonist at  3  4 nicotinic receptors Similar affinity for kappa opioid receptors as ibogaine Significantly lower affinity for delta opioid receptors than ibogaine –This is presumed to be the reason for the difference in effects on morphine induced locomotion

11. Has much lower affinities than ibogaine for NMDA and sigma-2 receptors, sodium channels, and the 5-HT transporter Like ibogaine, is sequestered in fat Metabolism catalyzed by CYP2C19 Primary metabolite: 18-hydroxycoronaridine (18-HC)

12. Limitations Has only been tested on laboratory animals Has only been administered intraperitonally Studies have been conducted by a small set of researchers May not be psychedelic - this could conceivably be a limitation, as the visualizations caused by ibogaine seem to play a significant role in its therapeutic actions in humans

13. References Glick, S. D., Kuehne, M. E, Maisonneuve, I. M., Bandarage, U. K., and Molinari, H. H. (1995). 18-Methoxycoronaridine, a non-toxic iboga alkaloid congener: effects on morphine and cocaine self-administrtion and on mesolimbic dopamine release in rats. Brain Research, Vol. 719, 29 -35. Glick, S. D., Maisonneuve, I. M., and Dickinson, H. A. (2000). 18-MC reduces methamphetamine and nicotine self-administration in rats. NeuroReport, Vol. 11, 2013 - 2015. Glick, S. D., Maisonneuve, I. M., and Dickinson, H. A. (2000). 18- Methoxycoronaridine attenuates nicotine-induced dopamine release and nicotine preferences in rats. Psychopharmacology, Vol. 139, 274 - 280. Glick, S., D., Maisonneuve, I. M., Kitchen, B. A., Fleck, M. W. (2002). Antagonism of A3B4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. European Journal of Pharmacology, Vol 438., 99- 105. Maisonneuve, I. M., Visker, K. E., Mann G. L., Bandarage, U. K., Kuehne, M. E, Glick, S. D. (1997). Time- dependent interactions between iboga agents and cocaine. European Journal of Pharmacology, Vol. 336, 123 - 126. Mundey, M. K., Blaylock, N. A., Mason, R., Glick, S. D., Maisonneuve, I. M., and Wilson, V. G. (2000). Pharmacological comparison of the effect of ibogaine and 18-methoxycoronaridine on isolated smooth muscle from the rat and guinea-pig. British Journal of Pharmacology, Vol. 129, 1561 - 1568.

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