THE NEUROSCIENCES INSTITUTE Albany Medical Center for Neuropharmacology and Neuroscience Ibogaine Analogues: Drug Development for Addictive Disorders Stanley D. Glick, Ph. D. , M. D.
Drug Abuse / Drug Dependence = Drug/substance abuse = Self-administered use of any drug/substance in a manner that deviates from the approved medical or social standards within a given culture = Addiction or psychological dependence = Repeated, compulsive seeking or use of a substance despite adverse social, psychological and/ or physical consequences = Chronic relapsing disorder = Physical dependence = Adaptive, physiological state produced by repeated drug administration that is manifested as a withdrawal syndrome. ADDICTION can occur without PHYSICAL DEPENDENCE can occur without ADDICTION
Addicts are desperate for new therapies July 10, 1996 Dr. M. A. Geyer Managing Editor Psychopharmacology Department of Psychiatry School of Medicine University of California San Diego La Jolla, CA 92093 -0804 Dear Dr. Geyer: Enclosed are four copies of our revised manuscript (MS 96 MG-095) entitled, "Ibogaine And The Dopaminergic Response To Nicotine, " authored by S. D. Glick, G. L. Mann, C. R. Deibel and myself which we would like to resubmit for publication in Psychopharmacology. 1 - We do not think that it would be appropriate to discuss the report of. Dworkin et al. (1995) in this manuscript, since we do not report any self-administration results. Dworkin, using Fisher rats, reported that ibogaine alters all reinforcers (food, drug) with limited effects a day later. Our laboratory, using Sprague Dawley rats, showed that ibogaine alters all reinforcers (water, drug) on the day of its administration, but only the drug reinforcers later on (Glick et al. 1991). The strain difference may explain this inconsistency. It should also be noted that Cappendijk and Dzoljic (1993) reported effects of ibogaine on cocaine self-administration that were very similar to our results (Glick et al. 1994). The effects of mecamylamine on DOPAC and HVA increases induced by nicotine are described in the results section and, as requested by the reviewer, plotted as Figure 3. We have incorporated in Figure 2 the dopamine baseline values preceding mecamylamine administration and the 30 min levels prior to nicotine infusion. In the discussion (pages 12 -13) the effects of ibogaine and mecamylamine on the dopamine response to nicotine are compared, and the greater efficacy of ibogaine to alter the nicotine-induced increase in dopamine as compared to DOPAC and HVA is addressed. It is true that the phenomenon of nicotineinduced desensitization has been widely studied using numerous techniques. However, direct in vivo neurochemical measurements were made only by Damsma in 1989 who did not observe any acute tolerance to the dopaminergic response to nicotine. In this context, our findings are very interesting. Thank you for your consideration. IShofd Sincerely, Isabelle Maisonneuvebbbbbbb July 10, 1996 Dr. M. A. Geyer Managing Editdggggor Psychopharmacology University of California Sa Dear Dr. Geyer: Enclosed are four copies of our revised manuscript (MS 96 MG-095) entitled, "Ibogaine And The Dopaminergic Response To Nicotine, " authored by S. D. Glick, G. L. Mann, C. R. Deibel and myself which we would like to resubmit for publication in Psychopharmacolog 1 - We do not think that it would be appropriate to discuss the report of Dworkin et al. (1995) in this manuscript, since we do not report any self-administration results. Dworkin, using Fisher rats, reported that ibogaine alters all reinforcers (food, drug) with limited effects a day later. Our laboratory, using Sprague Dawley rats, showed that ibogaine alters all reinforcers (water, drug) on the day of its administration, but only the drug reinforcers later on (Glick et al. 1991). The strain difference may explain this inconsistency. It should also be noted that Cappendijk and Dzoljic (1993) reported effects of ibogaine on cocaine self-administration that were very similar to our results (Glick et al. 1994). The effects of mecamylamine on DOPAC and HVA increases induced by nicotine are described in the results section and, as requested by the reviewer, plotted as Figure 3. We have incorporated in Figure 2 the dopamine baseline values preceding mecamylamine administration and the 30 min levels prior to nicotine infusion. In the discussion (pages 12 -13) the effects of ibogaine and mecamylamine on the dopamine response to nicotine are compared, and the greater efficacy of ibogaine to alter the nicotine-induced increase in dopamine as compared to DOPAC and HVA is addressed. It is true that the phenomenon of nicotineinduced desensitization has been widely studied using numerous techniques. However, direct in vivo neurochemical measurements were made only by Damsma in 1989 who did not observe any acute tolerance to the dopaminergic response to nicotine. In this context, our findings are very interesting. Thank you for your consideration. Wtray Sincerely, Isabelle Maisonneuve, December 9, 1999 “…I am currently married and have a three year old daughter. I have used heroin on and off since I was 16 years old, more on than off… I have attended numerous substances abuse program and detoxes… I started a business and bought a house with my wife. Unfortunately, I am losing both due to my addiction. I crave heroin constantly, only heroin. I overdosed ten days ago and this wasn’t the first time. I’ll try anything that might help me to stay clean and straight. Please consider me as a candidate for your research protocol…” VTA February 16, 2000 “…I am 63 years old and I have been using heroin for well over 25 years, never having the willpower or success to kick the habit once and for all. At this point I know that I must stop and desperately want to. Somehow, I’ve managed to hold onto my county job for the past 13 years, and must continue to keep it for at least 4 more years. We have recently filed for bankruptcy, and our condo is in foreclosure; yet it can become even worse if I don’t get a grip on this habit. I have many reasons to stop, not least of all for the sake of my children, grandchildren and wife who is not at all that well herself. I would be so very grateful sir, if you could take the time to give me some idea, some direction as to how I might go about signing up or at least trying to participate in your research…”
Once upon a time in Africa… Tabernanthe iboga shrub Cameroon Eq. Guinea Gabon 2 Congos Ibogaine is contained in the roots of the shrubs. Ibogaine has been used for centuries in rituals of the Bwiti religion.
At very high concentrations, side effects are present… Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. O'Hearn, E. and Molliver, M. E. Neuroscience 55: 303 -310 (1993).
The search for a better ibogaine… 1. It had to be as effective as ibogaine. 2. It had to lack all the side effects of ibogaine.
Is 18 -MC a potential treatment for drug dependence? 1. Is 18 -MC effective in reducing drug self-administration? 2. Is 18 -MC effective in reducing signs of drug withdrawal?
Drug self-administration
Effect of an ideal treatment number of responses The ideal treatment will not affect responding for a nondrug reinforcer (e. g. , water, food, sucrose). The ideal treatment will depress responding for a drug of abuse Treatment dosage
Effects of 18 -MC on responding for morphine, cocaine and water 18 -MC selectively decreases morphine and cocaine selfadministration. * * Ibogaine also affects responding for water. * *
Effects of 18 -MC on responding for methamphetamine and nicotine Female rats * * * * 18 -MC selectively decreases methamphetamine and nicotine selfadministration, but is most potent in decreasing nicotine self-administration.
Effects of 18 -MC on alcohol intake * * * 18 -MC decreases alcohol intake at doses that do not affect food intake. Rezvani et al. , Pharmacol. Biochem. Behav. , 58: 615 -619 (1997).
18 -MC reduces the efficacy of morphine 18 -MC produces a significant downward shift in the doseresponse curve for morphine selfadministration. I don’t like morphine as much since I took 18 -MC
18 -MC’s effects on drug selfadministration are persistent 18 -MC decreases morphine self-administration for 48 hours * * 18 -MC decreases cocaine self-administration for 24 hours * * *
Opioid withdrawal • weight loss • wet dog shakes • flinching • teeth chattering • grooming • burying • diarrhea
* * Diarhea Flinching Grooming * * Burying Teeth chattering Wet dog shakes Weight loss Effects of 18 -MC on opioid withdrawal signs * 18 -MC reduces the intensity of several signs of morphine withdrawal *
18 -MC is a potentially effective anti-addictive treatment 1. 18 -MC decreases the selfadministration of multiple drugs of abuse. 2. 18 -MC alleviates several signs of morphine withdrawal.
Does 18 -MC have side effects? 1. Nerve cell damage? 2. Cardiovascular toxicity? 3. Is 18 -MC likely to cause hallucinations? 4. Is 18 -MC addictive (i. e. , reinforcing)?
18 -MC has no cerebellar toxicity Ibogaine 18 -MC One month after 3 x 100 mg/kg, i. p. Ibogaine at very high doses damages Purkinje cells. 18 -MC at very high doses does not produce any Purkinje cell damage.
Effects of 18 -MC and ibogaine on heart rate and blood pressure 18 -MC (200 mg/kg, ip) has no apparent effects on heart rate and blood pressure. Ibogaine (200 mg/kg, ip) decreases heart rate without altering blood pressure.
18 -MC does not increase extracellular serotonin levels * ** Ibogaine, but not 18 -MC, increases extracellular serotonin levels in the nucleus accumbens. * * * So I won’t hallucinate?
Cumulative responses cocaine saline 18 -MC saline Cumulative responses 18 -MC itself is not reinforcing cocaine (0. 4 mg/kg/infusion) cocaine(0. 8 mg/kg/infusion) 18 -MC saline (0. 4 mg/kg/infusion)
18 -MC has no apparent side effects 1. Unlike ibogaine, 18 -MC does not induce tremors and does not damage the cerebellum. 2. Unlike ibogaine, 18 -MC has no ill effect on the heart. 3. 18 -MC may not be hallucinogenic. 4. 18 -MC is not reinforcing and should not be liable to abuse.
What are the pharmacokinetic properties of 18 -MC? 1. What is its half-life? 2. Is it uniformly distributed throughout the body? 3. Does it have any metabolites?
Pharmacokinetics of 18 -MC (40 mg/kg, i. v. ) The data do not fit a one-compartment model.
Tissue distribution of 18 -MC (4 hr) 18 -MC is sequestered in fat.
18 -MC metabolites (TLC) Volume ( l) of sample spotted 18 -MC may have several metabolites; the most important one has been shown to be 18 -OH-coronaridine.
What is the mechanism of action of 18 -MC? PFC NAC 18 -MC may interact with the “reward pathways”. VTA PFC = prefrontal cortex NAC = nucleus accumbens VTA = ventral tegmental area dopaminergic neurons
In vivo microdialysis
Effect of 18 -MC on sensitized cocaine-induced dopamine release After chronic administration cocaine Acute cocaine 18 -MC abolishes the releases much more increases dopamine sensitization of cocaine dopamine in the release in the nucleus -induced dopamine nucleus accumbens. release. This is called sensitization.
18 -MC abolishes drug sensitization. Why is this important? relapse craving abstinence use abuse addiction Drug sensitization may underlie craving and the cyclic nature of addiction. By abolishing drug sensitization 18 -MC may prevent relapse and promote abstinence.
Ibogaine and 18 -MC binding affinities (Ki in M) With which receptors does 18 -MC interact? 18 -MC has no affinity for NMDA receptors. 18 -MC has very low affinity for sigma receptors. 18 -MC has no affinity for 5 -HT uptake sites.
Effect of 18 -MC on nicotine-induced dopamine release 18 -MC, administered 19 hours beforehand, abolishes nicotine-induced dopamine release in the nucleus accumbens. * * * So 18 -MC may block nicotinic receptors. But which ones?
Patch-clamp electrophysiology Whole-cell recording Recording system Patch-pipette Cell Receptor
Whole-cell recording In the presence of receptor agonist Movement of positive ions from the outside to the inside of the cell is an INWARD current and is shown as a DOWNWARD deflection. This is due to receptor desensitization.
18 -MC interacts with 3 4 nicotinic receptors 1 sec Ach 1 m. M 18 -MC 20 m. M IBO 20 m. M 200 p. A 1 sec 18 -MC and ibogaine block the n. Ach receptor currents in cells cotransfected with rat a 3 and b 4 receptor subunits.
18 -MC does not interact with 4 2 nicotinic receptors 50% inhibition Ach 300 M 18 -MC 5 m. M IBO 5 m. M 10 sec 250 p. A 10 sec Ibogaine, but not 18 -MC, blocks the n. Ach receptor currents in cells cotransfected with rat a 4 and b 2 receptor subunits.
Where are 3 4 nicotinic receptors located ? medial habenula interpeduncular nucleus
Connections between habenulointerpeduncular and mesolimbic systems m. Hb NAC IP VTA PFC NAC m. Hb MD VTA IP NAC m. Hb R VTA IP m. Hb = medial habenula IP = interpeduncular nucleus VTA = ventral tegmental area NAC = nucleus accumbens R = raphe nuclei PFC = prefrontal cortex MD = medial dorsal thalamic nucleus
Is 18 -MC blockade of 3 4 nicotinic receptors relevant to its anti-addictive effects? 1. Effects of combination of low doses of nonspecific 3 4 nicotinic receptors on drug selfadministration 2. Effects of interpeduncular administration of 18 -MC on drug self-administration 3. Correlations between potencies of 18 -MC congeners to block 3 4 nicotinic receptors and their effects on drug self-administration
Non-specific 3 4 nicotinic antagonists DRUG IC 50 ( M) mecamylamine bupropion dextromethorphan 0. 09 -1. 0 (Papke et al. , 2001; Hernandez et al. , 2000) 1. 4 (Fryer and Lukas, 1999) 8. 9 (Hernandez et al. , 2000) 18 -MC 0. 75 (Glick et al. , 2002) Mecamylamine, an antihypertensive agent (Inversine®), is a nonspecific nicotinic receptor antagonist. Bupropion, an antidepressant (Wellbutrin®) and an anti-smoking aid (Zyban®), is also a dopamine uptake blocker. Dextromethorphan, an antitussive in many OTC cough medicines (Benylin®, Delsym®, Dex. Alone™, Pertussin®, Robitussin®, Sucrets®), is also a NMDA receptor antagonist.
Effects of 3 4 drug combinations on morphine self-administration * * Mec 1 Bup 5 DM 5 MC 1 Mec 1 = mecamylamine (1 mg/kg, i. p. ) Bup 5 = bupropion (5 mg/kg, i. p. ) * * Mec 1 DM 5 MC 1 + + + Bup 5 DM 5 MC 1 Bup 5 DM 5 = dextromethorphan (5 mg/kg, s. c. ) MC 1 = 18 -methoxycoronaridine (1 mg/kg, i. p. ) At low doses, NONE of these agents affected morphine self. All drug administration. combinations REDUCED morphine selfadministration.
Effects of 3 4 drug combinations on methamphetamine self-administration * * * Mec 1 Bup 10 DM 10 MC 5 All drug combinations REDUCED methamphetamine selfadministration. Mec 1 DM 10 DM 5 MC 5 + + + Bup 10 DM 5 MC 2 Bup 10 Mec 1 = mecamylamine (1 mg/kg, i. p. ) Bup 10 = bupropion (10 mg/kg, i. p. ) DM 5 = dextromethorphan (5 mg/kg, s. c. ) DM 10 = dextromethorphan (10 mg/kg, s. c. ) MC 2 = 18 -methoxycoronaridine (2 mg/kg, i. p. ) MC 5 = 18 -methoxycoronaridine (5 mg/kg, i. p. )
Effects of 3 4 drug combinations on nicotine self-administration * Mec. 1 Bup 5 DM. 5 MC. 1 * * * All drug combinations REDUCED nicotine selfadministration. Mec. 1 DM. 5 MC. 1 + + + Bup 5 DM. 5 MC. 1 Bup 5 Mec. 1 = mecamylamine (0. 1 mg/kg, i. p. ) Bup 5 = bupropion (5 mg/kg, i. p. ) DM. 5 = dextromethorphan (0. 5 mg/kg, s. c. ) MC. 1 = 18 -methoxycoronaridine (0. 1 mg/kg, i. p. )
Effects of 3 4 drug combinations on water responding NONE of the drug combinations had an effect on responding for water. Mec 1 Bup 10 DM 10 MC 5 Mec 1 DM 10 DM 5 MC 5 + + + Bup 10 DM 5 MC 2 Bup 10 Mec 1 = mecamylamine (1 mg/kg, i. p. ) Bup 10 = bupropion (10 mg/kg, i. p. ) DM 5 = dextromethorphan (5 mg/kg, s. c. ) DM 10 = dextromethorphan (10 mg/kg, s. c. ) MC 2 = 18 -methoxycoronaridine (2 mg/kg, i. p. ) MC 5 = 18 -methoxycoronaridine (5 mg/kg, i. p. )
Effects of interpeduncular administration of 18 -MC on drug self-administration * interpeduncular nucleus Local administration of 18 -MC (10 µg in 1 µl) into both interpeduncular nuclei, immediately prior to the session, decreased responding for morphine by 35%.
Correlations between blockade of 3 4 nicotinic receptors and drug self-administration How much a congener of 18 -MC decreases drug selfadministration is related to how well it can block 3 4 nicotinic receptors.
Is 18 -MC blockade of 3 4 nicotinic receptors relevant to its anti-addictive effects? 1. Combinations of low doses of non-specific 3 4 nicotinic receptor antagonists decrease drug self-administration. 2. Interpeduncular administration of 18 -MC decreases morphine self-administration. 3. There are significant correlations between potencies of 18 -MC congeners to block 3 4 nicotinic receptors and their effects on drug self-administration.
Conclusions 1. 18 -MC may be useful in treating many forms of drug addiction, including opioid (e. g. , heroin) and stimulant (e. g. , cocaine, methamphetamine) abuse, alcoholism and smoking. 2. 18 -MC should lack all of ibogaine’s prominent side effects. 3. 18 -MC abolishes the dopamine sensitization that occurs with chronic drug administration and that may underlie craving and relapse. 4. An antagonist action at 3 4 nicotinic receptors appears to be 18 -MC’s most important action. 18 -MC has greater selectivity for this site than either ibogaine or other existing agents.
Clinical application Antagonism of acetylcholine’s actions at 3 4 nicotinic receptors may constitute a novel mechanism and strategy for reducing addiction to multiple drugs. Low dose combinations of existing agents (i. e. , dextromethorphan, mecamylamine and bupropion) may be viable therapies, and readily testable, in lieu of single agents acting specifically at this site.
COLLABORATORS Isabelle Maisonneuve PFC Martin Kuehne VTA Lindsay Hough Milt Teitler NAC Katharine Herrick-Davis Helen Molinari Mark Fleck
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