Ibogaine Analogues: Drug Development for Addictive Disorders Stanley D. Glick, Ph.D., M.D. Center for Neuropharmacology and NeuroscienceTHE EUROSCIENCES N EUROSCIENCESINSTITUTE Albany Medical Center

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 PHYSICAL DEPENDENCE can occur without ADDICTION

July 10, 1996 Dr. M.A. Geyer Managing Editor Psychopharmacology Department of Psychiatry School of Medicine University of California San Diego La Jolla, CA Dear Dr. Geyer: Enclosed are four copies of our revised manuscript (MS96MG-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 nicotine-induced 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. Sincerely, Isabelle Maisonneuvebbbbbbb VTA 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…” 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…” July 10, 1996 Dr. M.A. Geyer Managing Editdggggggggor Psychopharmacology University of California Sa Dear Dr. Geyer: Enclosed are four copies of our revised manuscript (MS96MG-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 nicotine-induced 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. Sincerely, Isabelle Maisonneuve, IShofd Wtray Addicts are desperate for new therapies

Once upon a time in Africa… Tabernanthe iboga shrub Ibogaine is contained in the roots of the shrubs. Ibogaine has been used for centuries in rituals of the Bwiti religion. Cameroon Eq. Guinea Gabon 2 Congos

At very high concentrations, side effects are present… 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: (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 Treatment dosage number of responses The ideal treatment will not affect responding for a non- drug reinforcer (e.g., water, food, sucrose). The ideal treatment will depress responding for a drug of abuse

Effects of 18-MC on responding for morphine, cocaine and water 18-MC selectively decreases morphine and cocaine self- administration.       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 self- administration, but is most potent in decreasing nicotine self-administration.        

Effects of 18-MC on alcohol intake    Rezvani et al., Pharmacol. Biochem. Behav., 58: (1997). 18-MC decreases alcohol intake at doses that do not affect food intake.

18-MC reduces the efficacy of morphine I don’t like morphine as much since I took 18-MC 18-MC produces a significant downward shift in the dose- response curve for morphine self- administration.

18-MC’s effects on drug self- administration are persistent      18-MC decreases cocaine self-administration for 24 hours 18-MC decreases morphine self-administration for 48 hours

Opioid withdrawal weight loss wet dog shakes flinching teeth chattering grooming burying diarrhea

18-MC reduces the intensity of several signs of morphine withdrawal     Weight loss Wet dog shakes Flinching Burying Grooming   Teeth chattering Diarhea Effects of 18-MC on opioid withdrawal signs

18-MC is a potentially effective anti-addictive treatment 1.18-MC decreases the self- administration of multiple drugs of abuse 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 3x100mg/kg, i.p. 18-MC at very high doses does not produce any Purkinje cell damage. Ibogaine at very high doses damages Purkinje cells.

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?

saline Cumulative responses 18-MC (0.8 mg/kg/infusion) Cumulative responses 18-MC itself is not reinforcing cocaine (0.4 mg/kg/infusion) Cumulative responses cocaine cocaine (0.4 mg/kg/infusion) Cumulative responses saline Cumulative responses 18-MC

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 MC may not be hallucinogenic 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 = prefrontal cortex NAC = nucleus accumbens VTA = ventral tegmental area VTA NAC PFC 18-MC may interact with the “reward pathways”. dopaminergic neurons

In vivo microdialysis

Effect of 18-MC on sensitized cocaine-induced dopamine release Acute cocaine increases dopamine release in the nucleus accumbens. After chronic administration cocaine releases much more dopamine in the nucleus accumbens. This is called sensitization. 18-MC abolishes the sensitization of cocaine-induced dopamine release.

18-MC abolishes drug sensitization. Why is this important? abuse addiction abstinence relapse use craving 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) 18-MC has no affinity for NMDA receptors. 18-MC has no affinity for 5-HT uptake sites. 18-MC has very low affinity for sigma receptors. With which receptors does 18-MC interact?

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 Patch-pipette Cell Receptor Recording system

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 18-MC and ibogaine block the nAch receptor currents in cells co- transfected with rat  3 and  4 receptor subunits. 200 pA 1 sec Ach 1 mM 18-MC 20  M IBO 20  M

18-MC does not interact with  4  2 nicotinic receptors Ibogaine, but not 18-MC, blocks the nAch receptor currents in cells co-transfected with rat  4 and  2 receptor subunits. 250 pA 10 sec Ach 300  M 18-MC 5  M IBO 5  M 50% inhibition

Where are  3  4 nicotinic receptors located ? interpeduncular nucleus medial habenula

IP mHb VTA NAC Connections between habenulo- interpeduncular and mesolimbic systems mHb = medial habenula IP = interpeduncular nucleus VTA = ventral tegmental area NAC = nucleus accumbens R = raphe nuclei PFC = prefrontal cortex MD = medial dorsal thalamic nucleus IP mHb VTA NAC PFC IP mHb VTA NAC R MD

Is 18-MC blockade of  3  4 nicotinic receptors relevant to its anti-addictive effects? 1.Effects of combination of low doses of non- specific  3  4 nicotinic receptors on drug self- administration 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 IC50 (  M) mecamylamine (Papke et al., 2001; Hernandez et al., 2000) bupropion1.4 (Fryer and Lukas, 1999) dextromethorphan8.9 (Hernandez et al., 2000) 18-MC 0.75 (Glick et al., 2002) Mecamylamine, an antihypertensive agent (Inversine®), is a non- specific 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®, DexAlone™, Pertussin®, Robitussin®, Sucrets®), is also a NMDA receptor antagonist.

Effects of  3  4 drug combinations on morphine self-administration All drug combinations REDUCED morphine self- administration. Mec1 Bup5 DM5 MC1 Mec1 Mec1 Mec1 DM5 DM5 MC Bup5 DM5 MC1 Bup5 MC1 Bup5 Mec1 = mecamylamine (1 mg/kg, i.p.) Bup5 = bupropion (5 mg/kg, i.p.) DM5 = dextromethorphan (5 mg/kg, s.c.) MC1 = 18-methoxycoronaridine (1 mg/kg, i.p.)       At low doses, NONE of these agents affected morphine self- administration.

Effects of  3  4 drug combinations on methamphetamine self-administration All drug combinations REDUCED methamphetamine self- administration. Mec1 Bup10 DM10 MC5 Mec1 Mec1 Mec1 DM10 DM5 MC Bup10 DM5 MC2 Bup10 MC2 Bup10 Mec1 = mecamylamine (1 mg/kg, i.p.) Bup10 = bupropion (10 mg/kg, i.p.) DM5 = dextromethorphan (5 mg/kg, s.c.) DM10 = dextromethorphan (10 mg/kg, s.c.) MC2 = 18-methoxycoronaridine (2 mg/kg, i.p.) MC5 = 18-methoxycoronaridine (5 mg/kg, i.p.)      

Effects of  3  4 drug combinations on nicotine self-administration All drug combinations REDUCED nicotine self- administration. Mec.1 Bup5 DM.5 MC.1 Mec.1 Mec.1 Mec.1 DM.5 DM.5 MC Bup5 DM.5 MC.1 Bup5 MC.1 Bup5 Mec.1 = mecamylamine (0.1 mg/kg, i.p.) Bup5 = 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. Mec1 Bup10 DM10 MC5 Mec1 Mec1 Mec1 DM10 DM5 MC Bup10 DM5 MC2 Bup10 MC2 Bup10 Mec1 = mecamylamine (1 mg/kg, i.p.) Bup10 = bupropion (10 mg/kg, i.p.) DM5 = dextromethorphan (5 mg/kg, s.c.) DM10 = dextromethorphan (10 mg/kg, s.c.) MC2 = 18-methoxycoronaridine (2 mg/kg, i.p.) MC5 = 18-methoxycoronaridine (5 mg/kg, i.p.)

Effects of interpeduncular administration of 18-MC on drug self-administration 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%. interpeduncular nucleus 

Correlations between blockade of  3  4 nicotinic receptors and drug self-administration How much a congener of 18-MC decreases drug self-administration 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 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 MC should lack all of ibogaine’s prominent side effects 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.

VTA NAC PFC COLLABORATORS Isabelle Maisonneuve Martin Kuehne Lindsay Hough Milt Teitler Katharine Herrick-Davis Helen Molinari Mark Fleck