Ibogaine Analogues: Drug Development for Addictive Disorders Stanley D. Glick, Ph.D., M.D. Center...

Ibogaine Analogues: Ibogaine Analogues: Drug Development for Drug Development for

Addictive Disorders Addictive Disorders

Stanley D. Glick, Ph.D., M.D.

Center for Neuropharmacology and Neuroscience

THETHE

NEUROSCIENCESEUROSCIENCESINSTITUTEINSTITUTE

Albany Medical Center

Drug Abuse / Drug Drug Abuse / Drug DependenceDependence

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 DEPENDENCEADDICTION can occur without PHYSICAL DEPENDENCEPHYSICAL DEPENDENCE can occur without ADDICTIONPHYSICAL DEPENDENCE can occur without ADDICTION

July 10, 1996

Dr. M.A. GeyerManaging EditorPsychopharmacologyDepartment of PsychiatrySchool of MedicineUniversity of California San DiegoLa Jolla, CA 92093-0804

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. GeyerManaging EditdggggggggorPsychopharmacologyUniversity 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 Psychopharmacolog1- 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 Addicts are desperate for new therapiesfor new therapies

Once upon a time in Once upon a time in Africa…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.

CameroonEq. GuineaGabon2 Congos

At very high concentrations, At very high concentrations, side effects are present…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…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 treatmentIs 18-MC a potential treatmentfor drug dependence?for drug dependence?

1. Is 18-MC effective in reducingdrug self-administration?

2. Is 18-MC effective in reducing signs of drug withdrawal?

Drug self-administrationDrug self-administration

Effect of an ideal treatmentEffect of an ideal treatment

Treatment dosage

num

ber

of

resp

on

ses

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

0 10 20 30 40

0

20

40

60

80

100

120

Perc

ent

of b

asel

ine

18-MC (mg/kg, i.p.)

Water Cocaine Morphine

Effects of 18-MC on respondingEffects of 18-MC on respondingfor morphine, cocaine and waterfor morphine, cocaine and water

18-MC selectively decreases

morphine and cocaine self-

administration.

0 10 20 30 400

20

40

60

80

100

120

Perc

ent

of b

asel

ine

I bogaine (mg/kg, i.p.)

Water Cocaine Morphine

Ibogaine also affects responding

for water.

0 10 20 30 40

0

20

40

60

80

100

120

Perc

ent

of b

asel

ine

18-MC (mg/kg, i.p.)

Methamphetamine Nicotine

Effects of 18-MC on respondingEffects of 18-MC on respondingfor methamphetamine and for methamphetamine and

nicotinenicotineFemale 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 intakeEffects of 18-MC on alcohol intake

0 10 20 30 400

10

20

30

40

50

0 10 20 30 400

25

50

75

100

Food

inta

ke (g

/kg/

day)

18-MC (mg/kg, i.p.)

Food intake Alcohol intake

Alcohol intake (m

l/kg/day)

Rezvani et al., Pharmacol. Biochem. Behav., 58:615-619 (1997).

18-MC decreases alcohol intake at doses that do not

affect food intake.

18-MC reduces 18-MC reduces the efficacy of morphinethe efficacy of morphine

0.00 0.04 0.08 0.12 0.160

10

20

30

Infu

sion

s/ho

ur

Morphine (mg/kg/infusion)

Vehicle 18-MC (40 mg/kg, p.o.)

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-18-MC’s effects on drug self-administration are persistentadministration are persistent

Base Day 1 Day 2 Day 3 Day 6 Day 70

20

40

60

Mor

phin

e in

fusi

ons/

hour

Test Session

Control 18-MC (40 mg/kg, i.p.)

Base Day 1 Day 2 Day 3 Day 6 Day 70

10

20

30

Coca

ine

infu

sion

s/ho

ur

Test SessionBase Day 1 Day 2 Day 3 Day 6 Day 7

0

20

40

60

Mor

phin

e in

fusi

ons/

hour

Test Session

Control 18-MC (40 mg/kg, i.p.)

18-MC decreasescocaine self-

administration for 24 hours

18-MC decreasesmorphine self-administration

for 48 hours

Opioid withdrawalOpioid withdrawal

•weight loss•wet dog shakes•flinching•teeth chattering•grooming•burying•diarrhea

18-MC reduces the intensity of several signs of

morphine withdrawal

Control 10 20 400

5

10

15

Wei

ght

loss

18-MC (mg/kg, i.p.)

Control 10 20 400

20

40

60

80

100

Wet

dog

sha

kes

18-MC (mg/kg, i.p.)Control 10 20 40

0

5

10

15

20

Groo

min

g

18-MC (mg/kg, i.p.)

Control 10 20 400

5

10

Bury

ing

18-MC (mg/kg, i.p.)

Control 10 20 400

1

2

3

Dia

rrhe

a

18-MC (mg/kg, i.p.)

Weig

ht

loss

Wet

dog

shake

s

Control 10 20 400

5

10

15

Flin

chin

g

18-MC (mg/kg, i.p.)Fl

inch

ing

Bu

ryin

gG

room

ing

Control 10 20 400

10

20

30

Teet

h ch

atte

ring

18-MC (mg/kg, i.p.)

Teeth

chatt

eri

ng

Dia

rhea

Effects of 18-MCEffects of 18-MCon opioid withdrawal signson opioid withdrawal signs

18-MC is a potentially effective 18-MC is a potentially effective anti-addictive treatmentanti-addictive treatment

1. 18-MC decreases the self-administration of multiple drugs of abuse.

2. 18-MC alleviates several signs of morphine withdrawal.

Does 18-MC have side effects?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 toxicity18-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 ibogaineEffects of 18-MC and ibogaineon heart rate and blood pressureon heart rate and blood pressure

18-MC (200 mg/kg, ip) has no apparent effects on

heart rate and blood pressure.

0 20 40 60 80 100 120 140 160 180 200 220 240

75

100

125

Per

cent

of

base

line

18-MCvehicle

Time (minutes)

Systolic Diastolic Heart rate

0 20 40 60 80 100 120 140 160 180 200 220 240

75

100

125

ibogainevehicle

Time (minutes)

Systolic Diastolic Heart rate

Per

cent

of

base

line

Ibogaine (200 mg/kg, ip) decreases heart rate without

altering blood pressure.

-60 0 60 120 1800

500

1000

1500

2000

2500

3000

Per

cent

of

Base

line

Time (minutes)

I bogaine 18-MC

(40 mg/kg, i.p.)

18-MC does not increase18-MC does not increaseextracellular serotonin levelsextracellular serotonin levels

Ibogaine, but not 18-MC, increases

extracellular serotonin levels in

the nucleus accumbens.

So I won’t hallucinate

?

0 10 20 30 40 50 600

10

20

30

40

Time (min)

saline

Cu

mu

lati

ve r

esp

on

ses

0 10 20 30 40 50 600

10

20

30

40

Time (min)

18-MC (0.8 mg/kg/infusion)

Cu

mu

lati

ve r

esp

on

ses

18-MC itself is not reinforcing18-MC itself is not reinforcing

0 10 20 30 40 50 600

10

20

30

40

Time (min)

cocaine (0.4 mg/kg/infusion)

Cu

mu

lati

ve r

esp

on

sescocaine

0 10 20 30 40 50 600

10

20

30

40

Time (min)

cocaine (0.4 mg/kg/infusion)

Cum

ula

tive r

esp

onse

s

saline

0 10 20 30 40 50 600

10

20

30

40

Time (min)

saline

Cum

ula

tive r

esp

onse

s

18-MC

18-MC has no apparent18-MC has no apparentside effectsside 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 What are the pharmacokinetic properties of 18-MC?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 Pharmacokinetics of 18-MC (40 mg/kg, i.v.)(40 mg/kg, i.v.)

0 20 40 60 80 100 1200

1000

2000

3000

4000

5000

6000

n=5 one-compartment fit

T1/2

= 10.2 min two-compartment fit

T1/2a = 6.2 min

T1/2b = 109.4 min

Plas

ma

(±)-

18-M

C (n

g/m

l)

Time (minutes)

The data do not fit a one-

compartment model.

Tissue distribution of 18-MCTissue distribution of 18-MC(4 hr)(4 hr)

Plasma Brain Fat0

500

1000

1500

2000

ng/g

or

ng/m

l

p.o. i.p.

Plasma Brain0

20

40

60

18-MC is sequestered in fat.

18-MC metabolites18-MC metabolites(TLC)(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 What is the mechanism of action of 18-MC?of action of 18-MC?

PFC = prefrontal cortexNAC = nucleus accumbensVTA = ventral tegmental area

VTANAC

PFC

18-MC may interact with the “reward pathways”.

dopaminergic neurons

In vivo In vivo microdialysismicrodialysis

Effect of 18-MC on sensitized Effect of 18-MC on sensitized cocaine-induced dopamine cocaine-induced dopamine

releaserelease

-60 0 60 120 1500

500

1000

1500

2000

2500

Perc

ent

of b

asel

eine

Cocaine(20 mg/kg, i.p.)

Acute

Time (min)-60 0 60 120 150

0

500

1000

1500

2000

2500

Perc

ent

of b

asel

eine


AcuteChronic cocaine:

Vehicle- pretreated

Time (min)

Acute cocaine increases dopamine

release in the nucleus accumbens.

-60 0 60 120 1500

500

1000

1500

2000

2500

Perc

ent

of b

asel

eine


AcuteChronic cocaine:

Vehicle- pretreated

18-MC- pretreated

Time (min)

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 18-MC abolishes drug sensitization.sensitization.

Why is this important?Why is this important?

abuse addiction

abstinencerelapse

usecraving

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 With which receptorsreceptors

does 18-MC does 18-MC interact?interact?

-30 0 30 6050

100

150

200

250

300

350

Nicotine (80 g, i.v., 5 min)

Per

cent

of

Base

line

Time (minutes)

Vehicle 18-MC (40 mg/kg, i.p.)

Effect of 18-MCEffect of 18-MCon nicotine-induced dopamine releaseon 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 electrophysiologyPatch-clamp electrophysiologyWhole-cell recordingWhole-cell recording

Patch-pipette

Cell Receptor

Recording system

Whole-cell recordingWhole-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 18-MC interacts with aa33bb4 nicotinic receptors4 nicotinic receptors

18-MC and ibogaine block the

nAch receptor currents in cells co-transfected

with rat a3 andb4 receptor subunits.

20

0 p

A

20

0 p

A

20

0 p

A

1 sec 1 sec 1 sec

Ach 1 mM18-MC 20 MIBO 20 M

18-MC does not interact with 18-MC does not interact with aa44bb2 nicotinic receptors2 nicotinic receptors

Ibogaine, but not 18-MC, blocks the

nAch receptor currents in cells co-transfected

with rat a4 andb2 receptor subunits.

25

0 p

A

25

0 p

A

10 sec 10 sec

Ach 300 M18-MC 5 MIBO 5 M

50% inhibition

Where are Where are aa33bb4 nicotinic 4 nicotinic receptorsreceptors located ?located ?

interpeduncular nucleus

medial habenula

IP

mHb

VTANAC

Connections between habenulo-interpeduncular and mesolimbic

systems

mHb = medial habenula IP = interpeduncular nucleus VTA = ventral tegmental areaNAC = nucleus accumbensR = raphe nucleiPFC = prefrontal cortexMD = medial dorsal thalamic nucleus

IP

mHb

VTANAC

PFC

IP

mHb

VTANACR

MD

Is 18-MC blockade of Is 18-MC blockade of aa33bb4 nicotinic 4 nicotinic receptors relevant toreceptors relevant to

its anti-addictive effects?its anti-addictive effects?

1. Effects of combination of low doses of non-specific a3b4 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 a3b4 nicotinic receptors and their effects on drug self-administration

Non-specific Non-specific aa33bb4 nicotinic 4 nicotinic antagonistsantagonistsDRUG IC50 (M)

mecamylamine 0.09-1.0 (Papke et al., 2001; Hernandez et al.,

2000) bupropion 1.4 (Fryer and Lukas, 1999)

dextromethorphan 8.9 (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 Effects of aa33bb4 drug combinations4 drug combinationson morphine self-administrationon morphine self-administration

All drug combinations

REDUCED morphine self-administration.

Mec1 Bup5 DM5 MC1 Mec1 Mec1 Mec1 DM5 DM5 MC1 + + + + + + Bup5 DM5 MC1 Bup5 MC1 Bup5

Mec1 = mecamylamine (1 mg/kg, i.p.)Bup5 = bupropion (5 mg/kg, i.p.)

0

5

10

15

20

25

30

35

40

45

Mor

phin

e In

fusi

ons/

hour

Baseline Treatment

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.

0

5

10

15

20

25

30

35

Met

ham

phet

amin

e In

fusi

ons/

hour

Baseline Treatment

Effects of Effects of aa33bb4 drug combinations4 drug combinationson methamphetamine self-on methamphetamine self-

administrationadministration


REDUCEDmethamphetami

ne self-administration.


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.)

0

5

10

15

20

25

30

35

40

Nic

otin

e In

fusi

ons/

hour

Baseline Treatment

Effects of Effects of aa33bb4 drug combinations4 drug combinationson nicotine self-administrationon nicotine self-administration


REDUCEDnicotine self-

administration.

Mec.1 Bup5 DM.5 MC.1 Mec.1 Mec.1 Mec.1 DM.5 DM.5 MC.1 + + + + + + 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.)

0

200

400

600

800

1000

1200

Wat

er B

ar P

ress

es/h

our

Baseline Treatment

Effects of Effects of aa33bb4 drug combinations4 drug combinationson water respondingon water responding

NONE of the drug

combinations had an effect on responding for

water.


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.)

0

5

10

15

20

25

30

35

Mor

phin

e In

fusi

ons/

hour

Vehicle (n=8) 18-MC (n=10)

Effects of interpeduncular Effects of interpeduncular administration of 18-MC administration of 18-MC

on drug self-administrationon 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

20

40

60

80

100

85 90 95 100

20

40

60

80

100

85 90 95 100

Percent of a3b4 inhibition

Perc

ent of

bas

elin

e: sel

f-ad

min

istr

atio

n

morphiner = -.67p < 0.05

methamphetaminer = -.75p < 0.02

Per

cent

of

base

line:

sel

f-ad

min

istr

atio

n

Percent of a3b4 inhibition

Correlations between Correlations between blockade of blockade of aa33bb4 nicotinic receptors4 nicotinic receptors

and drug self-administrationand drug self-administration

How much a congener of 18-MC decreases

drug self-administration is related to how

well it can block a3b4 nicotinic

receptors.

Is 18-MC blockade of Is 18-MC blockade of aa33bb4 nicotinic 4 nicotinic receptors relevant toreceptors relevant to

its anti-addictive effects?its anti-addictive effects?

1. Combinations of low doses of non-specific a3b4 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 a3b4 nicotinic receptors and their effects on drug self-administration.

ConclusionsConclusions1.1. 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.

2.2. 18-MC should lack all of ibogaine’s prominent side effects.

3.3. 18-MC abolishes the dopamine sensitization that occurs with chronic drug administration and that may underlie craving and relapse.

4. An antagonist action at a3b4 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 applicationClinical application

Antagonism of acetylcholine’s actions at a3b4 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 HoughMilt Teitler

Katharine Herrick-Davis

Helen MolinariMark Fleck

Ibogaine Analogues: Drug Development for Addictive Disorders Stanley D. Glick, Ph.D., M.D. Center...

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