Download - Ibogaine Dr.Moshe Zer-Zion Beer-Yaacov Mental Health Center Israel

IbogaineDr.Moshe Zer-Zion

Beer-Yaacov Mental Health CenterIsrael

Ibogaine

Ibogaine

Ibogaine is a naturally occurring plant alkaloid in the West Central Africa’s shrub Tabernante Iboga

The plant is used for religious and medical purposes by the Bwiti culture. (Gabon)

NIDA has given significant support to animal research and the FDA has approved Phase I studies in humans

Evidence for Ibogaine’s effectiveness includes reduced drug use and less withdrawal signs in animals and humans.

Ibogaine

Is the most abundant alkaloid in the root bark of the shrub Tabernanthe iboga.

In the dried root bark total alkaloid content is reportedly 5% to 6%

It undergoes demethylation to form it’s principal metabolite noribogaine.

18 MC is an Ibogaine congener.It seems to have efficacy similar to I.with less potential toxicity

Forms in Current Use

• Botanical - root bark


Total alkaloid extract Large piece 2cm x 2cm, approx 4

grams Estimate 15% Ibogaine


Purified Ibogaine HCl (Endabuse) 99.4% purity

Brief Historical Time Line


1864-A first description of T.Iboga is published 1885- A published description of the ceremonial use of

the T.Iboga in Gabon appears. 1901- I. Is isolated and crystallized from T.Iboga root

bark 1939-1970 I. Is sold in France as Lambarene ,”a

neuromuscular stimulant” for fatigue,depression and recovery from infectious disease


1962-1963 In the USA Howard Lotsof administered I. to 19 individuals at dosages of 6 to 19 mg/kg including 7 with Opioid dependency who noted an apparent effect on acute withdrawal symptoms

1969-Claudio Naranjo ,a psychiatrist, received a French patent for the psychotherapeutic use of I. at a a dosage of 4 to 5 mg/kg

1967-1970 The WHA classifies I. With hallucinogens and stimulants .The FDA: assigns I. Schedule I classification


1985- Howard Lotsof received a US patent for use of I. To treat Opioid withdrawal(additional patents for indications of dependency on cocaine,alcohol,nicotine and poly-substance abuse)

1988-1994-US and Dutch researchers published initial findings in animals:diminished Opioid self administration and withdrawal + diminished cocaine self administration

1991-NIDA :I. Project.(pre-clinical toxicological evaluation and

development of a human protocol)


1993-Dr Deborah Mash got approval for human trials.The dosage:1,2,5 mg/kg.Activity is eventually suspended

NIDA ends its I.project:opinions of the industry mostly critical 1997 begins the I. Mailing List


1990-2001 I. Becomes increasingly available in alternative settings in view of the lack of approval in the USA and Europe.(Panama- St.Kitts)

Mechanisms of Action

I. Appears to have a novel mechanism of action I.effects may result from complex interactions

between multiple neurotransmitter systems I.reaches high concentrations in the brain after

injection of 40 mg/kg intra-peritoneal.

Glutamate

Glutamate

There’s evidence that antagonists of the NMDA subtype of Glutamate receptors are a potentially promising class of agents for the development of medications for addiction

I.apparent activity as a noncompetitive NMDA antagonist has been suggested to be a possible mechanism of anti-addictive action

Glutamate

Ibogaine Competitively inhibits the binding of the NMDA

antagonist MK 801 Reduced Glutamate induced cell death in neuronal

cultures Reduction of NMDA-activated currents in hippocampal

cultures Prevention of NMDA-mediated depolarization in frog

moto-neurons Protection against NMDA-induced seizures Glycine attenuates I.effect I.lowered the concentration of Dopamine and its

metabolites but MK 801 did not

Glutamate

Learning ,memory and neuro-physiology

Da and Glutamate are involved in neuroplastic modulation of normal and pathological learning (hippocampus)

It is apparent that Ibogaine influences the neurological processes involved in learning addictive behavior

Through NMDA receptors, Ibogaine influences the process of LTP (learning,memory and neuroplasticity)

Opioid

Opioid

Ibogaine and noribogaine are Mu and Kappa receptor agonists

But Ibogaine and Noribogaine have not anti-nociceptive effects.

I. May act at the second messenger level Ibogaine and Noribogaine potentiated Morphine

induced inhibition of adenylyl cyclase in the Mo. occupied receptors

Opioid

Kappa stimulants imitate the action of Ibogaine at reducing cocaine and morphine self administration

Serotonin

Serotonin

Ibogaine binds to Serotonin transporter and increases Serotonin levels in the NAc

Noribogaine binds x 10 strongly than Ibogaine. Some suggest I. May reduced Dopamine secretion

through Serotonin activity in the NAc

Dopamine

Dopamine Ibogaine is a competitive dopamine

transporter blocker I.reduces dopamine levels and increases

dopamine metabolites levels I. decreases Prolactin levels

Acetylcholine

Ibogaine is a nonselective and weak inhibitor of binding to muscarinic receptor subtypes.

Functional evidence of muscarinic agonistic effect:decrease heart rate and effects on the EEG (dyssynchrony)

Ganglionic nicotinic blockade with reduced secretion of Catecholamines in cultures

Sigma Receptors There are not known natural endogenous

ligands for them Sigma2 receptors binding is relatively strong in

the CNS The I. Toxic effects are attributed to mediation

through sigma2receptors. They increase the NMDA receptors activity.

Sigma Receptors

Sigma 2 receptors contribute to motoric behavior regulation.Some attribute them a role in the mechanism of side effects like TD and dysthonia

Their activation causes cell death through apoptosis.

Iboga alkaloids selectively bind sigma 2 receptors.They increase the [Ca] and activate apoptosis.

Glial cell line-derived neurotrophic factor (GDNF)

A molecular mechanism that mediates the desirable activities of Ibogaine on ethanol intake.

Microinjection of Ibogaine into the ventral tegmental area (VTA) reduced self-administration of ethanol

Systemic administration of Ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA.

Summary of Mechanisms of Action of Ibogaine

Kappa agonist Opioid (morphine) and stimulant (cocaine)

self-administration NMDA antagonist

Opioid self-administration Opioid physical dependence (withdrawal)

Nicotinic antagonist Nicotine self-administration (smoking)

Summary of Mechanisms of Action of Ibogaine

Serotonin uptake inhibitor Alcohol intake Hallucinations

Sigma-2 agonist Cerebellar neurotoxicity

Lipid solubility and metabolism Long -term effects

Possible effects on Neuroadaptations Related to Drug Sensitization or Tolerance

Ibogaine treatment might result in the “resetting”or “normalization”of neuro-adaptations related to drug sensitization or tolerance.

Ibogaine pretreatment blocked the expression of sensitization-induced increases in the release of dopamine in the Nac shell.

Opposition or reversal of effects on second messenger (adenylyl cyclase)

Evidence of efficacy in Animal models

Drug Self-administration Acute Opioid withdrawal Conditioned place preference Locomotor activity Dopamine efflux.

Drug Self-Administration Reduction in morphine,heroine,cocaine,alcohol and

nicotine self-administration. The effects are apparently persistent (five days in rats) but

water intake stopped just for a day. The results improved with repeated treatments. Noribogaine has also been reported to reduce |Mo,Cocaine

and Heroine self administration Some of the Iboga alkaloids tested produce tremors. 18-MC reduces drugs intake but not water intake.

Acute Opioid withdrawal


Dose-dependent attenuation of Naloxone precipitated Opioid withdrawal symptoms.

Similar results were evident in monkeys.

Conditioned place preference

Ibogaine is reported to prevent the acquisition of place preference when given 24 h previous to amphetamine or Morphine.

Locomotor activity

Diminishes Locomotor activation in response to Morphine.

Dopamine efflux.

In Ibogaine,Noribogaine or 18-MC treated animals t was shown a reduction of Da secretion in the Nac.

The effects on the Nac’s shell explain the motivational effects and those on the Nac’s core explain the motor actions.

This action is supposed to be related to the effect on Da secretion through NMDA and kappa receptors.

Evidence of efficacy and subjective effects in humans

Acute Opioid withdrawal Accounts of the addicts themselves,whose

demand has led to an informal treatment network in Europe and the US.

Opioid dependence is the most common indication

Common reported features are reduction in drug craving and opiate withdrawal signs and symptoms within 1 to 2 hours and sustained effects


Alper et al. summarized 33 cases treated for the indication of Opioid detoxification : Resolution of the withdrawal signs and symptoms without

further drug seeking behavior in 25 patients. Significantly reduced craving

Mash et al .reported having treated more than 150 patients in St.Kitts,West Indies. (2001) Reduction of measures of craving and depression were stable

till one month Ibogaine showed equally effective in methadone and heroine

detoxification

Long-TermOutcomes Lotsof presented at a NIDA Ibogaine Review Meeting Held in March 1995 a summary of patients treated between 1993 – 1962:

38 reported some use of Opioid 10 of them were additionally dependent on other

drugs(cocaine,alcohol or sedative-hypnotics) Total of 52 treatments 15 (29%) Cessation of use for less than 2 months 15 (29%)Cessation of use for more than 2 months but less

than 6 months. 7 (13% )for at least 6 months but less than a year. 10 (19%) for a period greater than a year. 5 (10% )of outcomes could not be determined

Subjective Effects

Subjective Effects Acute :

The onset of this phase is within 1 to 3 hours of ingestion with a duration of 4 to 8 hours

The predominant reported experiences appear to be a panoramic readout of long-term memory(“visit to the ancestors ,archetype”)

“Oneiric experience”

Subjective Effects

Evaluative or visualization: Onset after 4 to 8 hours after ingestion with a

duration of 8 to 20 hours The volume of material recalled slows Attention is still focused on inner subjective

experience rather than external environment. Patients are easily distracted and annoyed

and prefer little environmental stimulation

Subjective Effects

Residual stimulation The onset of this phase is approximately 12

to 24 hours after ingestion with a duration in the range of 24 to 72 hours.

Allocation of attention to the external environment

Less subjective psychoactive experience Mild residual subjective arousal or vigilance Some patients report reduced need for

sleep for several days to weeks

Pharmacokinetics

Absorption: Dose dependent oral bio-availability Greater bio-availability in females because of gender related

differences in absorption kinetics. High hepatic first pass effect

Distribution: High hepatic extraction Highly lipophilic [Ibogaine] 100 times grater in fat and 30 times greater in brain Platelets might sequester Ibogaine

Pharmacokinetics

Metabolism The main metabolite is Noribogaine.It’s formed through

demethylation via CYP2D6 isoform. Noribogaine is a more polar substance

Because Pharmacokinetics differences, poor,good and intermediate metabolizers were identified.

Excretion Half- life on the order of 7.5 hours in humans .I. And

Noribogaine are excreted through the kidneys and GI system. In humans’ 90% of a single 20mg/kg oral dose are eliminated

in 24 hours Noribogaine is eliminated much slower.(“high half life”)

Each form has

1. Different onset

2. Different duration of action

3. And significant diversity across the patient population


Onset of Effects (min)

020406080

100120140160

HCl Extract

Full EffectOnset

Period of visuaization (hours)

02468

10121416

HCl Extract

Exte nde d

Visua liza t io n

Onse t


Duration of Action (days)

0123456789

10

HCl Extract

Re sidua l

Principa l


Effect on sleep (weeks)

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10

HCl

Re sidua l

Principa l


Dose and Dose Regimen

1.Single dose

2.Multiple

1.Escalating

2.Deescalating

3.Linear


All doses are representative.

Doses, including single administration doses are determined on a patient by patient basis.

The graphs of dose regimens and information that follow should not be used by persons without experience to self-administer or administer to others any dose of Ibogaine or total alkaloid extract of Tabernanthe iboga.


Single dose regimens usually fall between 10mg/kg and 22mg/kg depending on type of therapy offered: Opioid dependency, stimulant dependency, psycho spiritual, etc.

Most doses fall in the 15mg/kg - 20mg/kg dose range to reach full therapeutic effects.


ibogaine HCl (mg/ hour)20mg methadonetotal - 1000mg

350

175 175 175125

050

100150200250300350400

0 h1 h2 h3 h4

HCl


ibogaine HCl (mg/ kg/ hour)heroin therapytotal 21.5mg.kg

courtesy Eric Taub

2,5

14

5

2468

10121416

0 1h h12

HCl


ibogaine HCl (mg/ kg/ hour)methadone therapytotal 36.5 mg/ kg

courtesy Eric Taub

2,5 2,5 2,5 2,5 2,5

12

3 3 3 32468

10121416

0 13 23 30 34 36 59 68 77 89 100

HCl

Frequent side effects of Ibogaine

Coordination disturbances (unstable gait and tendency to fall)

Hallucinations-like experiences Sleep disturbances Concentration and speech

troubles Heart rate and blood pressure

changes Nausea and vomiting Dizziness Light sensitivity Tiredness Muscles soreness

Safety

Neurotoxicity Tremor Cardiovascular effects Fatalities Abuse liability

Safety

Neurotoxicity Multiple laboratories have reported on the

degeneration of Cerebellar Purkinje cells in rats given 100mg/kg I.p.

This neurotoxicity is mediated through NMDA receptors activated by sigma 2 agonists in the Olivo-Cerebellar projection.

Safety

Tremor Positive with Ibogaine Negative with Noribogaine which lacks a

methoxy group at position 10 or 11 Negative with 18-MC which lacks methoxy

group at position 10 but in position 16 LD50 145 mg-kg ip and 327 mg kg po in Rats

Observations in Humans

Postural stability Body and appendicular tremor Cardiovascular effects

Mash et al .:intensive cardiac monitoring in 39 human subjects dependent on cocaine and/or heroine who received fixed p.o. doses of 500 mg, 600mg, 800mg ,1000mg

Six of them exhibited some significant decrease of resting pulse rate relative to baseline

One of them experienced a decrease in BP because vasovagal reflex.

No EKG change was identified Possible hypotensive response in some cocaine dependent

subjects (responsive to volume repletion)


Fatalities: between 1990-1994 a few patients previously treated with Ibogaine died in Holland,France,G.Britain and the US In France :a woman age 44 died 4 hours after

receiving a dose of 4.5 mg/kg p.o. Autopsy revealed an old MI and severe IHD The possibility of a direct toxic effect of Ibogaine was

excluded. In Holland : a patient aged 24 died as a result of

respiratory arrest. The PM was not revealing and they were evidences of

surreptitious heroine use


There are evidences of increase toxicity of opiates while using them with Ibogaine

This incident call the attention to the need for adequate monitoring and for the completition of dose escalation studies

In the US : a patient died 25 days after treatment.The cause was an aortic clott.

It was established that Ibogaine had no causal relationshiop to death

The patient got 4 Ibogaine treatments in the year and a half previous to death

Abuse liability The available evidence does not appear to suggest a

significant potential for abuse I. Is reportedly neither rewarding or aversive in the

Conditioned place preference paradigm Rats given Ibogaine for 6 days showed no withdrawal

symptoms after interruption. Animals do not self administer 18-MC None of the consultants to NIDA in the 1995 Ibogaine

Review Meeting identified the possible abuse as a possible safety concern

According to Kaplan and Sadock:there’s little concern about Ibogaine liability to abuse because users do not like the physical side effects at a hallucinogenic dose of 1500mg

Ibogaine Testing

Download - Ibogaine Dr.Moshe Zer-Zion Beer-Yaacov Mental Health Center Israel

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