Download IBOGAINE

DPA - Nov. 2009
What We Know….
What We Don’t Know…
What We think We Know.
Jeffrey D. Kamlet, MD, FASAM, DABAM
FABFE, DABFM, DABFP,
Brief History
 Derived from the route bark of the West African Shrub
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Tabernanthe iboga.
Tribes in Gabon and Cameroon still use the drug as a sacrament.
1950-1960’s; Ciba-Geigy patents the drug for ‘potentiation of
Morphine Analgesia’.
1962; Howard Lotsof, serendipitously discovers ibogaine’s antiaddictive properties.
1985; Lotsof patents the drugs use as a rapid method for
“interrupting narcotic addiction syndrome.”
Studies at Albany Medical College, showed drugs efficacy in
animal studies. (Glick, et. al)
University-run human clinical trials begin in Rotterdam,
Netherlands.
Brief History
 1993; Dutch government withdrew support from study due
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to a single death of a patient post, ibogaine (What role, if
any ibogaine played in the death remains uncertain.)
1991-1995; NIDA initiates its own US clinical studies.
1995; under pressure of pharmaceutical industry
continued ibogaine research is deemed ‘too expensive’.
1995; D. Mash,PhD, receives FDA approval to conduct lowdose tests on cocaine-dependent human subjects at
University of Miami.
1996; Mash self funds her study by treating paying
customers in an off shore clinic on St. Kitts, BWI.
1996; Mash recruits Dr. Jeffrey Kamlet, an addictionist,
internist and former ER Director, in the clinical trials.
Brief History
 2005; St. Kitts clinic closed.
 2007; Mash submits data to the FDA.
 Private patents expire and ibogaine’s applications entered public
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domain, resulting in the inability of ‘Big Pharma’ to have
exclusive rights to drug’s applications.
Average cost to bring a prospective drug through clinical trials as
required by FDA costs around $300,000-$500,000 millions
Ibogaine vs. noribogaine as the treatment of the future?
18-MC vs. noribogaine as the active metabolite has been debated.
18 –MC appears as one of many active CNS metabolites of
ibogaine associated with the visionary, introspective, addiction
interrupting and anti craving effects of single dose ibogaine
administration.
Mechanism of Action
 Ibogaine,HCl, administered orally, is converted via hepatic,
Cytochrome P-450, II-D6, (CPD450) pathway into the fat
soluble/CNS/ long acting metabolite
noribogaine.
 Ibogaine is psychoactive and visionary. No one has been
able to divorce ibogines visionary (mislabled
hallucinogenic) effects from it’s addiction blocking
properties. Thus issues of societal bias and safety concerns
arose. Terminology is important <Hallucinogen vs.
Entheogen vs. Remogen>
 Noribogaine, the active metabolite, is a pseudo-irreversible
agonist of Mu and Kappa opiate receptors.
 A long acting, ‘Depo’ effect, exists for noribogaine
 Resulting in, rapid detoxification from opiates and other
drugs dependency. High affinity for specific opioid receptor
with low intrinsic activity
 alleviation of PAWS (Post Acute Withdrawal Syndrome) for
30-90 days post single Ibogaine ingestion.
 Increased serotonin levels post treament-Super, sticky,
long acting Prozac like effect after single dose ibogaine
administration. Mechanism of action of ibogaine’s
metabolites on CNS serotonin levels, must be a different
then that of SSRI’s, as side effect profiles, differ greatly
from each other.
 No causal link between ibogaine use and reported Post
- ibogaine treatment deaths (24 hours) or Peri ibogaine treatment deaths (72 hours), has been
determined.
 Approximately 11 people died within 72 hours of
ibogaine ingestion as DOA treatment between 1990
and 2006. (Dr. Ken Alper’s studies).
 More deaths have since been reported.
 Mash and/or Kamlet, have successfully treated over
500 without any morbidity or mortalities.
Safety Issues
 Hepatic metabolism via P450,II-D6 metabolism.
 Other p-450 metabolized drugs, foods, fruits , beverages, or neutricueticals on
board at time of treatment is extremely dangerous!
 P450 hepatic metabolism, is directly related prolonged ‘QT interval’ on ECG’s
 The “QTc”, is the corrected QT interval for associated heart rate.)
 QT prologation causes, Ventricular tachyarrhythmia's
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TDP “torsades de pointes”
VPC’s
V-tach
V-fib
Negative Chronotropic effect = brady-cardia = slowing of heart rate.
ST-T wave morphology changes of uncertain etiology reported that appear to
be unrelated to QTc.
Hypotension, possibly due to bradycardic effect of Ibogaine?
“Seizure like attack”, reported in NEJM 01/15/09). Dose related?
Observations and Hypothesis
 Cardiac irritability, maybe related to the DOA being taken prior to ibogaine
administration, increasing cardiac adverse events.
 Changes in S-T and T wave morphology anecdotally noted occurring from peak Ibogaine
levels (conversion of ibogaine to noribogaine) and lasting up to 24 hours.
 Possibly related ibogaine conversion to nor-Ibogaine (Hepatic vs. direct cardiac effects
vs. CNS effects).
 Ibogaine and /or it’s metabolites, be acting as, Cardiac, Ca+, Mg+, K+, Na+ Channel
Blockers. (Ca+ Channel Blockers are known Cardiac/HTN, prescription medications)
 Slow, Average and Rapid, Hepatic Metabolizers, of ibogaine. The way a client will
metabolize ibogaine is directly related to one’s genetics, thus affecting their ibogaine
experience and possibly, the amount of noribogaine made
 A small percentage of the population has genetic “Prolonged QT Syndrome”.
 Metabolism genetics may correlate to the period of “dream like visualization phase ” vs.
“analytical phase” and the amount of noribogaine produced.
 ?- Tachyarrhythmias and or prolonged QT interval related to serum electrolyte levels
(Mg+, K+, Ca+). Doesn’t appear to be the answer but low or high serum electrolytes will
always place a patient at increased risk for cardiac arrthymias
Long-QT Syndrome Induced by the Antiaddiction Drug Ibogaine
N ENGL J MED 360;3 NEJM.ORG JANUARY 15, 2009
 31 year old woman, received Ibogaine in Netherlands for
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treatment resistant alcohol addiction.
Admitted to ER with ‘seizure like attack’ after single ingestion of
3.5 grams of Ibogaine 15% (Usual dose 2-6 grams).”
??? Was she detoxified from alcohol first???information not given in NEJM report.
Remember, acute alcohol (ETOH) withdrawal, in an ETOH
dependent patient carries a high intrinsic risk of withdrawal
seizures , which peak at 48-72 hours after ETOH cessation.
‘No reported drugs or alcohol in her system’ at time of admission
to ICU.
No family history of cardiac-rhythm abnormalities.
Patient’s ECG
ECG
 Severe prolonged QT interval 548 msec/ QTc 616 msec
 Prolonged ventricular tachyarrhythmias
 Mild hypo-magnesemia
 Hypo-kalemia
 Normal serum osmol gap
 Despite rapid correction of her serum electrolyte
levels, the QT interval remained prolonged and did
not normalize for 42 hours.
 The patient was subsequently discharged in good
condition
Question and Hypothesis
 Has cardiac rhythm abnormalities, induced by QT interval
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lengthening, played a role in any Ibogaine deaths???
Acute withdrawal of ETOH and Benzodiazepines in
patients dependent to these substances have a high,
inherent, risk of acute withdrawal seizures.
Typical anti seizure prophylaxis drugs, have NOT been
shown to be effective as prophylaxis for alcohol or benzo
acute cessation
? Ibogaine efficacy for quick detoxification of
benzodiazepine dependent patients. Does it work for
benzo’s at all?
Dopamine pathway vs. GABA pathway. DOA’s specific
effects on CNS.
Conclusion
Future trials of the drug should be permitted only under strict medical guide lines of;
pre-clearance,
patient selection,
continuous electrocardiographic, vital signs, and other monitoring.
Murphy’s Law
Be prepared for any possible medical problem. Addicts are in general, not a physically healthy patient population
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Treatment should be administered by trained medical personnel.
Ibogaine, Clinic and Treatment Provider Certification. A hope for the future.
PRIMUM, NO NOCERE
Informed consent from means cogent knowledge of the full; Generalities, Alternatives and Risk, of
treatment
Safety Measures
 Pre screening:
 CBC, full electrolytes, renal function, LFT’s, TFT’s, Serum Mg+ levels
…..(comprehensive metabolic panels). You can’t be too cautious or
check too much.
 Complete medical and family history.
 Understanding of poly-pharmacy of drugs and all other substances,
illegal and legal, regardless of route of ingestion, in the clients system,
before and at time of treatment.
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DOA screening. <Qualitative vs. Quantitative>.
Caution with all centrally acting/CNS drugs .
Caution with Seretonergic drugs .
P450-II D6 drugs
Drugs with long acting half lives. (Oxycontin, fentanyl patches, methadone,
LAAM, depo injections), should be D/C’d, prior to ibogaine treatment (3-4 half
lives)
Switch over to short acting medications. (ie; methadone and buprenorphine
patients changed to short acting opiates like,HC, hydromorphone, morphine)
Safety Measures Pre-treatment
 ECG
 24 hour holter monitoring
 Consider echocardiogram
 Caution! Benzodiazepines – Keep on or detox off first.
 Caution! alcohol dependency – stabilize first
 Patient selection, Patient selection, patient selection!
 “One size does not fit all.”
Immediate, Pre Treatment Safety
Protocols:
 Hydrate (NS or RL, 1-2 liters pre-ibogaine ingestion).
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Caution with patients with renal failure, HTN, CHF
Continuous Cardiac, BP, pulse, pulse-oximetry monitoring.
Pre treatment with diphenhydramine, IM
Include Mg+ and consider KCl, in pre treatment IV fluids
Continuous IV access during and post treatment until
vitals and ECG have been stable (16-24+ hours on average)
Every case is unique and nothing should be ever, “rubber
stamped !”
QT Prolongation and Methadone as a
Correlate to Ibogaine Administration
 SAMHSA and FDA Launch Methadone Safety
campaign
 Mandatory ECG screening at onset and yearly for
MMT
 Annals of Internal Medicine, published guidelines
 Critical need for thoroughly understanding torsade de
pointes
 Netherlands study  low incidents, low mortality in
MMT patients
Ventricular Arrhythmias vs. TDP
 Recognition of the correct arrhythmia is critical
 Class II-b anti-arrhythmic’s, contra-indicated for treatment
of TDP
arrthymics
Recognition of;
ectopy”.
IV Lidocaine, vs.
IV Mg+, vs.
Cardio-version, vs.
Synchronized cardio-version, vs.
2nd and 3rd generation IV anti“Significant” vs. “non-significant
What is on the Horizon????
 2005, ibogaine, reportedly found to express GDNF
(glia-derived-neurotropic-factor). ???? In theory….
 Regenerates dopamine neurons suppressed by drugs of
abuse
 ‘Back-signals’ , to cell nucelii to express more GDNF
 Results in a benign, self-sustaining, loop that obviates
need for artificial elevation of dopamine levels.
 Persists without administration of additional Ibogaine.
What is on the Horizon?
 Anti-viral effects
 ?? A, direct effect of, or as a result off ??
 Hepatitis C
 HTLV-I
 HTLV-III
 HIV
What is on the Horizon?
 Psychiatric illness
 Depression
 OCD
 ?- personality disorders
IF THIS IS MUMBO JUMBO TO YOU,
DON’T TREAT!
 Every answer gives birth to one hundred new
questions.
Experts are available.
Consider risk vs. benefit.
There are always other means of detoxification and
stabilization.