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A preliminary report on the safety and pharmacokinetics of ibogaine
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BIOL PSYCHIATRY 1995;37:593-683
Antipsychotic plasma level or dose/clinical response relationships can be viewed as parallel issues, in that they both may define a threshold for response as well as an upper end to a possible therapeutic window. We have conducted a two-phase targeted haloperidol plasma level study in which 91 acutely psychotic hospitalized patients were randomly assigned to a low, middle, or high plasma level based on data from previous fixed dose studies. In phase A the low group mean plasma level was 2.0 ng/ml, the middle group was 13 ng/ml, and the high group 41 ng/ml on average doses of 3.3 mg/day, 25 mg/day, and 51 rag/day, respectively. Changes in total BPRS scores, the psychosis factor, or positive symptom subscale did not differ among the three groups. In phase B, 50% of the phase A nonresponders in the low and high groups were randomly reassigned to the middle range. When the low and middle plasma level groups were compared, there was a significant positive correlation between response and plasma level (i.e., threshold; r= 0.58; p = 0.007). We also found a significant negative correlation between resfxmse and plasma level for the middle- and the high-dose group comparison (i.e., r= ~).40; p = 0.02). In our study the threshold for response lies at or below 2 ng/ml (mean dose = 3.3 mg/day), with an average dose of 3.3 mg sufficient for many patients. Adjusting the plasma level into the middle range led to a greater improvement in our nonresponding low- or high-group patients, however.
212. A PRELIMINARY REPORT ON THE SAFETY A N D PHARMACOKINETICS OF IBOGAINE D.C. Mash I, R. Douyon 2, W.L. Hearn 3, N.C. SamboP, & J. Sanchez-Ramos 1 1Departments of N e u r o l o g y and 2Psychiatry, University of M i a m i School o f Medicine, 33101; 3Metro-Dade C o u n t y Medical E x a m i n e r D e p a r t m e n t , M i a m i , FL 33136, and the 4School o f P h a r m a c y , University o f California, San Francisco, C A 94143
FRIDAY, MAY 19
lbogaine (NIH 10567) is a psychoactive indole alkaloid derived from the roots of the rain forest shrub Tabernanthe iboga. The use of ibogaine for the treatment of drug dependence has been based on the anecdotal reports from addict self-help groups that it may decrease the signs of opiate withdrawal and reduce craving for cocaine and heroin for extended time periods. Preclinical studies in rodents have shown that ibogaine reduces morphine self-administration, ameliorates signs of opiate withdrawal, and decreases cocaine preference. Ibogaine and other indole alkaloids are centrally acting drugs that produce tremorogenic and hallucinogenic effects. At present, there is little information available on ibogaine levels in body fluids or on the identification of major or minor metabolites. Information on the phannacokinetics and metabolism of ibogaine is important for developing optimal dosing schedules for clinical trials. The purpose of the present study was to develop a pharmacokinetic-pharmacodynamic model for the characterization of the neurological and behavioral effects of ibogaine in human patient volunteers. Safety assessments in this study included standard laboratory tests and electrocardiograms. The patients were evaluated with a neurological battery that focused on cerebellar signs including postural and kinetic tremors, truncal ataxia, and gait instability. Blood and urine samples were assayed for ibogaine and metabolites by liquid-liquid extraction and gas chromatography/mass spectrometry (GC/MS). We have identified the primary metabolite as 12-hydroxyibogamine (noribogaine) by evaluation of its full scan electron impact mass spectrum and its identity confirmed by comparison with an authentic standard (s.a. OmniChem, Louvain-la Neuve, Belgium). The preliminary model that best fit the ibogaine and noribogaine data simultaneously was one which includes a peripheral compartment for ibogaine (i.e., a twocompartment model), some first-pass metabolism of ibogaine to noriIx~gaine, conversion of ibogaine to noribogaine postabsorption, and additional elimination of ilx~gaine (other than by conversion to noribogaine). The time required to eliminate the majority of absorbed ibogaine (>90%) was 24 hr postdose. The time course for the appearance of mild tremor and ataxia was best correlated with the blood levels or the parent drug. The pharmacokinetic data demonstrate that the amount of noribogaine in blood at 24 hr was still quite appreciable. These results suggest that the primary metabolite of ibogaine may have a long half-life in humans. We speculate that the putative anticraving properties of ibogaine may result from the slow elimination of the active metabolite noribogaine.
BIOL PSYCHIATRY 1995;37:593-683
Antipsychotic plasma level or dose/clinical response relationships can be viewed as parallel issues, in that they both may define a threshold for response as well as an upper end to a possible therapeutic window. We have conducted a two-phase targeted haloperidol plasma level study in which 91 acutely psychotic hospitalized patients were randomly assigned to a low, middle, or high plasma level based on data from previous fixed dose studies. In phase A the low group mean plasma level was 2.0 ng/ml, the middle group was 13 ng/ml, and the high group 41 ng/ml on average doses of 3.3 mg/day, 25 mg/day, and 51 rag/day, respectively. Changes in total BPRS scores, the psychosis factor, or positive symptom subscale did not differ among the three groups. In phase B, 50% of the phase A nonresponders in the low and high groups were randomly reassigned to the middle range. When the low and middle plasma level groups were compared, there was a significant positive correlation between response and plasma level (i.e., threshold; r= 0.58; p = 0.007). We also found a significant negative correlation between resfxmse and plasma level for the middle- and the high-dose group comparison (i.e., r= ~).40; p = 0.02). In our study the threshold for response lies at or below 2 ng/ml (mean dose = 3.3 mg/day), with an average dose of 3.3 mg sufficient for many patients. Adjusting the plasma level into the middle range led to a greater improvement in our nonresponding low- or high-group patients, however.
212. A PRELIMINARY REPORT ON THE SAFETY A N D PHARMACOKINETICS OF IBOGAINE D.C. Mash I, R. Douyon 2, W.L. Hearn 3, N.C. SamboP, & J. Sanchez-Ramos 1 1Departments of N e u r o l o g y and 2Psychiatry, University of M i a m i School o f Medicine, 33101; 3Metro-Dade C o u n t y Medical E x a m i n e r D e p a r t m e n t , M i a m i , FL 33136, and the 4School o f P h a r m a c y , University o f California, San Francisco, C A 94143
FRIDAY, MAY 19
lbogaine (NIH 10567) is a psychoactive indole alkaloid derived from the roots of the rain forest shrub Tabernanthe iboga. The use of ibogaine for the treatment of drug dependence has been based on the anecdotal reports from addict self-help groups that it may decrease the signs of opiate withdrawal and reduce craving for cocaine and heroin for extended time periods. Preclinical studies in rodents have shown that ibogaine reduces morphine self-administration, ameliorates signs of opiate withdrawal, and decreases cocaine preference. Ibogaine and other indole alkaloids are centrally acting drugs that produce tremorogenic and hallucinogenic effects. At present, there is little information available on ibogaine levels in body fluids or on the identification of major or minor metabolites. Information on the phannacokinetics and metabolism of ibogaine is important for developing optimal dosing schedules for clinical trials. The purpose of the present study was to develop a pharmacokinetic-pharmacodynamic model for the characterization of the neurological and behavioral effects of ibogaine in human patient volunteers. Safety assessments in this study included standard laboratory tests and electrocardiograms. The patients were evaluated with a neurological battery that focused on cerebellar signs including postural and kinetic tremors, truncal ataxia, and gait instability. Blood and urine samples were assayed for ibogaine and metabolites by liquid-liquid extraction and gas chromatography/mass spectrometry (GC/MS). We have identified the primary metabolite as 12-hydroxyibogamine (noribogaine) by evaluation of its full scan electron impact mass spectrum and its identity confirmed by comparison with an authentic standard (s.a. OmniChem, Louvain-la Neuve, Belgium). The preliminary model that best fit the ibogaine and noribogaine data simultaneously was one which includes a peripheral compartment for ibogaine (i.e., a twocompartment model), some first-pass metabolism of ibogaine to noriIx~gaine, conversion of ibogaine to noribogaine postabsorption, and additional elimination of ilx~gaine (other than by conversion to noribogaine). The time required to eliminate the majority of absorbed ibogaine (>90%) was 24 hr postdose. The time course for the appearance of mild tremor and ataxia was best correlated with the blood levels or the parent drug. The pharmacokinetic data demonstrate that the amount of noribogaine in blood at 24 hr was still quite appreciable. These results suggest that the primary metabolite of ibogaine may have a long half-life in humans. We speculate that the putative anticraving properties of ibogaine may result from the slow elimination of the active metabolite noribogaine.