Effects of low dose ibogaine on subjective mood state and psychological performance.

ETHNOPHARMACOLOGICAL RELEVANCE: Root bark from Tabernanthe iboga has been used traditionally in West Africa as a psychoactive substance in religious rituals. In smaller doses it is reported anecdotally to have stimulant properties. AIM OF THE STUDY: To evaluate the influence of a single 20mg ibogaine dose on psychological variables reflecting subjective mood state and a range of cognitive functions. MATERIALS AND METHODS: 21 healthy male volunteers received single 20mg doses of ibogaine after 6 days pretreatment with double-blind paroxetine or placebo. We compared responses to a battery of psychometric tests and subjective mood ratings performed before and 2h after ibogaine dosing, and assessed relationships between changes in test scores and concentrations of active moiety (the sum of molar noribogaine and ibogaine concentrations). Psychological tests were chosen based on responsiveness to opioid and serotonergic ligands. RESULTS: Ibogaine had minimal influence on psychological tests and mood ratings. The ability to selectively ignore distracting spatial information showed some evidence of modulation; however because this effect was limited to the less challenging condition calls into question the reliability of this result. CONCLUSION: We were unable to identify stimulant effects after single 20mg doses of ibogaine. Future research is needed to confirm whether active moiety concentrations impact selective attention abilities while leaving other cognitive functions and mood state unaffected.

Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers.

Conversion of ibogaine to its active metabolite noribogaine appears to be mediated primarily by CYP2D6. We compared 168 hours pharmacokinetic profiles of both analytes after a single oral 20 mg dose of ibogaine in 21 healthy subjects who had been pretreated for 6 days with placebo or the CYP2D6 inhibitor paroxetine. In placebo-pretreated subjects, ibogaine was rapidly converted to noribogaine. Median peak noribogaine concentrations occurred at 4 hours. Compared with placebo-pretreated subjects, paroxetine-pretreated subjects had rapid (Tmax = 1.5 hours) and substantial absorption of ibogaine, with detectable levels out to 72 hours, and an elimination half-life of 10.2 hours. In this group, ibogaine was also rapidly converted to noribogaine with a median Tmax of 3 hours. Extent of noribogaine exposure was similar in both groups. CYP2D6 phenotype was robustly correlated with ibogaine AUC0-t (r = 0.82) and Cmax (r = 0.77). Active moiety (ibogaine plus noribogaine) exposure was ∼2-fold higher in paroxetine-pretreated subjects. Single 20 mg ibogaine doses were safe and well tolerated in all subjects. The doubling of exposure to active moiety in subjects with reduced CYP2D6 activity suggests it may be prudent to genotype patients awaiting ibogaine treatment, and to at least halve the intended dose of ibogaine in CYP2D6 poor metabolizers.

Lack of evidence of human papillomavirus-induced squamous cell carcinomas of the oral cavity in southern Germany.

OBJECTIVES: The aim of the present study was to identify HPV-attributable SCC of the oral cavity (OSCC) in a cohort of patients from southern Germany. MATERIALS AND METHODS: A sensitive PCR-enzyme immunoassay (EIA) was followed by a more specific in situ hybridization (ISH) to detect high risk human papillomavirus (HPV). An immunohistochemical dual-staining for p16(INK4a) and the proliferation marker Ki-67 was used to assess whether co-expression of p16(INK4a)/Ki-67 is a better surrogate marker for HPV in OSCC than p16(INK4a) alone, based on the hypothesis that combined p16(INK4a) and Ki-67 expression might specifically discriminate oncogene-induced p16(INK4a) expression from cell-cycle arrest-inducing senescence-associated p16(INK4a) expression. RESULTS: HPV-DNA by PCR-EIA could be detected in 25.1% (69/275) of the tumors, but ISH was negative in all of them. Diffuse p16(INK4a) overexpression was detected in 11 HPV PCR-positive tumors, but also in 6 HPV PCR-negative tumors. p16(INK4a)-expressing cells in diffusely positive tumors co-expressed Ki-67, irrespective of the HPV status. Neither the sole HPV status nor combined HPV/p16(INK4a) status nor the sole p16(INK4a) status was significantly associated with disease free or overall survival, however a trend towards better overall survival of patients whose tumor expressed p16(INK4a) in a focal pattern (=p16(INK4a)-positive/Ki-67-negative cells) compared to no p16(INK4a) expression (p=0.09) was observed. CONCLUSION: Viral DNA can be detected in some tumors by a sensitive PCR, but absence of ISH signals indicates that the HPV-attributable fraction is smaller than estimated from PCR positivity. p16(INK4a)/Ki-67 co-expression is detectable in a fraction of OSCC irrespective of the HPV status.