The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients.

OBJECTIVE: Ibogaine is a hallucinogenic drug that may be used to treat opioid use disorder (OUD). The relationships between pharmacokinetics (PKs) of ibogaine and its metabolites and their clinical effects on side effects and opioid withdrawal severity are unknown. We aimed to study these relationships in patients with OUD undergoing detoxification supported by ibogaine. METHODS: The study was performed in 14 subjects with OUD. They received a single dose of 10mg/kg ibogaine hydrochloride. Plasma PKs of ibogaine, noribogaine, and noribogaine glucuronide were obtained during 24 h. Cytochrome P450 isoenzyme 2D6 (CYP2D6) genotyping was performed. The PKs were analyzed by means of nonlinear mixed effects modeling and related with corrected QT interval (QTc) prolongation, cerebellar ataxia, and opioid withdrawal severity. RESULTS: The PK of ibogaine were highly variable and significantly correlated to CYP2D6 genotype (p < 0.001). The basic clearance of ibogaine (at a CYP2D6 activity score (AS) of 0) was 0.82 L/h. This increased with 30.7 L/h for every point of AS. The relation between ibogaine plasma concentrations and QTc was best described by a sigmoid Emax model. Spearman correlations were significant (p < 0.03) for ibogaine but not noribogaine with QTc (p = 0.109) and cerebellar effects (p = 0.668); neither correlated with the severity of opioid withdrawal symptoms. CONCLUSIONS: The clearance of ibogaine is strongly related to CYPD2D6 genotype. Ibogaine cardiac side effects (QTc time) and cerebellar effects are most likely more driven by ibogaine rather than noribogaine. Future studies should aim at exploring lower doses and/or applying individualized dosing based on CYP2D6 genotype.

[Severe hypomagnesemia in a man with alcohol dependence: a forgotten electrolyte in a neglected population]. / Ernstig magnesiumtekort bij alcoholverslaving.

BACKGROUND: Symptoms of acute alcohol withdrawal like tremors, seizures and delirium are commonly treated with benzodiazepines and vitamins. When complaints are not reacting to this treatment, an alternative diagnosis must be considered. Although hypomagnesemia is present in at least 30 percent of the patients with alcohol dependence, it can provoke and maintain these complaints. CASE DESCRIPTION: We present a 43-year-old man with alcohol dependence, who shows neurological, muscular, and cardiac consequences of an undiagnosed hypomagnesemia. CONCLUSION: In daily clinical practice there is not enough attention for magnesium deficits, especially in patients with alcohol dependence. Serious complications can be prevented by recognizing and treating magnesium deficiency more adequately.

Towards adherence monitoring using breath or oral fluid as a matrix in a methadone maintenance treatment program for patients with a chronic heroin use disorder: Issues and interpretation of the results.

Urine has been the preferred matrix for monitoring heroin and methadone adherence due to its large detection window. Drawbacks such as privacy concerns and adulteration however require other matrices. The study aims to determine if oral fluid and exhaled breath are suitable alternatives for heroin and methadone monitoring and to assess the detection time in exhaled breath. Forty-three participants, all on methadone and heroin-assisted treatment, were studied. Participants were monitored after the first and right before the second dosage of heroin. At both time points, oral fluid and exhaled breath samples were collected with urine at the second time point. All samples were screened for opiates, methadone and other drugs using immunoassay and LC-MS-MS. At the second time point, 98% of oral fluid samples and all exhaled breath samples tested positive for 6-monoacetylmorphine (6-MAM). Regarding morphine detection, the findings were reversed (100% in oral fluid, 98% in exhaled breath). Methadone-related results were 100% positive across all matrices, as expected. Notable is the detection of the heroin marker acetylcodeine in oral fluid and exhaled breath samples, which resulted in relatively low negative predictive value (average 54.6%). Oral fluid and exhaled breath are suitable alternatives for heroin and methadone maintenance monitoring. Clinicians should consider ease of collection, adulteration risk, costs, turn-around time and the substance of interest while choosing a matrix. In addition, even in cases when medicinal heroin is used, medical professionals should be aware of the presence of acetylcodeine in these alternate matrices.

rTMS Reduces Craving and Alcohol Use in Patients with Alcohol Use Disorder: Results of a Randomized, Sham-Controlled Clinical Trial.

(1) Background: Current evidence-based treatments for alcohol use disorder (AUD) are moderately effective. Studies testing repetitive transcranial magnetic stimulation (rTMS) in AUD commonly apply a limited number of rTMS sessions with different rTMS settings, showing inconsistent effects on craving for alcohol. This study tested the efficacy of a robust rTMS protocol on craving and alcohol use. (2) Methods: In a single-blind randomized controlled trial in recently detoxified patients with AUD, ten days of high-frequency rTMS over the right dorsolateral prefrontal cortex on top of treatment as usual (n = 14) was compared with sham rTMS (n = 16). Outcome measures were alcohol craving and use over a follow-up period of one year. Analysis was performed by means of repeated measures multivariate analysis of variance. (3) Results: The results showed a main group-by-time interaction effect on craving (Wilks' Λ = 0.348, F (12, 17) = 2.654, p = 0.032) and an effect of group on alcohol use (Wilk's Λ = 0.44, F (6, 23) = 4.9, p = 0.002), with lower alcohol craving and use in the group with active rTMS compared to the control group. Differences in craving between groups were most prominent three months after treatment. At 12 months follow-up, there was no effect of rTMS on craving or abstinence. (4) Conclusions: This small-scale randomized controlled trial showed the efficacy of high-frequency rTMS over the right dlPFC diminished alcohol craving and use in recently detoxified patients with AUD during the first months after detoxification. These findings suggest that rTMS might be an effective add-on in treating patients with AUD and warrant replication in future large-scale studies.

Safety of ibogaine administration in detoxification of opioid-dependent individuals: a descriptive open-label observational study.

BACKGROUND AND AIMS: Ibogaine is an indole alkaloid used in rituals of the African Bwiti tribe. It is also used in non-medical settings to treat addiction. However, ibogaine has been linked to several deaths, mainly due to cardiac events called torsades des pointes preceded by QTc prolongation as well as other safety concerns. This study aimed to evaluate the cardiac, cerebellar and psychomimetic safety of ibogaine in patients with opioid use disorder. DESIGN: A descriptive open-label observational study. SETTING: Department of psychiatry in a university medical center, the Netherlands. PARTICIPANTS: Patients with opioid use disorder (n = 14) on opioid maintenance treatment with a lasting wish for abstinence, who failed to reach abstinence with standard care. INTERVENTION AND MEASUREMENTS: After conversion to morphine-sulphate, a single dose of ibogaine-HCl 10 mg/kg was administered and patients were monitored at regular intervals for at least 24 hours assessing QTc, blood pressure and heart rate, scale for the assessment and rating of ataxia (SARA) to assess cerebellar side effects and the delirium observation scale (DOS) to assess psychomimetic effects. FINDINGS: The maximum QTc (Fridericia) prolongation was on average 95ms (range 29-146ms). Fifty percent of subjects reached a QTc of over 500ms during the observation period. In six out 14 subjects prolongation above 450ms lasted beyond 24 hours after ingestion of ibogaine. No torsades des pointes were observed. Severe transient ataxia with inability to walk without support was seen in all patients. Withdrawal and psychomimetic effects were mostly well-tolerated and manageable (11/14 did not return to morphine within 24 hours, DOS scores remained below threshold). CONCLUSIONS: This open-label observational study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.