Buprenorphine-cannabis interaction in patients undergoing opioid maintenance therapy.

Buprenorphine is a partial µ-opioid agonist widely used for opioid maintenance therapy (OMT). It is mainly metabolized to pharmacologically active norbuprenorphine by the cytochrome P450 (CYP) isozyme 3A4. This may give rise to drug-drug interactions under combinations with inhibitors or inducers of CYP3A4. Cannabis is a potential inhibitor of CYP3A4, and there is a large degree of concomitant cannabis use among OMT patients. We performed a retrospective analysis on liver healthy OMT patients substituted with buprenorphine, either with (n = 15) or without (n = 17) concomitant use of cannabis. Patients with additional illicit drugs or medications affecting CYP3A were excluded. Measured blood concentrations of buprenorphine and norbuprenorphine were compared between the two groups. Cannabis users and non-users received similar doses, but users had 2.7-fold higher concentrations of buprenorphine (p < 0.01) and 1.4-fold for norbuprenorphine (1.4-fold, p = 0.07). Moreover, the metabolite-to-parent drug ratio was 0.98 in non-users and 0.38 in users (p = 0.02). Female gender did not produce significant effects. These findings indicate that cannabis use decreases the formation of norbuprenorphine and elevates buprenorphine and norbuprenorphine concentrations in blood most probably by inhibition of CYP3A4. The pharmacokinetic interaction may give rise to enhanced or altered opioid activity and risk of intoxications. Physicians should inform patients about this risk and supervise cannabis users by regular control of buprenorphine blood levels, i.e., by therapeutic drug monitoring.

[Opioid maintenance treatment and Cannabis use]. / Opioidsubstitutionsbehandlung und Cannabiskonsum.

OBJECTIVES: More than 30 % of patients participating in an opioid maintenance program consume cannabis. This article describes the effects of additional cannabis use during an opioid maintenance treatment program. METHODS: Narrative literature research using online publication databases (MedLine, PubMed) RESULTS: The additional use of cannabis during an opioid maintenance treatment program may have negative side effects. CONCLUSION: Cannabis use should be discussed with the patient. It is in principle not a reason for discontinuing an opioid maintenance treatment program.

The Cannabinoid CB1/CB2 Agonist WIN55212.2 Promotes Oligodendrocyte Differentiation In Vitro and Neuroprotection During the Cuprizone-Induced Central Nervous System Demyelination.

AIM AND METHODS: Different types of insults to the CNS lead to axon demyelination. Remyelination occurs when the CNS attempts to recover from myelin loss and requires the activation of oligodendrocyte precursor cells. With the rationale that CB1 receptor is expressed in oligodendrocytes and marijuana consumption alters CNS myelination, we study the effects of the cannabinoid agonist WIN55212.2 in (1) an in vitro model of oligodendrocyte differentiation and (2) the cuprizone model for demyelination. RESULTS: The synthetic cannabinoid agonist WIN55212.2 at 1 µM increased the myelin basic protein mRNA and protein expression in vitro. During cuprizone-induced acute demyelination, the administration of 0.5 mg/kg WIN55212.2 confers more myelinated axons, increased the expression of retinoid X receptor alpha, and declined nogo receptor expression. Controversially, 1 mg/kg of the drug increased the number of demyelinated axons and reduced the expression of nerve growth factor inducible, calreticulin and myelin-related genes coupling specifically with a decrease in 2',3'-cyclic nucleotide 3' phosphodiesterase expression. CONCLUSION: The cannabinoid agonist WIN55212.2 promotes oligodendrocyte differentiation in vitro. Moreover, 0.5 mg/kg of the drug confers neuroprotection during cuprizone-induced demyelination, while 1 mg/kg aggravates the demyelination process.

Risks associated with the non-medicinal use of cannabis.

BACKGROUND: Cannabis is the most commonly consumed illicit drug around the world; in Germany, about 4.5% of all adults use it each year. Intense cannabis use is associated with health risks. Evidence-based treatments are available for health problems caused by cannabis use. METHODS: Selective literature review based on a search of the PubMed database, with special emphasis on systematic reviews, meta-analyses, cohort studies, randomized controlled trials (RCTs), case-control studies, and treatment guidelines. RESULTS: The delta-9-tetrahydrocannabinol content of cannabis products is rising around the world as a result of plant breeding, while cannabidiol, in contrast, is often no longer detectable. Various medical conditions can arise acutely after cannabis use, depending on the user's age, dose, frequency, mode and situation of use, and individual disposition; these include panic attacks, psychotic symptoms, deficient attention, impaired concentration, motor incoordination, and nausea. In particular, intense use of high doses of cannabis over many years, and the initiation of cannabis use in adolescence, can be associated with substance dependence (DSM-5; ICD-10), specific withdrawal symptoms, cognitive impairment, affective disorders, psychosis, anxiety disorders, and physical disease outside the brain (mainly respiratory and cardiovascular conditions). At present, the most effective way to treat cannabis dependence involves a combination of motivational encouragement, cognitive behavioral therapy, and contingency management (level 1a evidence). For adolescents, family therapy is also recommended (level 1a evidence). No pharmacological treatments can be recommended to date, as evidence for their efficacy is lacking. CONCLUSION: Further research is needed to elucidate the causal relationships between intense cannabis use and potential damage to physical and mental health. Health problems due to cannabis use can be effectively treated.

Behavioral and neurochemical characterization of kratom (Mitragyna speciosa) extract.

OBJECTIVE: Mitragyna speciosa and its extracts are named kratom (dried leaves, extract). It contains several alkaloids and is used in traditional medicine to alleviate musculoskeletal pain, hypertension, coughing, diarrhea, and as an opiate substitute for addicts. Abuse and addiction to kratom is described, and kratom has attracted increasing interest in Western countries. Individual effects of kratom on opioidergic, adrenergic, serotonergic, and dopaminergic receptors are known, but not all of the effects have been explained. Pharmacokinetic and pharmacodynamic data are needed. METHODS: The effects of kratom extract on mice behavior were investigated following oral (po), intraperitoneal (ip), and intracerebroventricular (icv) application. Receptor-binding studies were performed. RESULTS: In µ opioid receptor knockout mice (-/-) and wild type (+/+) animals, the extract reduced locomotor activity after ip and low po doses in +/+ animals, but not after icv administration. The ip effect was counteracted by 0.3 mg/kg of apomorphine sc, suggesting dopaminergic presynaptic activity. An analgesic effect was only found in -/- mice after icv application. Norbinaltorphimine abolished the analgesic effect, but not the inhibitory effect, on locomotor activity, indicating that the analgesic effect is mediated via κ opioid receptors. Oral doses, which did not diminish locomotor activity, impaired the acquisition of shuttle box avoidance learning. There was no effect on consolidation. Binding studies showed affinity of kratom to µ, δ, and κ opioid receptors and to dopamine D1 receptors. CONCLUSIONS: The results obtained in drug-naïve mice demonstrate weak behavioral effects mediated via µ and κ opioid receptors.

[Pregnant opioid addicted patients and additional drug intake. Part I. Toxic effects and therapeutic consequences]. / Therapie von schwangeren Patientinnen mit Abhängigkeit von Opioiden und begleitenden Suchtstoffen. Teil I: Toxische Folgen und therapeutische Konsequenzen.

Opioid dependent patients often are dependent from the illegal consumption of heroin and, in addition, perform a polytoxicomanic way of consuming drugs. They suffer of various somatic and psychiatric diseases. Moreover, pregnancies of drug addicted women are classified as high-risk pregnancies. With respect to the particular consumed drug substances other than opioids during pregnancy variable forms of teratogenic and toxic effects can be assigned to the baby. Critical values of maternal substance abuse referring to fetal impairment do not exist. With regard to the possible teratogenic and toxic fetal effects of maternal consume of alcohol, tobacco, sedativa, cannabis, cocaine and amphetamines, withdrawal treatment of polytoxicomanic pregnant patients under inpatient medical supervision including medication if necessary represent the first-line-treatment. With respect to smoking, it is possible to detoxicate the patients also by an outpatient treatment. However, referring to heroin addiction, a maintenance therapy with L-methadone, D/L-methadone or buprenorphine should be preferred since fetal withdrawal symptoms of opioids otherwise can cause severe complications which even can lead to the loss of the fetus and also increase the risks for the mother. Increasing the dose of the opioid substitute may be necessary, for example, to avoid premature uterus contractions. It is to be pointed out that substitution treatment with methadone or buprenorphine also improve the medicinal compliance and psychosocial circumstances of the pregnant patients. Subsequent to delivery, the maintenance treatment should initially be pursued over a further period of time. In the follow up, the question of continuing with maintenance treatment or starting a withdrawal treatment of opioids should be discussed on an individual basis. To sum up, proceeded interdisciplinary care during pregnancy and afterwards by all the professions involved like general practioners as well as social workers, gynaecologists, paediatrists, pharmacists, psychologists and psychiatrists should be ensured. Futhermore, diagnosis and therapy of the comorbid psychiatric and infectious diseases like hepatitis A, B, C and HIV are necessary and described (see Part II. Comorbidity and their treatment).

Acute treatment with cannabinoid receptor agonist WIN55212.2 improves prepulse inhibition in psychosocially stressed mice.

Cannabis, similar to psychosocial stress, is well known to exacerbate psychotic experiences and can precipitate psychotic episodes in vulnerable individuals. Cannabinoid receptors 1 (CB1) are widely expressed in the brain and are particularly important to mediate the effects of cannabis. Chronic cannabis use in patients and chronic cannabinoids treatment in animals is known to cause reduced prepulse inhibition (PPI). Similarly, chronic psychosocial stress in mice impairs PPI. In the present study, we investigated the synergistic effects of substances modulating the CB1-receptors and chronic psychosocial stress on PPI. For this purpose, adult C57Bl/6J mice were exposed to chronic psychosocial stress using the resident-intruder paradigm. The cannabinoid receptor agonist WIN55212.2 served as a surrogate marker for the effects of cannabis in the brain. After exposure to stress mice were acutely injected with WIN55212.2 (3 mg/kg) with or without pre-treatment with Rimonabant (3 mg/kg), a specific CB1-receptor antagonist, and subjected to behavioral testing. Stressed mice displayed a higher vulnerability to WIN55212.2 in the PPI test than control animals. The effects of WIN55212.2 on PPI were antagonized by Rimonabant suggesting an involvement of CB1-receptors in sensorimotor gating. Interestingly, WIN55212.2 increased PPI in psychosocially stressed mice although previous studies in rats showed the opposite effects. It may thus be possible, that depending on the doses of cannabinoids/CB1-receptor agonists applied and environmental conditions (psychosocial stress), opposite effects can be evoked in different experimental animals. Taken together, our data imply that CB1-receptors might play a crucial role in the synergistic effects of psychosocial stress and cannabinoids in brain.

Psychiatric comorbidity and additional abuse of drugs in maintenance treatment with L- and D,L-methadone.

Sixty D,L- or L-methadone treated patients in maintenance therapy were interviewed for additional drug abuse and psychiatric comorbidity; 51.7% of the entire population had a comorbid Axis-I disorder, with a higher prevalence in females (P=0.05). Comorbid patients tended to have higher abuse of benzodiazepines, alcohol, cannabis, and cocaine, but not of heroin. They had received a significantly lower D,L- (P<0.05) and L-methadone dose than non-comorbid subjects. The duration of maintenance treatment showed an inverse relationship to frequency of additional heroin intake (P<0.01). Patients with additional heroin intake over the past 30 days had been treated with a significantly lower L-methadone dosage (P<0.05) than patients without. Axis-I comorbidity appears to be decreased when relatively higher dosages of D,L- (and L-methadone) are administered; comorbid individuals, however, were on significantly lower dosages. Finally, L-, but not D,L-methadone seems to be more effective in reducing additional heroin abuse.