Methadone, Buprenorphine, and Clonidine Attenuate Mitragynine Withdrawal in Rats.

Background: Kratom or Mitragyna speciosa Korth has been widely used to relieve the severity of opioid withdrawal in natural settings. However, several studies have reported that kratom may by itself cause dependence following chronic consumption. Yet, there is currently no formal treatment for kratom dependence. Mitragynine, is the major psychoactive alkaloid in kratom. Chronic mitragynine treatment can cause addiction-like symptoms in rodent models including withdrawal behaviour. In this study we assessed whether the prescription drugs, methadone, buprenorphine and clonidine, could mitigate mitragynine withdrawal effects. In order to assess treatment safety, we also evaluated hematological, biochemical and histopathological treatment effects. Methods: We induced mitragynine withdrawal behaviour in a chronic treatment paradigm in rats. Methadone (1.0 mg/kg), buprenorphine (0.8 mg/kg) and clonidine (0.1 mg/kg) were i.p. administered over four days during mitragynine withdrawal. These treatments were stopped and withdrawal sign assessment continued. Thereafter, toxicological profiles of the treatments were evaluated in the blood and in organs. Results: Chronic mitragynine treatment caused significant withdrawal behaviour lasting at least 5 days. Methadone, buprenorphine, as well as clonidine treatments significantly attenuated these withdrawal signs. No major effects on blood or organ toxicity were observed. Conclusion: These data suggest that the already available prescription medications methadone, buprenorphine, and clonidine are capable to alleviate mitragynine withdrawal signs rats. This may suggest them as treatment options also for problematic mitragynine/kratom use in humans.

Proteomic analysis reveals brain Rab35 as a potential biomarker of mitragynine withdrawal in rats.

Mitragyna speciosa, also known as kratom, has been used for mitigating the severity of opioid withdrawal in humans. Its main indole alkaloid, mitragynine, has been considered as a pharmacotherapy for pain conditions and opioid replacement therapy. However, at high doses, chronic mitragynine may also have an addiction potential. The effects of chronic action of mitragynine in the brain are still unknown. The present study developed a mitragynine withdrawal model in rats and used it for a proteomic analysis of mitragynine withdrawal effects. Mitragynine (30 mg/kg, i.p.) was administered daily over a period of 14 days and then withdrawn. A proteomic analysis revealed that from a total of 1524 proteins identified, 31 proteins were upregulated, and 3 proteins were downregulated in the mitragynine withdrawal model. The Rab35 protein expression increased most profoundly in the mitragynine withdrawal group as compared to vehicle group. Therefore, it is proposed that Rab35 in the brain might be considered as a potential biomarker during mitragynine withdrawal and might be valuable target protein in developing new pharmacotherapies in the future.

Mitragynine Attenuates Morphine Withdrawal Effects in Rats-A Comparison With Methadone and Buprenorphine.

BACKGROUND: Opiate addiction is a major health problem in many countries. A crucial component of the medical treatment is the management of highly aversive opiate withdrawal signs, which may otherwise lead to resumption of drug taking. In a medication-assisted treatment (MAT), methadone and buprenorphine have been implemented as substitution drugs. Despite MAT effectiveness, there are still limitations and side effects of using methadone and buprenorphine. Thus, other alternative therapies with less side effects, overdosing, and co-morbidities are desired. One of the potential pharmacotherapies may involve kratom's major indole alkaloid, mitragynine, since kratom (Mitragyna speciosa Korth.) preparations have been reported to alleviate opiate withdrawal signs in self-treatment in Malaysian opiate addicts. METHODS: Based on the morphine withdrawal model, rats were morphine treated with increasing doses from 10 to 50 mg/kg twice daily over a period of 6 days. The treatment was discontinued on day 7 in order to induce a spontaneous morphine abstinence. The withdrawal signs were measured daily after 24 h of the last morphine administration over a period of 28 abstinence days. In rats that developed withdrawal signs, a drug replacement treatment was given using mitragynine, methadone, or buprenorphine and the global withdrawal score was evaluated. RESULTS: The morphine withdrawal model induced profound withdrawal signs for 16 days. Mitragynine (5-30 mg/kg; i.p.) was able to attenuate acute withdrawal signs in morphine dependent rats. On the other hand, smaller doses of methadone (0.5-2 mg/kg; i.p.) and buprenorphine (0.4-1.6 mg/kg; i.p.) were necessary to mitigate these effects. CONCLUSIONS: These data suggest that mitragynine may be a potential drug candidate for opiate withdrawal treatment.

Neurobiology of Kratom and its main alkaloid mitragynine.

Kratom or its main alkaloid, mitragynine is derived from the plant Mitragyna speciosa Korth which is indigenous to Southeast Asian countries. This substance has become widely available in other countries like Europe and United States due to its opium- and coca-like effects. In this article, we have reviewed available reports on mitragynine and other M. speciosa extracts. M. speciosa has been proven to have a rewarding effect and is effective in alleviating the morphine and ethanol withdrawal effects. However, studies in human revealed that prolonged consumption of this plant led to dependence and tolerance while cessation caused a series of aversive withdrawal symptoms. Findings also showed that M. speciosa extracts possess antinociceptive, anti-inflammatory, anti-depressant, and muscle relaxant properties. Available evidence further supports the adverse effects of M. speciosa preparations, mitragynine on cognition. Pharmacological activities are mainly mediated via opioid receptors as well as neuronal Ca2+ channels, expression of cAMP and CREB protein and via descending monoaminergic system. Physicochemical properties of mitragynine have been documented which may further explain the variation in pharmacological responses. In summary, current researchs on its main indole alkaloid, mitragynine suggest both therapeutic and addictive potential but further research on its molecular effects is needed.

Occurrence of a mosquito vector in bird houses: Developmental consequences and potential epidemiological implications.

Even with continuous vector control, dengue is still a growing threat to public health in Southeast Asia. Main causes comprise difficulties in identifying productive breeding sites and inappropriate targeted chemical interventions. In this region, rural families keep live birds in backyards and dengue mosquitoes have been reported in containers in the cages. To focus on this particular breeding site, we examined the capacity of bird fecal matter (BFM) from the spotted dove, to support Aedes albopictus larval growth. The impact of BFM larval uptake on some adult fitness traits influencing vectorial capacity was also investigated. In serial bioassays involving a high and low larval density (HD and LD), BFM and larval standard food (LSF) affected differently larval development. At HD, development was longer in the BFM environment. There were no appreciable mortality differences between the two treatments, which resulted in similar pupation and adult emergence successes. BFM treatment produced a better gender balance. There were comparable levels of blood uptake and egg production in BFM and LSF females at LD; that was not the case for the HD one, which resulted in bigger adults. BFM and LSF females displayed equivalent lifespans; in males, this parameter was shorter in those derived from the BFM/LD treatment. Taken together these results suggest that bird defecations successfully support the development of Ae. albopictus. Due to their cryptic aspects, containers used to supply water to encaged birds may not have been targeted by chemical interventions.