7-hydroxymitragynine and Substance-Related-Disorders

The basic science and clinical use of morphine and other "opioid" drugs are based almost exclusively on the extracts or analogues of compounds isolated from a single source, the opium poppy (Papaver somniferum). However, it now appears that biological diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-[(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[3,2-h]quinolizin-2-yl]-3-methoxyprop-2-enoic acid methyl ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogues of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compounds suggest a classic "opioid" mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compounds suggest novelty, particularly chemical structure and possible greater separation from side effects. We review the chemical and pharmacological properties of these compounds.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Humans; Secologanin Tryptamine Alkaloids; Substance-Related Disorders

Mitragynine is the main active compound of Mitragyna speciose (Kratom in Thai). The understanding of mitragynine derivative metabolism in human body is required to develop effective detection techniques in case of drug abuse or establish an appropriate dosage in case of medicinal uses. This in silico study is based upon in vivo results in rat and human by Philipp et al. (J Mass Spectrom 44:1249-1261, 2009).. Gas-phase structures of mitragynine, 7-hydroxymitragynine and their metabolites were obtained by quantum chemical method at B3LYP/6-311++G(d,p) level. Results in terms of standard Gibbs energies of reaction for all metabolic pathways are reported with solvation energy from SMD model. We found that 7-hydroxy substitution leads to changes in reactivity in comparison to mitragynine: position 17 is more reactive towards demethylation and conjugation with glucuronic acid and position 9 is less reactive towards conjugation with glucuronic acid. Despite the changes, position 9 is the most reactive for demethylation and position 17 is the most reactive for conjugation with glucuronic acid for both mitragynine and 7-hydroxymitragynine. Our results suggest that 7-hydroxy substitution could lead to different metabolic pathways and raise an important question for further experimental studies of this more potent derivative.

Topics: Animals; Computer Simulation; Demethylation; Glucuronic Acid; Humans; Metabolic Networks and Pathways; Mitragyna; Models, Chemical; Molecular Structure; Rats; Secologanin Tryptamine Alkaloids; Substance Abuse Detection; Substance-Related Disorders

An increasing number of drugs of abuse are sold word wide over the internet. Names like "legal highs", "herbal highs" etc. give the impression that these are safe products, although the risk of fatal reactions might be substantial. Leaves from the plant Mitragyna speciosa, contain active compounds like mitragynine and 7-hydroxymitragynine. It has been reported that the potency of 7-hydroxymitragynine at the μ-opioid receptor is 30 times higher than that of mitragynine and 17 times higher than that of morphine. Case reports regarding poisoning with Kratom are reported, but the toxic or lethal ranges for the concentrations of the active substances have not been established, and concentrations of 7-hydroxymitragynine have not been reported previously. We present a case report where a middle aged man was found dead at home. The deceased had a history of drug abuse and mental illness for several years. At autopsy, there were no significant pathological findings. Post-mortem analysis of peripheral blood revealed: zopiclone 0.043mg/L, citalopram 0.36mg/L and lamotrigine 5.4mg/L, i.e. concentrations regularly seen after therapeutic ingestion of these drugs. Additionally mitragynine 1.06mg/L and 7-hydroxymitragynine 0.15mg/L were detected in blood and both also in urine. The high concentrations of mitragynine and 7-hydroxymitragynine indicate that the cause of death is intoxication by these substances; and the circumstances point toward the manner of death being accidental. We recommend that both mitragynine and 7-hydroxymitragynine are analyzed for in cases with suspected Kratom intoxication.

Topics: Accidents; Drug Overdose; Humans; Male; Middle Aged; Plant Extracts; Plant Leaves; Secologanin Tryptamine Alkaloids; Substance-Related Disorders