Evaluation of the rewarding effects of mitragynine and 7-hydroxymitragynine in an intracranial self-stimulation procedure in male and female rats.

BACKGROUND: Kratom (Mitragyna speciosa Korth.) has been used in Southeast Asia for hundreds of years to increase energy, for relaxation, and to diminish opioid withdrawal. Kratom use has recently spread to Western countries. Kratom could potentially be used for the treatment of opioid withdrawal and pain, but more insight is needed into its abuse potential. Therefore, we investigated the rewarding properties of the primary kratom alkaloid mitragynine and its active metabolite 7-hydroxymitragynine, and morphine as a reference drug in male and female rats. These compounds have agonist activity at mu-opioid receptors. METHODS: The compounds were tested in an intracranial self-stimulation (ICSS) procedure, which allows for the evaluation of the rewarding/aversive and sedative effects of drugs. Rewarding doses of drugs decrease the brain reward thresholds, and aversive drug doses have the opposite effect. RESULTS: Mitragynine, 7-hydroxymitragynine, and morphine affected the brain reward thresholds. A high dose of 7-hydroxymitragynine (3.2 mg/kg) increased the brain reward thresholds, whereas an intermediate dose of morphine (10 mg/kg) decreased the reward thresholds. 7-Hydroxymitragynine and morphine affected the response latencies. Five mg/kg of morphine increased response latencies. 7-Hydroxymitragynine tended to increase the response latencies, but the post hoc analyses did not reveal a significant effect. There were no sex differences in the effects of mitragynine, 7-hydroxymitragynine, and morphine on the reward thresholds and the response latencies. CONCLUSIONS: These initial findings indicate that mitragynine and 7-hydroxymitragynine are not rewarding in the ICSS procedure. The present results suggest that these kratom alkaloids do not have abuse potential.

Induction and analysis of the alkaloid mitragynine content of a Mitragyna speciosa suspension culture system upon elicitation and precursor feeding.

This study aimed to determine the effects of different concentrations and combinations of the phytohormones 2,4-dichlorophenoxy acetic acid (2,4-D), kinetin, 6-benzylaminopurine (BAP), and 1-naphthaleneacetic acid (NAA) on callus induction and to demonstrate the role of elicitors and exogenous precursors on the production of mitragynine in a Mitragyna speciosa suspension culture. The best callus induction was achieved from petiole explants cultured on WPM that was supplemented with 4 mg L⁻¹ 2,4-D (70.83%). Calli were transferred to liquid media and agitated on rotary shakers to establish Mitragyna speciosa cell suspension cultures. The optimum settled cell volume was achieved in the presence of WPM that contained 3 mg L⁻¹ 2,4-D and 3% sucrose (9.47 ± 0.4667 mL). The treatment of cultures with different concentrations of yeast extract and salicylic acid for different inoculation periods revealed that the highest mitragynine content as determined by HPLC was achieved from the culture treated with 250 mg L⁻¹ yeast extract (9.275 ± 0.082 mg L⁻¹) that was harvested on day 6 of culturing; salicylic acid showed low mitragynine content in all concentrations used. Tryptophan and loganin were used as exogenous precursors; the highest level of mitragynine production was achieved in cultures treated with 3 µM tryptophan and harvested at 6 days (13.226 ± 1.98 mg L⁻¹).

Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa korth).

BACKGROUND: Kratom (Mitragynia speciosa korth) is recognized increasingly as a remedy for opioid withdrawal by individuals who self-treat chronic pain. CASE DESCRIPTION: A patient who had abruptly ceased injection hydromorphone abuse self-managed opioid withdrawal and chronic pain using kratom. After co-administering the herb with modafinil he experienced a tonic-clonic seizure, but he reported only modest abstinence once kratom administration stopped. We confirmed the identity of the plant matter he ingested as kratom and identified no contaminants or adulterants. We also conducted high-throughput molecular screening and the binding affinity at mu, delta and kappa receptors of mitragynine. CONCLUSION: We report the self-treatment of chronic pain and opioid withdrawal with kratom. The predominant alkaloid of kratom, mitragynine, binds mu- and kappa-opioid receptors, but has additional receptor affinities that might augment its effectiveness at mitigating opioid withdrawal. The natural history of kratom use, including its clinical pharmacology and toxicology, are poorly understood.