Mitragynine

Source: Wikipedia, the free encyclopedia.
Mitragynine
Clinical data
Addiction
liability		High[1]
Legal status
Legal status
Identifiers
  • methyl (16E)-9,17-dimethoxy-16,17-didehydro-20β-corynan-16-carboxylate
JSmol)
Melting point102–106 °C[4]
  • COC1=CC=CC2=C1C3=C([C@@](C[C@H](/C(C(OC)=O)=C\OC)[C@H](CC)C4)([H])N4CC3)N2
  • InChI=1S/C23H30N2O4/c1-5-14-12-25-10-9-15-21-18(7-6-8-20(21)28-3)24-22(15)19(25)11-16(14)17(13-27-2)23(26)29-4/h6-8,13-14,16,19,24H,5,9-12H2,1-4H3/b17-13+/t14-,16+,19+/m1/s1
  • Key:LELBFTMXCIIKKX-QVRQZEMUSA-N

Mitragynine is an

kratom.[5] The total alkaloid concentration in dried leaves ranges from 0.5 to 1.5%. In Thai varieties, mitragynine is the most abundant component (up to 66% of total alkaloids) while 7-hydroxymitragynine is a minor constituent (up to 2% of total alkaloid content). In Malaysian kratom varieties, mitragynine is present at lower concentration (12% of total alkaloids).[6] Such preparations are orally consumed and typically involve dried kratom leaves which are brewed into tea[5][6] or ground and placed into capsules.[6] Mitragynine consumption for medicinal and recreation purposes dates back centuries, although early use was primarily limited to Southeast Asian countries such as Indonesia and Thailand where the plant grows indigenously.[7] Recently, mitragynine use has spread throughout Europe and the Americas as both a recreational and medicinal drug.[8]
While research into the effects of kratom have begun to emerge, investigations on the active compound mitragynine are less common.

Uses

Medical

As of April 2019[update], the United States Food and Drug Administration (FDA) had stated that there were no approved clinical uses for kratom, and that there was no evidence that kratom was safe or effective for treating any condition.[9] This reiterated the conclusion of an earlier report by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA): As of 2023, kratom had not been approved for any medical use.[10][11] As of 2018, the FDA had noted, in particular, that there had been no clinical trials to study safety and efficacy of kratom in the treatment of opioid addiction.[12]

Ethnopharmacology

Analgesia

Mitragynine-containing kratom extracts, with their accompanying array of

antinociceptive effects in hotplate and tail-flick tests to a level comparable to oxycodone.[14][15]

Chronic pain

Kratom is commonly used in the United States as self-treatment for pain and opioid withdrawal.[16] A 2019 review of existing literature suggested the potential of kratom as substitution therapy for chronic pain.[17]

Opioid withdrawal

As early as the 19th century, kratom was in use for the treatment of

opioid replacement and withdrawal as primary motivations for kratom use: almost 50% of the approximately 8,000 kratom users surveyed indicated kratom use that resulted in reduced or discontinued use of opioids.[13][18] Some animal models of opioid withdrawals suggest mitragynine can suppress and ameliorate withdrawal from other opioid agonists, e.g., after chronic administration of morphine in zebra fish.[5]

Recreational

Mitragynine and its metabolite

cough medicines—to potentiate the effects of the concentrated levels of mitragynine.[6] Effects of mitragynine-containing preparations from M. speciosa include analgesic, anti-inflammatory, anti-depressant, and muscle relaxant properties; adverse effects include a negative impact on cognition; in animal studies the potential for misuse has been found, including through the use of the conditioned place preference (CPP) test, which indicated a distinct reward-effect for 7-hydroxymitragynine.[14]

Dependence and withdrawal

See also: Mitragyna speciosa § Adverse effects

Due at least in part to the activity on opioid receptors of mitragynine and its derivatives, kratom can result in dependence and lead to withdrawal symptoms when discontinued. Regular users report withdrawal symptoms comparable to that of other opioids following the discontinuation of kratom.[5][19] Addiction to kratom can lead to physical and psychiatric issues that can affect one's ability to work; there have also been reports of psychotic symptoms in those who are addicted.[5] A 2014 study which included 1118 male kratom users indicated that more than half of the regular users (67% of total subjects) experienced withdrawal when attempting to discontinue kratom with symptoms that included pain, muscle spasms, and insomnia.[13] In a study following 239 male kratom users in Malaysia consuming between 40 and 240 mg of mitragynine per day, 89% indicated a previous attempt of discontinuing kratom consumption which resulted in withdrawal symptoms ranging from mild (65% of subjects) to moderate/severe (35% of subjects).[20] In the same study, withdrawal symptoms ranged from physical symptoms such as nausea, diarrhea, and muscle spasms to psychological symptoms such as restlessness, anxiety, and anger but lasted less than 3 days for most subjects.[20] However, the results from this study may be obfuscated by the occasional addition of other substances in the kratom preparation such as dextromethorphan and benzodiazepines, which could contribute to the withdrawal symptoms.[20] In an animal study, mitragynine withdrawal symptoms were observed following 14 days of mitragynine i.p. injections in mice and included displays of anxiety, teeth chattering, and piloerection, all of which are characteristic signs of opioid withdrawal in mice and are comparable to morphine withdrawal symptoms.[20]

Solubility of mitragynine

The solubility of mitragynine from kratom in neutral-pH and alkaline water is very low (0.0187 mg/ml at pH 9).[21] The solubility of mitragynie in acidic water is higher (3.5 mg/ml at pH 4), however, this alkaloid can become unstable, so certain products, such as low-pH beverages, have a very short shelf life.[21] Many vendors offer concentrated kratom products with claims of improved mitragynine solubility, however, those products are often formulated with solvents such as propylene glycol, which can make products unpleasant.

Pharmacology

Potential role of mitragynine as a biased agonist of the mu-opioid receptor (MOR), favoring beta arrestin independent signaling
Mitragyna speciosa alkaloids at opioid receptors
Compound
Ki
Tooltip Inhibitor constant)		 Ratio Ref
MOR
Tooltip μ-Opioid receptor
DOR
Tooltip δ-Opioid receptor
KOR
Tooltip κ-Opioid receptor		 MOR:DOR:KOR
Mitragynine 7.24 60.3 1,100 1:8:152 [22]
7-Hydroxymitragynine 13.5 155 123 1:11:9 [22]
Mitragynine pseudoindoxyl 0.087 3.02 79.4 1:35:913 [22]

Pharmacodynamics

Mitragynine acts on a variety of receptors in the

respiratory depression.[23] However, recent evidence suggests that low intrinsic efficacy at the mu opioid receptor is responsible for the improved side effect profile of mitragynine, as opposed to G protein bias.[24]

Pharmacokinetics

Pharmacokinetics parameters (N=10, human)[6]
t1⁄2 (h) 23.24 ± 16.07
Vd (L/kg) 38.04 ± 24.32
tmax
(h) 		0.83 ± 0.35
CL (L/h) 1.4 ± 0.73

peak plasma concentration within 1 hour of administration.[6]

Metabolism

Locations of hydrolysis and o-demethylation of mitragynine during the initial steps of phase I metabolism
CYP 1A2 3A4 2D6
IC50 (μg/mL) 39 (6) 0.78 (6) 3.6 (3), 0.636 (6)
Inhibitory effects of mitragynine on P450 enzymes.

Mitragynine is primarily metabolized in the liver, producing many metabolites during both phase I and phase II.[7]

Phase I

During phase I metabolism, mitragynine undergoes

phase I metabolism of mitragynine which reportedly has an inhibitory effect on multiple P450 enzymes, raising the possibility of adverse drug interactions.[26][5][23]

Phase II

During

phase II metabolism, phase I metabolites undergo glucuronidation and sulfation to form multiple glucuronide and sulfate conjugates, which are then excreted via urine.[23][5]

Toxicology

Mitragynine toxicity in humans is largely unknown, as animal studies show significant species-specific differences in mitragynine tolerance.

liver toxicity in kratom consumers have been reported.[27][28] Due to Cytochrome P450 enzyme inhibition, the combination of mitragynine with other drugs poses concern for adverse reactions to mitragynine.[26][5][6][23] Fatalities involving mitragynine tend to include its use in combination with opioids and some cough suppressants.[6] Post-mortem toxicology screens indicate a wide range of mitragynine blood concentrations ranging from 10 μg/L to 4800 μg/L, making it difficult to calculate what constitutes a toxic dose in humans.[28] These variations are suggested to result from differences in the toxicology assays used, and how long after death the assays were conducted.[28]

Legality

In the United States, kratom and its active ingredients are not scheduled under

kratom, while advocating for more research for a better understanding of kratom's safety profile.[33]

Research limitations

Inconsistencies in dosing, purity, and concomitant drug use makes evaluating the effects of mitragynine in humans difficult. Conversely, animal studies control for such variability but offer limited translatable information relevant to humans.[23] Experimental limitations aside, mitragynine has been found to interact with a variety of receptors, although the nature and extent of receptor interactions has yet to be fully characterized.[6] Additionally, the toxicity of mitragynine and associated kratom alkaloids have yet to be fully determined in humans, nor has the risk of overdose.[28] More studies are necessary to assess safety and potential therapeutic utility.[34]

References

  1. ^ {{Ventura, Frank BS1; John, Jaison S. MD1; Al-Saadi, Yamam I. MD1; Stevenson, Heather L. MD, PhD2; Khan, Kashif MD1. S2841 Autoimmune Hepatitis: Possible Relation to the Pfizer-BioNTech COVID-19 Vaccine?. The American Journal of Gastroenterology 116():p S1180, October 2021. | DOI: 10.14309/01.ajg.0000784896.23722.94}}
  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-15.
  3. ^ "指定薬物一覧" [List of designated drugs] (PDF). 障害福祉のお仕事の世界 (The world of disability welfare work) (in Japanese). Retrieved 5 December 2023.
  4. ^ "Kratom profile (chemistry, effects, other names, origin, mode of use, other names, medical use, control status)". European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).
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  10. ^ "Kratom profile (chemistry, effects, other names, origin, mode of use, other names, medical use, control status)". European Monitoring Centre for Drugs and Drug Addiction. 8 January 2015. Retrieved 12 September 2016.
  11. clinical trials
    in the United States, though it had been studied in cell culture and in animals. See Hassan et al. (2013), op. cit.
  12. ^ Gottlieb S (6 February 2018). "Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency's scientific evidence on the presence of opioid compounds in kratom, underscoring its potential for abuse". US Food and Drug Administration. Retrieved 6 February 2018.
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  15. ^ Kroll D. "Recreational Drug Kratom Hits the Same Brain Receptors as Strong Opioids". Chemical & Engineerin News. Retrieved 2020-05-15 – via Scientific American.
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  18. ^ An additional study included in the same review found that ~90% of 136 Malaysian kratom-users were substituting it for opioids, with ~84% reporting its effects helping with opioid withdrawal. See Swogger and Walsh (2018), op. cit.
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  25. ^ "EMCDDA | Kratom profile (chemistry, effects, other names, origin, mode of use, other names, medical use, control status)". www.emcdda.europa.eu. Retrieved 2019-11-18.
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  30. ^ Commons KM (2018-08-10). "Cracking Down on Kratom: FDA Investigation, Enforcement, Seizure, and Recall of Products Reported to Contain Kratom". Food and Drug Law Institute (FDLI). Retrieved 2020-05-15.
  31. ^ Gianutsos FG. "The DEA Changes Its Mind on Kratom". www.uspharmacist.com. Retrieved 2020-05-15.
  32. ^ "Kratom - an emerging drug of abuse". www.mangaloretoday.com. Retrieved 2020-05-15.
  33. ^ Office of the Commissioner (2020-03-24). "FDA issues warnings to companies selling illegal, unapproved kratom drug products marketed for opioid cessation, pain treatment and other medical uses". FDA. Retrieved 2020-08-05.
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