7-Hydroxymitragynine Explained

7-Hydroxymitragynine (7-OH) is a terpenoid indole alkaloid from the plant Mitragyna speciosa, commonly known as kratom.[1] It was first described in 1994[2] and is a natural product derived from the mitragynine present in the kratom leaf. 7-OH binds to opioid receptors like mitragynine, but research suggests that 7-OH binds with greater efficacy.[3]

Pharmacology

7-Hydroxymitragynine, like mitragynine, appears to be a mixed opioid receptor agonist/antagonist, acting as a partial agonist at μ-opioid receptors and as a competitive antagonist at δ- and κ-opioid receptors.[4] [5] Evidence suggests that 7-OH is more potent than both mitragynine and morphine. 7-OH does not activate the β-arrestin pathway like traditional opioids, meaning symptoms such as respiratory depression, constipation and sedation are much less pronounced.[4]

7-OH is generated from mitragynine in vivo by hepatic metabolism and may account for a significant portion of the effects traditionally associated with mitragynine. Although 7-OH occurs naturally in kratom leaves, it does so in such low amounts that any ingested 7-OH is inconsequential compared to the 7-OH generated in the body.[4]

Metabolism

7-Hydroxymitragynine can convert into mitragynine up to 45% in human liver microsomes over a 2 hour incubation and was degraded up to 27% in simulated gastric fluid and degraded up to 6% in simulated intestinal fluid.[6] 7-Hydroxymitragynine can metabolize to mitragynine pseudoindoxyl in the blood but not in the liver.[7] [8] Interestingly, this even more potent opioid was revealed to exist in a mixture of stereoisomers in biological systems.[8]

Mitragyna speciosa alkaloids at opioid receptors
Compound Affinities Ratio Ref
MOR:DOR:KOR
7-Hydroxymitragynine 13.5 155 123 1:11:9 [9]
7.24 60.3 1,100 1:8:152
0.087 3.02 79.4 1:35:913

See also

Further reading

Notes and References

  1. Matsumoto K, Horie S, Ishikawa H, Takayama H, Aimi N, Ponglux D, Watanabe K . Antinociceptive effect of 7-hydroxymitragynine in mice: Discovery of an orally active opioid analgesic from the Thai medicinal herb Mitragyna speciosa . Life Sciences . 74 . 17 . 2143–2155 . March 2004 . 14969718 . 10.1016/j.lfs.2003.09.054 .
  2. Ponglux D, Wongseripipatana S, Takayama H, Kikuchi M, Kurihara M, Kitajima M, Aimi N, Sakai S . 6 . A New Indole Alkaloid, 7 alpha-Hydroxy-7H-mitragynine, from Mitragyna speciosa in Thailand . Planta Medica . 60 . 6 . 580–581 . December 1994 . 17236085 . 10.1055/s-2006-959578 . 260252538 .
  3. Kruegel AC, Grundmann O . The medicinal chemistry and neuropharmacology of kratom: A preliminary discussion of a promising medicinal plant and analysis of its potential for abuse . Neuropharmacology . 134 . Pt A . 108–120 . May 2018 . 28830758 . 10.1016/j.neuropharm.2017.08.026 . 24009429 .
  4. Eastlack SC, Cornett EM, Kaye AD . Kratom-Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review . Pain and Therapy . 9 . 1 . 55–69 . June 2020 . 31994019 . 7203303 . 10.1007/s40122-020-00151-x .
  5. Chang-Chien GC, Odonkor CA, Amorapanth P . Is Kratom the New 'Legal High' on the Block?: The Case of an Emerging Opioid Receptor Agonist with Substance Abuse Potential . Pain Physician . 20 . 1 . E195–E198 . 2017 . 10.36076/ppj.2017.1.E195 . 28072812 . free .
  6. Evaluation of in Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Properties of Mitragynine, 7-Hydroxymitragynine, and Mitraphylline . 10.1055/s-0034-1368444 . 2014 . Planta Medica . 80 . 7 . 568–576 . 24841968 . Manda V, Avula B, Ali Z, Khan I, Walker L, Khan S .
  7. Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, Grinnell SG, Subrath JJ, Warner E, Kalra S, Hunkele A, Pagirsky J, Eans SO, Medina JM, Xu J, Pan YX, Borics A, Pasternak GW, McLaughlin JP, Majumdar S . 6 . Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2 . Journal of Medicinal Chemistry . 59 . 18 . 8381–8397 . September 2016 . 27556704 . 5344672 . 10.1021/acs.jmedchem.6b00748 .
  8. Kamble SH, León F, King TI, Berthold EC, Lopera-Londoño C, Siva Rama Raju K, Hampson AJ, Sharma A, Avery BA, McMahon LR, McCurdy CR . 6 . Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy . ACS Pharmacology & Translational Science . 3 . 6 . 1063–1068 . December 2020 . 33344889 . 7737207 . 10.1021/acsptsci.0c00075 .
  9. Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, Koyama F, Matsumoto K, Moriyama T, Yamamoto LT, Watanabe K, Murayama T, Horie S . 6 . Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands . Journal of Medicinal Chemistry . 45 . 9 . 1949–1956 . April 2002 . 11960505 . 10.1021/jm010576e .