Kratom: Difference between revisions
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== Current Research == | == Current Research == | ||
A study done in April of 2015 on the Pharmacokinetics of Mitragynine in Humans<ref>Trakulsrichai, Satariya, et al. “Pharmacokinetics of Mitragynine in Man.” Drug Design, Development and Therapy, Dove Medical Press, 29 Apr. 2015.</ref> showed promising results for Kratom to become a new substitute for opioid pain medication. While the sample size was low, the study observed ten males who chronically took Kratom without any adverse reactions. Dosing of the oral extract was controlled and vital signs within each individual were observed as well. Mitragynine was found to have a terminal half-life of approximately 24 hours and a time to reach maximum concentration in the plasma of approximately 50 minutes. Mitragynine’s ability to rapidly be absorbed into the bloodstream and take a day to be excreted exhibits a two-compartment model. The study also observed that concentrations of mitragynine were very low in the urine thus indicating low use of the kidneys for excretion. Researchers were given no evidence of emergent side effects or emergent vital signs. | A study done in April of 2015 on the Pharmacokinetics of Mitragynine in Humans<ref>Trakulsrichai, Satariya, et al. “Pharmacokinetics of Mitragynine in Man.” Drug Design, Development and Therapy, Dove Medical Press, 29 Apr. 2015.</ref> showed promising results for Kratom to become a new substitute for opioid pain medication. While the sample size was low, the study observed ten males who chronically took Kratom without any adverse reactions. Dosing of the oral extract was controlled and vital signs within each individual were observed as well. Mitragynine was found to have a terminal half-life of approximately 24 hours and a time to reach maximum concentration in the plasma of approximately 50 minutes. Mitragynine’s ability to rapidly be absorbed into the bloodstream and take a day to be excreted exhibits a two-compartment model. The study also observed that concentrations of mitragynine were very low in the urine thus indicating low use of the kidneys for excretion. Researchers were given no evidence of emergent side effects or emergent vital signs. | ||
Most opioids bind to the opioid receptors within the central nervous system thus they have the ability to cross the blood-brain barrier. The three most notable opioid receptors are the mu, delta, and kappa. A very exciting study finally crystallized <scene name='88/880940/Overall/3'>the mu-opioid receptor with the G-protein complex</scene>. The interactions between drugs and opioid receptors are not fully understood; though this is the case research in this field has made large strides in the right direction. By binding to opioid receptors neurotransmission to the brain is blocked. A study done titled “Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (''Mitragyna speciosa''): A systematic review”<ref>Ya, Kimheang, et al. “Pharmacokinetics of Mitragynine, a Major Analgesic Alkaloid in Kratom (Mitragyna Speciosa): A Systematic Review.” Asian Journal of Psychiatry, Elsevier Science B.V., 9 May 2019, www.sciencedirect.com/science/article/abs/pii/S1876201819302114.</ref> found that not only does mitragynine passively cross the blood-brain barrier it also binds to the mu, delta, and kappa opioid receptors. Many know of the common opioid receptor agonist morphine. As morphine enters the <scene name='88/880940/Mu-opioid_receptor_and_ligand/ | Most opioids bind to the opioid receptors within the central nervous system thus they have the ability to cross the blood-brain barrier. The three most notable opioid receptors are the mu, delta, and kappa. A very exciting study finally crystallized <scene name='88/880940/Overall/3'>the mu-opioid receptor with the G-protein complex</scene>. The interactions between drugs and opioid receptors are not fully understood; though this is the case research in this field has made large strides in the right direction. By binding to opioid receptors neurotransmission to the brain is blocked. A study done titled “Pharmacokinetics of mitragynine, a major analgesic alkaloid in kratom (''Mitragyna speciosa''): A systematic review”<ref>Ya, Kimheang, et al. “Pharmacokinetics of Mitragynine, a Major Analgesic Alkaloid in Kratom (Mitragyna Speciosa): A Systematic Review.” Asian Journal of Psychiatry, Elsevier Science B.V., 9 May 2019, www.sciencedirect.com/science/article/abs/pii/S1876201819302114.</ref> found that not only does mitragynine passively cross the blood-brain barrier it also binds to the mu, delta, and kappa opioid receptors. Many know of the common opioid receptor agonist morphine. As morphine enters the <scene name='88/880940/Mu-opioid_receptor_and_ligand/3'>binding pocket of the mu-opioid receptor</scene> an amine group orients across from an aspartic acid residue. The negatively charged amino acid and the positively charged amine group are able to form an ionic interaction. This interaction is not just unique to the mu-opioid receptor- it is conserved throughout all others as well. This illustrates the importance for this residue to be present in order for ligand and protein binding to occur. The ring structure of morphine allows orientation across from a histidine residue. Opioid receptors are made up of primarily membrane-spanning alpha-helices coupled to a G-protein. When opioid binding occurs it induces a conformational loop change on the inner side of the cell membrane activating and releasing the G-protein. This G-protein sometimes recruits another small protein called beta-arrestin. B-arrestin recruitment is one of the major reasons behind an opioid’s lethal side effects such as respiratory distress and desensitization which may lead to addiction. The alpha subunit of the G-protein that is released inhibits adenylyl cyclase while the beta and gamma subunits inhibit calcium channels and activate potassium channels<ref>“Mu Opioid Receptor.” Mu Opioid Receptor - Proteopedia, Life in 3D, proteopedia.org/wiki/index.php/Mu_Opioid_Receptor.</ref>. By inactivating adenylyl cyclase the drug is inhibiting cAMP production and thus turning off many extra-cellular signals. In addition, inhibition of calcium channels and activation of potassium channels creates a hyperpolarized environment<ref>“Hyperpolarization (Biology).” Wikipedia, Wikimedia Foundation, 18 Mar. 2021, en.wikipedia.org/wiki/Hyperpolarization_(biology).</ref>. This occurs when a cells’ membrane potential becomes more negative and thus a higher stimulus is required to reach an action potential threshold. This process ends up inhibiting action potentials. | ||
Mitragynine has a methyl-ether group that interacts with V143 and C217 present on the opioid receptor. Mitragynine has a secondary and tertiary amine that is capable of interacting with the important D147 residue as well as a ring structure that is capable of orienting across from the histidine residue. A recent study published in August of 2020 on mitragynine and 7-hydroxymitragynine binding to the mu-opioid receptor<ref>Dalibor Sames Group_Research, www.columbia.edu/cu/chemistry/groups/sames/news.html.</ref><ref name="wikimitra">“Mitragynine.” Wikipedia, Wikimedia Foundation, 25 Mar. 2021, en.wikipedia.org/wiki/Mitragynine#cite_note-:1-21.</ref> investigated if and how mitragynine was able to enter the active site. The study discovered that not only does mitragynine bind in the active site but it also activates the G-protein pathway. The interesting thing about the activation pathway is that the majority of the time it does not recruit beta-arrestin. Unfortunately, Cytochrome P450 metabolic enzymes have been shown to involve with the metabolism of mitragynine. The enzymes seem to be inhibited by mitragynine and therefore raise concern for adverse drug reactions. Cytochromes P450 are heme-containing enzymes that oxidize steroids, fatty acids, and xenobiotics. These enzymes also play a large role in clearing a hefty amount of compounds from the body and aid in hormone synthesis and decay<ref>“Cytochrome P450.” Wikipedia, Wikimedia Foundation, 20 Mar. 2021, en.wikipedia.org/wiki/Cytochrome_P450.</ref>. | Mitragynine has a methyl-ether group that interacts with V143 and C217 present on the opioid receptor. Mitragynine has a secondary and tertiary amine that is capable of interacting with the important D147 residue as well as a ring structure that is capable of orienting across from the histidine residue. A recent study published in August of 2020 on mitragynine and 7-hydroxymitragynine binding to the mu-opioid receptor<ref>Dalibor Sames Group_Research, www.columbia.edu/cu/chemistry/groups/sames/news.html.</ref><ref name="wikimitra">“Mitragynine.” Wikipedia, Wikimedia Foundation, 25 Mar. 2021, en.wikipedia.org/wiki/Mitragynine#cite_note-:1-21.</ref> investigated if and how mitragynine was able to enter the active site. The study discovered that not only does mitragynine bind in the active site but it also activates the G-protein pathway. The interesting thing about the activation pathway is that the majority of the time it does not recruit beta-arrestin. Unfortunately, Cytochrome P450 metabolic enzymes have been shown to involve with the metabolism of mitragynine. The enzymes seem to be inhibited by mitragynine and therefore raise concern for adverse drug reactions. Cytochromes P450 are heme-containing enzymes that oxidize steroids, fatty acids, and xenobiotics. These enzymes also play a large role in clearing a hefty amount of compounds from the body and aid in hormone synthesis and decay<ref>“Cytochrome P450.” Wikipedia, Wikimedia Foundation, 20 Mar. 2021, en.wikipedia.org/wiki/Cytochrome_P450.</ref>. | ||