Tuesday, 18 July 2017

Re: Review Explores Therapeutic Potential and Legal Status of Kratom

  • Kratom (Mitragyna speciosa, Rubiaceae)
  • Pharmacology
  • Legal Status
Date: 07-14-2017HC# 011746-572

Prozialeck WC. Update on the pharmacology and legal status of kratom. J Am Osteopath Assoc. December 2016;116(12):802-809.
In this commentary, Prozialeck, lead author of a 2012 review of the same plant, describes updated research findings and the changing legal climate of kratom (Mitragyna speciosa, Rubiaceae) leaf. Indigenous to Thailand, kratom leaves and infusions are traditionally used for fatigue, pain, diarrhea, coughs, and opioid (from opium poppy [Papaver somniferum, Papaveraceae]) withdrawal. Kratom and its constituents—including mitragynine, 7-hydroxymitragynine, paynantheine, speciogynine, and >20 others—produce dose-dependent stimulant and analgesic effects.
In their 2012 review, Prozialeck et al. determined that kratom's use was increasing in the United States for self-management of opioid withdrawal and pain. At that time, kratom was not among US Drug Enforcement Administration (DEA)-prohibited substances but was on its Drugs and Chemicals of Concern watch list. Like other herbs, it is subject to provisions of the Dietary Supplement Health and Education Act of 1994 (DSHEA). The DEA announced on August 30, 2016, its intent to add mitragynine and 7-hydroxymitragynine to its Schedule I, drugs of abuse with no medical value. Schedule I also includes heroin (from opium poppy), methamphetamines, hallucinogens, and cannabis (Cannabis sativa, Cannabaceae). After public outcry, the agency decided to reconsider. Several states have since outlawed kratom and its constituents, and the legal future of the plant remains in question. During the four years since Prozialeck et al.'s review, more than half of all available research on kratom has been published. Results of several analyses reveal that use in the United States continues to rise despite an increase in adverse event (AE) reports linked to kratom. Patient websites about kratom are generally laudatory; however, no controlled clinical trials on efficacy or safety have been published. Prozialeck tackles the most pressing questions in the kratom debate.
Should kratom and/or its mitragynine compounds be classified as opioids?
The DEA emphasizes kratom's opioid-like effects, but most evidence for these comes from animal studies that indicate mitragynines might interact with opioid receptors, and anecdotal reports. Unlike opioids, kratom produces mildly stimulating effects at moderate doses. Kratom does not produce an intense high or euphoria typical of opioids. Even at very high doses, kratom does not depress respiration, and the molecular structure of mitragynines is quite different from that of opioids. It has been reported that several mitragynine analogs are agonists at μ-opioid receptors and antagonists at δ-opioid receptors. And, while they activated the G-protein-mediated signaling pathway like opioids, mitragynines did not "recruit" β-arrestin-2, implicated in opioid AEs and dependency. Based on all evidence, kratom and its compounds should not be classified as opioids.
Is kratom effective for opioid withdrawal and/or pain?
Opioid abuse and addiction in the United States are rampant, according to the author, prompting new guidelines from the Centers for Disease Control and Prevention on opioid prescriptions. Physicians are discouraged from prescribing opioid pain relievers, especially long term, and patients with chronic pain are seeking alternatives. Lacking clinical studies, a systematic analysis of kratom user comments on one website found the majority reporting benefits in managing opioid withdrawal and pain, depression, and anxiety. Prozialeck describes these anecdotal reports as "compelling." More evidence comes from the US Patent Office that has issued and has pending several patents for kratom-based drugs. Evidence of kratom's potential medical value presumably had to be submitted with successful applications. Some abuse/addiction specialists fear kratom may be a "gateway" or "crutch" drug, leading more individuals to opioid abuse and/or becoming itself a drug of abuse, much like methadone and buprenorphine, widely used opioid maintenance substances. Notably, kratom is less toxic than methadone.
How serious is kratom's abuse or addiction potential?
While some may use kratom for its mind-altering effects and may, over time, become dependent or addicted, withdrawal from kratom is reported to cause milder symptoms than opioid withdrawal. Its potential benefits may well outweigh its risks.
Are kratom products safe?
The most commonly reported AEs at low to moderate doses (5-10 g raw leaves) are generally mild, including anxiety, irritability, nausea, and vomiting. More serious AEs including tachycardia, seizures, liver damage, and, perhaps, death have been reported with high doses, concentrated extracts, or supposed kratom products. The DEA, in announcing its proposed kratom compound ban, focused on 660 calls made between January 2010 and December 2015 to poison control centers concerning kratom. But in 2014 alone, over 28,000 people died of opioid poisoning. It is important to understand that there is virtually no data on kratom's possible interactions with common drugs that might be used concurrently by patients with chronic pain. Lack of regulation and standardization and the adulteration of kratom products with exogenous drugs also are causes for concern. A product called krypton, supposedly a potent form of kratom but containing the opioid-like neuromodulator O-desmethyltramadol, is implicated in at least nine deaths in Europe. How it may have interacted with mitragynine is unknown. Without some form of standardization and quality control, people using kratom products have no way of knowing what they may be taking. In its pure herbal form, kratom seems to be relatively benign, especially compared to hydrocodone, oxycodone, and heroin.
While additional research is vital to understand kratom's risks and benefits, placement in Schedule I would almost certainly have a chilling effect on research, as has been the case with cannabis, in addition to inherent difficulties of studying botanical substances.
—Mariann Garner-Wizard