Friday, 19 May 2017

Re: Review of Kratom Pharmacology and Safety

Date: 05-15-2017HC# 101638-568

Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792-799.

The leaves of kratom (Mitragyna speciosa, Rubiaceae), a plant indigenous to Southeast Asia, are used to combat fatigue and to manage pain, diarrhea, and opioid withdrawal. Americans are increasingly using kratom to self-manage pain and opioid withdrawal. In this article, the evidence regarding the pharmacology and safety of kratom is reviewed.
Kratom, kratom extracts, and some compounds isolated from kratom have been shown to have analgesic and antinociceptive effects in several animal models, including hot plate, tail flick, writhing, and pressure/inflammation tests. Although over 20 pharmacologically active compounds have been isolated from kratom, most investigations have focused on the indole alkaloids mitragynine and 7-hydroxymitragynine as the constituents responsible for the opioid-like effects. Studies suggest that the effects of mitragynine and 7-hydroxymitragynine are largely mediated by direct action on μ- and δ-type opioid receptors in the brain. The antinociceptive effects of mitragynine may also involve the activation of descending noradrenergic and serotonergic pathways in the spinal cord. Mitragynine may stimulate postsynaptic α2-adrenergic receptors and possibly even block 5-hydroxytryptamine2Areceptors. Mitragynine has also been shown to have anti-inflammatory effects.
Although 7-hydroxymitragynine is less abundant than mitragynine in kratom leaves, it has better oral bioavailability and blood-brain barrier penetration than mitragynine. Compared to morphine and mitragynine, 7-hydroxymitragynine has 13- and 46-fold greater potency, respectively. These data suggest that the analgesic effects of kratom are largely due to 7-hydroxymitragynine. The indole alkaloid constituents speciociliatine (a stereoisomer of mitragynine), speciogynine, and paynantheine have been shown to modulate smooth muscle function and behavioral responses in animals; however, these effects are not inhibited by opioid-receptor antagonists, suggesting that they may act via opioid-independent mechanisms.
In three studies, physical dependence and withdrawal symptoms like those of opioid withdrawal were observed in animals fed mitragynine or 7-hydroxymitragynine for five days or more.
Most of the information on the subjective effects of kratom is drawn from empirical and anecdotal reports, as evidence from controlled clinical trials is lacking. Kratom is reported to exert an unusual combination of both stimulant and opioid-like effects; these actions are dose-dependent and vary among individuals. At low to moderate doses (1-5 g), most people report a pleasant, mild stimulant effect; however, some individuals experience an unpleasant sense of anxiety and agitation. Ingested at moderate to high doses (5-15 g), kratom leaves produce opioid-like effects and are used to manage pain, diarrhea, and opioid withdrawal symptoms. Individuals who have used kratom to manage pain believe that its stimulant effects are more desirable than the sedative effects of opioids. At higher doses, the effect may be euphoric or dysphoric, depending upon the individual; the euphoric effects are reported to be less intense than those of opium and other opioids. At very high doses (>15 g), kratom leaves are sedating and like opioids, can induce stupor.
Adverse effects (AEs) associated with the use of kratom or kratom products include stimulant effects such as anxiety, irritability, and aggression, and opioid-like effects such as sedation, nausea, constipation, and itching. These AEs appear to be dose-dependent and vary among users. AEs associated with chronic, high-dose usage include tremor, anorexia, weight loss, psychosis, and hyperpigmentation of the cheeks. The rare reports of serious toxic effects (seizure, intrahepatic cholestasis) usually involve the use of very high doses of kratom (>15 g). "It is important to note that in each of these case reports, the patients may have had confounding health conditions, may have been using other drugs along with kratom, or both," write the authors.
The lack of clinical data and lack of understanding of how the constituents of kratom interact with prescription medications, drugs of abuse, or other herbal supplements impede an accurate evaluation of the safety of kratom. These problems are further compounded by the fact that the production and sale of kratom is relatively unregulated, and therefore, there may be significant variations in the quality, purity, and potency of kratom products. In Sweden, nine fatalities have been associated with the use of "Krypton," a product marketed as a very potent form of kratom. Forensic chemical analysis revealed that high concentrations of the pharmaceutical O-desmethyltramadol (a drug with opioid and neuromodulator activity) had been added to the plant material. Another fatal reaction was associated with the combination of propylhexedrine (an α-agonist and amphetamine-like stimulant) and mitragynine. This latter case highlights the fact that "high-potency" kratom products containing purified mitragynine, 7-hydroxymitragynine, and/or 7-acetoxymitragynine may be purchased over the internet. The combination of these purified extracts and other psychoactive drugs (alcohol, sedatives, opioids, stimulants, etc.) raises the potential for a range of serious drug interactions. [Note: In addition to adulteration with pharmaceutical drugs, suspected cases of kratom adulteration include artificially high concentrations of 7-hydroxymitragynine and the complete absence of 7-hydroxymitragynine.1,2]
In many anecdotal commentaries, kratom is said to be less addictive than classical opioids; however, it has also been reported to be highly addictive in some individuals. Some countries in Southeast Asia have prohibited the use of kratom because of its addiction potential. Most case reports of kratom addiction involve heavy, compulsive users who exhibited substantial tolerance to the effects of kratom and showed overt symptoms of withdrawal when discontinuing its use. Like opioid withdrawal, reported kratom withdrawal symptoms include irritability, dysphoria, nausea, hypertension, insomnia, yawning, rhinorrhea, myalgia, diarrhea, and arthralgia. Kratom and kratom-derived compounds are not detected in most routine drug testing, and the kratom-specific tests that have been developed are controversial and not yet widely available.
In summary, experimental studies have shown that kratom and its constituents mitragynine and 7-hydroxymitragynine exert analgesic and antinociceptive effects at opioid and other receptors. Other kratom constituents may also contribute to the overall analgesic effect via other mechanisms. These preclinical findings, taken together with empirical reports of analgesic efficacy, suggest that kratom may potentially be used to manage pain and opioid withdrawal symptoms. However, serious concerns have been raised regarding possible contraindications, toxic effects, drug interactions, and the abuse and addiction potential of kratom. These safety issues are confounded by the lack of regulatory oversight to ensure the quality, purity, and potency of commercial kratom products. The authors conclude that further research to evaluate the efficacy, safety, and addiction potential of kratom is needed.
Shari Henson
Editor's Note:
Although the authors state that kratom is legal in the United States (US), it should be noted that this article was published in 2012. Since 2014, kratom has been the subject of an import ban in the US (Import Alert 54-15) because the US Food and Drug Administration (FDA) ruled that kratom has no history of use in the US prior to 1994 and thus is a new dietary ingredient. The US Drug Enforcement Administration (DEA) published a notice of its intention to place an emergency Schedule I restriction on kratom in September of 2016. However, due to the unprecedented response from the scientific community and the public in general, a month later in October 2016, the DEA withdrew the proposed ban and announced that a six-week public consultation would be conducted, the results of which are still pending.
1Lydecker AG, Sharma A, McCurdy CR, Avery BA, Babu KM, Boyer EW. Suspected adulteration of commercial kratom products with 7-hydroxymitragynine. J Med Toxicol. 2016;12(4):341-349.
2Griffin OH 3rd, Daniels JA, Gardner EA. Do you get what you paid for? An examination of products advertised as kratom. J Psychoactive Drugs. 2016;48(5):330-335.