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Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source


Kratom and Other Mitragynines: The Chemistry and Pharmacology of Opioids from a Non-Opium Source by Robert B. Raffa, ed. Boca Raton, FL: CRC Press; 2015. Hardcover, 366 pages. ISBN: 978-1482225181. $139.95.

Though not clear from the title, this book is mostly about opioids (compounds that bind to the opioid receptors) that come from the leaves of the tree commonly known as kratom (Mitragyna speciosa, Rubiaceae), as well as other interesting analgesic and psychoactive alkaloids from other plants. The editor, Robert B. Raffa, PhD, notes that the book evolved from a course taught at Temple University School of Pharmacy in Philadelphia, Pennsylvania. The predominant viewpoint of this collection of essays seems to be one of medicinal chemistry and, as such, can be heavy on chemical structures and their specific activities. The book chapters are not so much defined topics in an ordered sequence but rather reflect the interest and expertise of the faculty of pharmacy and other chapter authors. There are also chapters on other plant species including the opium poppy, Papaver somniferum (Papaveraceae). The most notable effect of the opiates (and other opioids), of course, is powerful analgesia. Alkaloids from both plant species bind to these specific receptors in the brain, and affect our perception of pain.

Thus, in the second chapter, Raffa et al. discuss how morphine, codeine, and related opiates are not the only potent analgesics from plants. The primary analgesic alkaloids in kratom leaves are mitragynine (MG; typically the most prevalent) and 7-hydroxymitragynine (7-OH-MG; the most potent). 7-OH-MG may be 10 times stronger than morphine, so even though its concentration in kratom is much smaller than MG, it may be responsible for a significant  part of the total plant properties. Other species or varieties may have varying alkaloid contents, however. With long-term, heavy use, the addictive effects that may result are similar to those of opiates (and other opioids), and a withdrawal syndrome can be observed in animals after injection of the opioid antagonist naloxone. Other animal studies suggest that the kratom compounds are less toxic than the opiates and have some other behavioral differences that will require much more research to better understand.

Chapter 3 explores the pharmacology of other psychoactive indole alkaloids and Chapter 4 is about salvinorin A, a non-alkaloid opioid from the hallucinogenic plant Salvia divinorum (Lamiaceae), with considerable focus on chemistry and structure-activity relationships. Chapter 5 deals with the botany and taxonomy of M. speciosa and related species in the genus. The effects seen with a common traditional method of consumption (chewing the leaves while working in the fields) are different from the effects produced by opium poppy, however. The reasons for this are not entirely clear but probably relate to the degree of absorption of the alkaloids during the chewing process. Taste may also be a factor as many alkaloids are extremely bitter.

The chemistry of M. speciosa is dealt with in detail in chapters 6 to 9, while the chemistry and structure-activity relationships of the opioids are discussed in Chapter 10. Chapter 11 is a discussion of how the active compounds in M. speciosa are related to its use and abuse. Chapter 12 deals with metabolism of these compounds, and Chapter 13 describes the analgesic properties of the compounds and their analogs. Non-analgesic CNS properties of kratom are discussed in more detail in chapters 14 and 15. In addition to pain-relieving properties, kratom also will suppress coughs and cause constipation but perhaps less so than the classic opioids. Even very high doses of MG in rodents did not show as much emesis (vomiting) or respiratory depression as codeine.

Chapter 16 presents firsthand experiences with kratom and discusses indigenous use and abuse. The authors quote from postings by kratom users at Erowid, a non-profit educational website dealing with information on various psychoactive and other, usually plant-based, substances. The effects from chewing the leaves of kratom are actually more reminiscent of the indigenous use of coca (Erythroxylum spp., Erythroxylaceae) leaves, and result in a mild stimulation with increased energy and reduced hunger. Clearly, as with coca, there are others who use it for other reasons and in much higher doses. Higher doses of kratom are generally associated with the analgesic and euphoric properties. Had leaf-chewing been the only use of these plants, it is unlikely they would ever have come to the attention of the authorities.

The toxicology of indole alkaloids is discussed in Chapter 17 but seems off-subject in many respects and is without reference to the compounds’ chemistry or pharmacology and how these would relate to toxicity. On the other hand, Chapter 18 concerns itself with adverse effects of opioids other than those found in kratom. Toxicity of compounds found in kratom is discussed in Chapter 19. Here, it is mentioned that there are no verified reports of kratom causing death when used alone. There are kratom products adulterated with synthetic drugs, however, some of which appear to be considerably more toxic. Many of the studies dealing with kratom’s toxicity are obviously done with animals. Chapter 20 deals specifically with animal behavioral models used to measure tolerance, dependence, and abuse potential. These are clearly limited in what they can deliver, and more work from other disciplines needs to be integrated for a better understanding.

Chapter 21 concerns the epidemiology, abuse, and legal status of kratom, and it provides a background in which to understand the plant. Very little controlled human data are available. One interesting point is that the MG content in kratom extracts varies significantly by geographic origin. Use was exclusive to Southeast Asia until around 1990, when the internet made it easy to order from anywhere in the world. In Southeast Asia, kratom is widely used as a stimulant to increase work production and for the treatment of opioid withdrawal symptoms.

In the United States, the legal status of kratom is obviously undergoing a major upheaval at the time of writing (October 2016), with regulatory agencies proposing (and then temporarily withdrawing that proposal) to classify two of the active alkaloids in kratom as Schedule I substances, which would, in effect, criminalize kratom possession and distribution. The US public will have to wait until the dust settles before it knows if, and in what form(s), kratom might be legally available.

—Jerry Cott, PhD
Senior Pharmacologist
Silver Spring, Maryland