US Pharm. 2017;41(3):7-9.

When the Drug Enforcement Administration (DEA) proposes to use its emergency scheduling authority to place a temporary ban on a “legal” drug due to concerns about abuse and safety, it is usually a fairly routine event. However, one recent decision by the DEA to ban a substance was anything but routine, resulting in a widespread public backlash that was sufficient to convince the DEA to reconsider its action.

The substance causing the controversy is the herbal opioid-like drug kratom. In August 2016, the DEA announced that it would temporarily reclassify kratom as a Schedule I drug.1 This action brought about a strong reaction, including public demonstrations, petitions, and calls by Congress to overrule the decision. These events resulted in the DEA withdrawing its notice of intent to institute the emergency scheduling of the active ingredients of kratom in October 2016 and to solicit further public comment.2

What Is Kratom?

Kratom (Mitragyna speciosa) is a tropical tree that has a long history of traditional and ceremonial uses in Africa and Southeast Asia.3 The tree is indigenous to tropical and subtropical regions of Southeast Asia, including Thailand, Malaysia, Philippines, Myanmar (Burma), and New Guinea; it is also found in parts of Africa. Traditionally in these parts of the world, the leaves are chewed or consumed as powder to help reduce fatigue, in particular by seamen and manual laborers on rubber plantations, and also culturally by individuals whose religious practices prohibit alcohol consumption.3

A member of the coffee family, kratom has long been used to relieve pain and ease opiate withdrawal in parts of Asia.3 It is available in the United States in many forms, including dried/crushed leaves, powder, capsules, tablets, liquids, and gum/resin; the most common route of administration is ingestion as a brewed tea, although smoking, chewing the raw leaves, and the ingestion of extracts have also been reported.1 The substance has become an increasingly popular alternative therapy and drug of abuse and is readily available on the recreational drug market in the U.S.1

The main active constituents of the plant are believed to be mitragynine and 7-hydroxymitra-gynine (7-HMG),1 indole alkaloids structurally related to yohimbine.3 These active constituents have shown anti-inflammatory and analgesic activity in experimental animals and appear to exert their effects as partial agonists for the mu-opiate receptor (and possibly kappa receptors); they also bind as partial agonists or antagonists to the delta-opiate receptors.3,4 They likely affect other neurotransmitters as well, especially adrenergic systems.4

The raw plant contains higher concentrations of mitragynine than 7-HMG; however, 7-HMG has a higher affinity for the opiate receptors and is believed to have better bioavailability and central nervous system penetrability than mitragynine.4 Both substances are reported to be more potent than morphine, and many of their effects are reversible with naloxone.4

Most pharmacologic and therapeutic evidence about kratom comes from anecdotal reports and patient experiences. More than half of the available scientific literature on kratom has been published since 2012, and there are few, if any, controlled clinical trial results that have been published.5 The available evidence appears to show that kratom produces an unusual combination of stimulant- and opioid-like effects.1,3,4 The relative amount of stimulation or mood enhancement and sedation or analgesia can vary based upon both the strain of kratom chosen and the dosage ingested.3 The stimulant effects are reported at lower doses, while the opioid/analgesic effects occur at higher doses.3,4

Some adverse effects reported with high-dose use of kratom include tachycardia, dizziness, hypotension, constipation, tremor, anorexia, seizures, and psychosis.3 Significantly, however, the kratom alkaloids produce little to no respiratory depression, and tolerance and dependence appear to develop more slowly than with traditional opiates.6

What Did the DEA Decide to Do About Kratom?

The DEA announced its intent to temporarily place mitragynine and 7-HMG into Schedule I on August 31, 2016. The Controlled Substances Act (CSA) empowers the U.S. Attorney General to place a previously unscheduled substance temporarily into Schedule I if the DEA (in collaboration with the Department of Health and Human Services) determines it is necessary “to avoid an imminent hazard to public safety.”1 Prior to this announcement, kratom was regulated as an herbal product under FDA and DEA policies and, as such, was considered to be a legal substance in most of the U.S.4

Placing a drug into Schedule I means that in the DEA’s view, the drug has “no currently accepted medical use and a high potential for abuse.”7 Emergency scheduling is usually for a period of 2 years (with a 1-year extension available) while the DEA gathers additional information, after which a more permanent classification may be implemented using the formal administrative rulemaking process. Emergency scheduling is only for a Schedule I drug.1

When the DEA contemplates placing a drug into a schedule, it considers what is known as the Eight Factor Test, which includes data on the drug’s potential for abuse, pharmacology, and risks. For temporary scheduling, the agency is required to consider three of the eight factors: the substance’s history and current pattern of abuse; the scope, duration, and significance of abuse; and what, if any, risk there is to the public health.1 In making its decision, the DEA takes into consideration the drug’s actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution.1

In making this determination on kratom, the DEA stated that “available information indicates that these opioid substances, constituents of the plant kratom, have a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision.”1

In reaching this conclusion, the DEA found that kratom is “an increasingly popular drug of abuse and readily available on the recreational drug market in the United States.”1 The DEA also reported a large increase in seizures from kratom intended for the recreational market during the first half of 2016. The DEA was concerned that kratom is easily obtainable from smoke shops and the Internet. It is misused to self-treat chronic pain and opioid withdrawal, and users reported effects similar to those of prescription opioids. The DEA also noted that users report dose-dependent psychoactive effects including euphoria, simultaneous stimulation and relaxation, analgesia, vivid dreams, and sedation. In addition, addiction or dependence and withdrawal have been documented with long-term, regular use of kratom.1,8

An additional concern noted by the DEA is the wide variability of the concentration of the active components in available kratom products, leading to unpredictable effects when similar amounts of different products are consumed. It was also reported that other psychoactive products have been found in kratom samples, including synthetic cannabinoids and opioids.8

Further safety concerns cited by the DEA were reports that there were 660 calls to U.S. poison centers related to kratom exposure between January 2010 and December 2015.1,8 Of these, 65% were isolated exposure to kratom, while in other cases kratom was being used with additional substances (ethanol, narcotics, benzodiazepines, acetaminophen, and other botanicals).1,8 The DEA concluded that the “consumption of kratom individually, or in conjunction with alcohol or other drugs, is of serious concern as it can lead to severe adverse effects and death.”1 The DEA noted that roughly 30 deaths have been reported since 2009 either in the scientific literature or in autopsy and medical examiner reports, many occurring since 2014.1,8

The DEA also reported receiving correspondence from local officials of a significant number of overdoses and traffic fatalities involving kratom, as well as reports of toxicity including hepatotoxicity, psychosis, seizures, insomnia, tachycardia, poor concentration, and hallucinations. In the DEA’s view, this information “demonstrates the severe risks associated with kratom misuse,” which would justify emergency scheduling.1 The DEA also pointed out that kratom is currently banned in 15 countries and six states (Alabama, Arkansas, Florida, Indiana, Tennessee, and Wisconsin), with six more states considering implementing regulations.1,8

What Was the Basis of the Challenge to the DEA’s Decision?

The DEA’s action did not go unnoticed. A public backlash to the proposed ban quickly developed.9 This included organized efforts by advocacy groups such as the American Kratom Association and the Botanical Educational Alliance, a demonstration near the White House, phone calls to Congress, and a petition sent to the White House with over 100,000 signatures. In general, the reaction stressed the view that kratom does not possess the harm that the DEA claimed and that it is useful in managing pain and other conditions, as well as in reducing opiate addiction; therefore, it should remain available to the public without restrictions.9 Advocates maintained that kratom is safer than prescription opioids and that the relatively low number of deaths attributed to kratom when compared with opiates is due to other drugs being used simultaneously. Many testimonials from users touting kratom’s beneficial effects quickly appeared on numerous websites.

Underscoring the intensity of the reaction to the DEA’s decision, a bipartisan letter drafted by U.S. Representatives Mark Pocan (D-WI) and Matt Salmon (R-AZ) to the heads of the DEA and the Office of Management and Budget was signed by more than 50 members of Congress.10 It called for a delay in implementing the ban, calling the decision to ban the “internationally recognized herbal supplement” as “hasty” and noting that this would have a serious effect on consumer access and innovation in treating individuals suffering from addictions.

On October 13, 2016, the DEA announced that it would withdraw its intent to temporarily schedule mitragynine and 7-HMG because of “numerous comments from the public,” including “comments offering their opinions regarding the pharmacological effects of these substances,” citing the need to consider these statements and to provide an opportunity to receive further comments.2 The reversal by the DEA occurred less than 2 months after the original notice of intent to implement the emergency rescheduling. The DEA set a deadline of December 1, 2016 for submitting additional comments; more than 23,000 comments were received during the 6-week comment period, mostly supportive of maintaining access to the product.2 The reversal by the DEA was an unprecedented event; the closest parallel is the drug trifluoromethylphenylpiperazine (TFMPP), a “legal” alternative to ecstasy. TFMPP was temporarily banned in 2001, but the ban expired in 2004 with no permanent action taken.11

What Are the Consequences?

No final decision has been published by the DEA at this time, so there is not yet a final determination of the future status of kratom. However, even if the DEA decides to reassert a limited access to the substance, the intensity of the opposition and unprecedented reversal by the DEA demonstrates a model that advocates of other herbal psychoactive drugs may follow in the future. Moreover, if the initial decision to ban kratom is ultimately reversed, it would stand in stark contrast to the DEA’s August 2016 decision in another response to public and governmental appeals—to continue to regulate marijuana as a Schedule I drug.

REFERENCES

1. Drug Enforcement Administration (DEA). Schedules of controlled substances: temporary placement of mitragynine and 7-hydroxymitragynine into Schedule I. Fed Regist. 2016;81(169):59929-59934. www.gpo.gov/fdsys/pkg/FR-2016-08-31/pdf/2016-20803.pdf. Accessed January 23, 2017.

2. DEA. Withdrawal of notice of intent to temporarily place mitragynine and 7-hydroxymitragynine into Schedule I. Fed Regist. 2016;81(198):70652-70654. www.gpo.gov/fdsys/pkg/FR-2016-10-13/pdf/2016-24659.pdf. Accessed January 23, 2017.

3. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med. 2016;130(1):127-138.

4. 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.

5. Prozialeck WC. Update on the pharmacology and legal status of kratom. J Am Osteopath Assoc. 2016;116(12):802-809.

6. Varadi A, Marrone GF, Palmer TC, et al. Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit -arrestin-2. J Med Chem. 2016;59(18):8381-8397.

7. DEA. Drug schedules. www.dea.gov/druginfo/ds.shtml. Accessed January 23, 2017.

8. DEA. Mitragynine and 7-hydroxymitragynine: background information and evaluation of ‘three factor analysis’ (factors 4, 5 and 6) for temporary scheduling. August 2016.

www.regulations.gov/document?D=DEA-2016-0015-0004. Accessed January 23, 2017.

9. Harven M. Herbal drug kratom faces uncertain legal future, despite public outpouring. PBS NewsHour. December 12, 2016. www.pbs.org/newshour/updates/whats-next-kratom/. Accessed January 23, 2017.

10. Nelson S. Dozens of Congressmen ask DEA not to ban kratom next week. U.S. News. September 23, 2016. www.usnews.com/news/articles/2016-09-23/45-congressmen-ask-dea-not-to-ban-kratom-next-week. Accessed January 23, 2017.

11. DEA. 1-[3-(Trifluoro-methyl)-phenyl]piperazine. August 2013. www.deadiversion.usdoj.gov/drug_chem_info/tfmpp.pdf. Accessed February 22, 2017.



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