After public outcry and objections from members of Congress, the U.S. Drug Enforcement Administration has withdrawn its intent to classify two chemicals produced naturally by the kratom tree as Schedule I controlled substances. Instead, the DEA has opened a formal comment period for public and technical comments on their originally intended actions against the two alkaloids from kratom (Mitragyna speciosa Korth.): mitragynine and 7-hydroxymitragynine.

The withdrawal of the notice of intent and opening of the comment period, announced yesterday, was published this morning in the Federal Register. Those who have already provided comments to the DEA need not resubmit their input unless they have new information to add. The Federal Register announcement has instructions for the submission on comments electronically or via snail mail. The comment period ends on December 1, 2016.

Since the DEA’s August 31 announcement of their intent to schedule the two alkaloids to the most restrictive classification under the U.S. Controlled Substances Act, a groundswell of users who obtain benefit from the medicinal herb rose to object to the plan. DEA held that mitragynine and 7-hydroxymitragynine were opioids associated with dozens of deaths and hundreds of poison control center calls over the last five or six years. In addition, the agency held that kratom had no formal medical uses but had high abuse potential.

In contrast, users reported to DEA, congressional representatives and journalists the health benefits of powdered kratom leaves for ailments ranging from chronic pain and depression to alcohol and opioid dependence. Especially galling to this group was that the agency’s acting administrator had declared a public comment period could be bypassed since it would preclude action on what he deemed an imminent hazard to public health.

Three separate actions by congressional representatives were also issued over the last month: a letter of objection to the Office of Management and Budget by Rep. Mark Pocan (D-WI) and Rep. Matt Salmon (R-AZ) signed by 51 members of the House of Representatives, a Dear Colleague objection led by Sen Orrin Hatch (R-UT), and a strong letter to DEA from Sen. Cory Booker (D-NJ), Sen. Kirsten Gillibrand (D-NY) and Sen. Ron Wyden (D-OR).

At one point during the month, DEA spokesperson Melvin Patterson told me that he arrived each morning to over 200 kratom user testimonials on his voicemail.

The state of the science

The problem with these anecdotes, no matter how many, is that the medicinal claims have not been fully investigated under the auspices of a clinical trial. Rodents studies strongly support that individual kratom alkaloids have significant analgesic, or pain-killing, effects while causing minimal risk of respiratory depression and physical dependence. University of Mississippi drug abuse researcher, Christopher McCurdy, PhD, told me further that kratom had the potential to ease withdrawal symptoms due to morphine addiction in mice.

Then, two studies published this summer by research groups primarily at Columbia University and Memorial Sloan-Kettering Cancer Center showed that individual chemicals from kratom leaves and chemical relatives made in the lab had peculiar actions on opioid receptors that distinguished them from the strong opioids at the center of North America’s opioid epidemic, such as heroin, fentanyl and oxycodone. These studies showed that the kratom-derived compounds had self-limiting effects on the primary opioid receptor involved in pain and did so in a way the drove nerve cell signals toward a pathway associated with fewer side effects.

Mitragynine and 7-hydroxymitragynine had been known previously to act on opioid receptors. But this particular aspect of biased action toward a pathway involving a G-protein rather than another protein called beta-arrestin-2 is a new finding, one that the DEA would have been unlikely to include in their deliberations.

Who decides now?

The U.S. Food and Drug Administration, which sits in the Department of Health and Human Services, is the federal agency charged with providing the DEA with the scientific and medical evaluation of drugs and botanical medicines related to controlled substance classification. The DEA notes that a full evaluation has been requested of FDA and that some input has already been provided.

Normally, the FDA can rely on the results of clinical trials conducted during the drug approval process to evaluate the abuse and physical dependence potential of a new drug. This occurred, for example, with the weight loss drug, lorcaserin (Belviq; Eisai). Lorcaserin had a theoretical potential to provide rewarding effects based on animal studies as it was a stimulator, or agonist, at the serotonin receptor subtype, 5-HT2C. At higher doses than those used for weight loss, lorcaserin caused euphoria in 16% to 19% of obese subjects.

Related – Why Does Arena’s Obesity Drug Have Abuse Potential?

But in a study using volunteers who were recreational drug misusers, those high–or supra therapeutic–doses of lorcaserin caused increases in perceptive measures for “high”, “good drug feelings,” “hallucinations,” and “sedation.” As a result, the FDA recommended that the drug be treated as having some abuse potential. The DEA agreed and placed it on Schedule IV, a  classification for drugs with medical uses but a moderate potential for abuse. Other drugs on Schedule IV include the anti-anxiety benzodiazepine, lorazepam (Ativan), and the drug for insomnia, zolpidem (Ambien).

This post will be updated as more information and comments become available.