There are no human clinical trials or even case reports to assess or describe the efficacy of this very complex botanical. Here’s what we know.
In recent years, Americans have been increasingly interested in the use of kratom. The latest survey gauges there are at least 10 to 16 million people who use kratom in the United States, or roughly 3% to 4.9% of our population.1 Reasons for use include opioid replacement and pain management, and 58% to 67% of kratom users also endorse attempts to self-manage depressive symptoms and other mental health concerns.2-4 Of those who have taken kratom, 20.2% endorsed using the substance primarily to manage depression alone.4 In this context, self-reported perceived reductions in symptoms among survey participants were found.2-6 The majority of people who consume this botanical for managing depression were females, younger than 41 years of age, and with an income level inversely related to both the diagnosis of depression and use of kratom.3
The Google Trends report shown in the Figure illustrates that the number of searches for the use of kratom to manage depression (sharp rise in blue) parallels the increase in overall searches for management strategies of depression in general (more gradual rise in red) since 2004. Although there are limitations to such reports, it hints at the magnitude of use, especially in a time when mental health is being tested more than usual.
What is kratom?
Mitragyna speciosa (kratom) is a tropical evergreen tree, part of the coffee family, and native to Southeast Asia. Historically, it has been used by indigenous populations as a stimulant to enhance stamina and reduce fatigue. In traditional medicine, it has also been explored for a multitude of conditions including pain and as treatment for heroin addiction. The fresh or dried kratom leaves are typically chewed or drank as a tea or other concoction, with lemon often added to facilitate the extraction of the active ingredients. People may add honey or sugar to mask the bitter taste as well as salt to prevent constipation.
Less commonly, the leaves can be dried and smoked. Some may also mix the leaves as part of a cocktail containing a caffeinated soft drink and codeine-containing cough syrup called “4x100.” In the United States, those seeking the use of kratom may be able to procure it as leaves (dried or crushed), extracts, powders, capsules, tablets, liquids, or gum/resin. Such commercial products very often contain other contaminants, adulterants, and bulking agents as there is no quality control. These are readily available at shops or online with a dramatic increase in importation noted since 2016. To evade customs, these products are often declared and falsely labeled similar to other new drugs of abuse.
Kratom was legal to grow and purchase in all 50 states until 2015. The DEA identified kratom as a substance of concern; however, it is not currently scheduled, despite pressure from the US Food and Drug Administration due to safety concerns. Interestingly, the Drug Enforcement Agency had initially submitted a notice of intent to include kratom’s active components under schedule I of the Controlled Substance Act in August 2016, but the agency withdrew it in October 2016 following lobbying efforts from patients and the American Kratom Association. Regulations over use and sale have been imposed by certain states, individual counties, and even some towns. Use and sale in Thailand is illegal.
How kratom works
This botanical contains a multitude of constituents, among which are the indole alkaloids. To date 25 of these alkaloids have been identified. The 2 that account for the major psychoactive activity are mitragynine (MG), which makes up the majority of the alkaloid content, and 7-hydroxymitragynine (7OHMG), which is the highly active oxidized metabolite of mitragynine. The proportions of these 25 alkaloids vary tremendously depending on a multitude of plant and environmental factors, leading to plants with diverse potencies and properties. Behaviorally, lower doses of raw plant material have stimulatory cocaine-like effects while higher doses exert opioid-like effects and analgesia.
Pharmacologically, MG and 7OHMG are the most studied and understood of the alkaloids present in kratom. Both resemble opioids in structure and bind to the mu, kappa, and delta opioid receptors; however, they additionally act on many other serotonergic, noradrenergic, and dopaminergic receptors. MG was found to be an alpha-2 adrenergic receptor agonist, a 5-HT2A, 5-HT2C, 5-HT7 receptor antagonist, and a D1, D2 receptor agonist. MG may also act as an agonist at the A2A adenosine receptors.7,8 Although the pharmacological properties of the other 25 alkaloids in the plant are unclear, a simulation model predicted they may exhibit stronger binding profiles to adrenergic and serotonergic receptors.9
What are the risks?
Kidney injury, cardiotoxicity, acute lung injury, hypothyroidism, as well as neurological effects such as seizures and cognitive impairments have been associated with chronic use.10 The Table outlines all potential short- and long-term effects. Hepatic injury is a very concerning adverse outcome with numerous such reports emerging, and this involves primarily intrahepatic cholestasis. In recent years there has been a 10-fold increase in emergency department visits for adverse effects, and calls to poison control centers in the United States have increased from 1 a month to 2 daily.
A popular belief has been that deaths resulting from use of kratom alone are exceedingly rare, even impossible. Some fatality reports exist, however. In the majority of them, co-ingestions with opioids and other agents or adulterants in the case of kratom supplements were noted.11 The majority of deaths may actually be largely unaccounted for as autopsies do not include screening for kratom unless there is knowledge that it may be a contributing factor, and even if there is such suspicion, most laboratories do not have the ability to detect MG.
The risk of addiction is also increasingly evident.12 In Southeast Asia where this botanical is indigenous, dependence develops in 55% of people who regularly take kratom in as quickly as 3 months. Those new to using kratom report a 10-fold dose escalation within the first few weeks due to tolerance. As expected, on cessation such individuals are at risk for withdrawal13; following simple detox, the relapse rates reported are as high as 89% at 3 months.14
Reviews of kratom’s impact on mental health symptoms and conditions have relied heavily on the survey data mentioned previously, and reported outcomes.5,15 Although most reviews focused primarily on efficacy, some raised concerns over safety, particularly adverse effects of long-term use, such as the addictive potential.16
No clinical trials exist, regardless of randomization and placebo. No case reports describing benefit exist either. There are, however, case reports describing adverse outcomes or withdrawal from kratom in individuals who initially began using it as a way to manage mood symptoms.
There are 2 animal studies where MG alone or alkaloid extract was intraperitoneally administered while assessing various measures indicative of antidepressant effects in such models. These measures are the forced swim test, or FST (assesses absence of escape-oriented behaviors, timed from when the mouse is motionless except keeping head above water) and the tail suspension test (time from when the mouse is immobile with tape attached to its tail for suspension above ground). No long-term animal studies exist.
In 1 study, 2 different doses of MG (10 mg/kg and 30 mg/kg) and a control were intraperitoneally injected and found that both FST and tail suspension significantly reduced immobility time when compared with control.17 This finding mimics previous results seen when antidepressants were used as the test dose. Additionally, changes in the stress hormone cortisol were also similar to the antidepressant studies.
In the other animal study18, MG was administered to male Winstar rats and male ICR mice; investigators found that a single administration of the alkaloid extract of kratom containing approximately a 66% MG concentration in doses of 60mg/kg and 90 mg/kg led to decreased immobility time as assessed by FST. Here, locomotion (an indication of a stimulant effect) was not found to be affected. They also found that a higher level of FOS protein was found in dorsal raphe nuclei (which carries a high density of serotonin to the forebrain) in the test animals, raising the question of whether one of the perceived antidepressant effects may be mediated through activation of the c-Fos pathway.
The bottom line
In recent years, there has been increased interest among the general public surrounding the use of kratom to self-manage a multitude of symptoms and conditions—including depressive disorders and associated symptoms. Apart from social media endorsements and user self-reports, there are no human clinical trials or even case reports to assess, or describe, the efficacy of this very complex botanical. The available survey data stem from those who endorse depression, or symptoms of such, and not clinically diagnosed depression, and the reported benefits are very much subjective.
Depressive disorders carry a high risk of morbidity and mortality and need to be addressed in a timely manner and in accordance with the highest level of evidence. Concerning the question evaluated here, the adverse effects associated with kratom are worrisome, and its use for management of major depressive disorder is an endeavor not supported by science and carries significant risks.
Dr Stanciu is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is addiction section editor for Psychiatric Times.
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