A Kratom Primer: Miracle Medicine or Herb of Abuse?

19 November 2020
A Kratom Primer: Miracle Medicine or Herb of Abuse?

Kratom could be clinically beneficial for pain management and substance use disorders. Its promise lies in the identification of our most-utilizable alkaloids, allowing for synthetic production capable of being replicated, mass-produced, and most importantly, studied in a standardized manner.

With patients increasingly leaning toward alternative and complementary pain-relieving agents, such as marijuana, CBD products, coca tea, ephedra, and kratom, healthcare providers are facing more questions – and more responsibilities – to understand these “natural” products. Many of these substances are inconsistently regulated and lack data behind them, leaving clinicians unable to disseminate quality information about risks and benefits to their patients.

Kratom, in particular, is an herbal substance with snowballing use in the United States. It was first imported to the US in the 1980s, and has an estimated 3 to 5 million users in America today.1 People are using kratom to help manage a variety of conditions and symptoms, such as opioid dependence, constipation, mood disorders, chronic pain, and muscle spasms.

Herein, we tackle what is known about kratom’s history, pharmacology, risks, and benefits, with the goal of empowering pain management providers to partner with their patients in openly discussing its use.

Historical Use of Kratom

Kratom is the common name for the leaves of Mitragyna speciosa, a tree in the coffee family native to Indonesia, Malaysia, Thailand, the Philippines, Borneo, and New Guinea.1,2 Its use has been recorded for more than 150 years with the first documented use in 1836 as an opium substitute.1 Traditional Southeast Asian uses include chewing leaves by laborers for sustained energy and analgesia after a hard day’s work, as well as brewed tea in the evening for relaxation.1-3,4

Despite its actions as an opioid agonist and reports of causing sexual dysfunction, kratom has also been used as an aphrodisiac.1,2 One case report suggested the mechanism for sexual dysfunction may be linked to increased prolactin levels, causing secondary hypogonadism.

Kratom’s Pharmacology

Kratom is a plant-based psychoactive substance that contains more than 40 different alkaloids. Its pharmacology is complex as the concentrations of the numerous alkaloids can vary widely. A detailed review of the varying alkaloids and their properties have been described elsewhere,6 however pertinent data on the five most prevalent alkaloids are shown in Table I.

Mitragynine and 7-hydroxymitragynine are the primary active alkaloids responsible for the effects of kratom.7 Despite its interaction with opioid receptors, mitragynine is not structurally similar to traditional opioid medications.5

Opioid Receptor Activity

7-hydroxymitragynine is more potent than mitragynine but is less prevalent in kratom. Mitragynine’s main activity is on mu opioid receptors and is responsible for the opioid-like effects including analgesia seen with kratom use. 7-hydroxymitragynine is estimated to be 13 times more potent than morphine and 46 times more potent than mitragynine in animal studies.5 There are conflicting reports of mitragynine and 7-hydroxymitragyne’s binding activity at mu, kappa, and delta opioid receptors.6,7

Based on the dose dependent response seen with kratom use, partial agonism at mu opioid receptors seems likely and is supported by research.8,9  Reported dysphoria and reduced addiction potential associated with kratom use may imply kappa agonism is more likely, but that has not been consistently described in the literature.10

Another key difference between kratom and traditional opioids is the lack of beta-arrestin-2 recruitment, which may explain the reduced side effects and risk of respiratory depression seen with kratom.6

Noradrenergic and Serotonergic Pathways

In addition to opioid receptor activity, mitragynine also has effects on descending noradrenergic and serotonergic pathways, postsynaptic alpha-2 receptors, and blockade of 5-hydroxytryptamine2A (5HT2A) receptors.6 It has been postulated that in addition to the opioid receptor effects, kratom may provide a second mechanism to potentially alleviate pain with these pathways that have already been well characterized and utilized for modern approaches to pain management with TCAs and SNRI medications.7 There is also evidence to suggest kratom has anti-inflammatory effects from cyclooxygenase-2 inhibition.6

Dose Dependent Effects and Withdrawal Symptoms

A key feature of kratom is its dose dependent effects. Low doses, between 1 gram to 5 grams, are most likely to result in stimulant-like effects, such as increased alertness, energy, and restlessness. At doses greater than 5 grams, the opioid-like effects of kratom are predominant, including analgesia, sedation, and possible euphoria.11 This unique feature is observed even when reviewing historical use by indigenous populations.

Kratom use to alleviate opioid withdrawal symptoms has also been reported. The alpha-2 noradrenergic activity of kratom may explain its reported use for minimizing opioid withdrawal symptoms. Clonidine is an alpha-2 agonist commonly used in opioid withdrawal protocols.12 Stimulation of alpha-2 receptors is also believed to contribute to the stimulant like effects seen at low doses.3

Drug Interactions

Kratom has been shown to inhibit various CYP450 enzymes, including CYP2C9, CYP2D6, CYP1A2, and CYP3A4, resulting in a large number of possible drug-drug interactions.3 Mitragynine appears to demonstrate greater inhibition for CYP2D6 versus CYP2C9 or CYP3A4.13 Although the clinical significance of these pharmacodynamics interactions is unknown, a thorough medication history and review for possible interactions should be conducted in all patients with known kratom use due to the high likelihood of interacting medications. Specifically, caution should be taken with medications with a narrow therapeutic index, such as warfarin.

Several OTC medications and herbal supplements, including antacids, grapefruit juice, dextromethorphan, and watercress, have been described to potentiate the effects of kratom.14 A cocktail containing kratom, soda containing caffeine, and cough syrup containing dextromethorphan, codeine, and diphenhydramine utilizes CYP drug interactions to increase the effects with kratom.15 Referred to as “4 x 100,” this cocktail is frequently used among the adolescent population in Thailand.15 Krypton is a combination of kratom with o-desmethyltramadol, the active metabolite of tramadol with higher affinity for the mu-opioid receptor and a substantial upgrade in overall potency.16

The risk of overdose with krypton is increased given the additive opioid effects with o-desmethyltramadol. Krypton gained recognition in the public eye after being linked to nine deaths in Sweden.2 Kratom (specifically mitragynine) has also been found in K2 (cannabinoid) products.15

Preparations and Dosage Forms

There are three primary strains of kratom, named by the appearance of the Mitragyna speciosa leaves: red vein, which is indigenous to Bali, and white and green vein strains, from Indonesia. The presence of alkaloids varies in each strain, which is thought to be responsible for their varying effects.17

  • Red vein is said to have relaxing, analgesic, and sedating benefits, most commonly recommended for insomnia or pain.
  • White vein, in lower doses, can provide “wakefulness,” and possesses stimulating properties, providing the user with alertness and motivation.
  • Green vein leaves provide a mix of red and white vein benefits and are considered milder.

The variable benefits from these strains are believed to be related to varying proportions of the differing alkaloids in the leaves.3,14 In high performance liquid chromatography mass spectrometry analyses, variations in 7-hydroxymitaygnine content was between the strains, with higher levels in red vein strains, trace levels in green vein strains, and none identified in white vein strain.17

Although kratom can be smoked or insufflated, oral administration is the most common. This is due to high volume required and destruction of alkaloids during combustion with smoking or insufflation.14,15 The traditional preparation in Thailand is to chew whole leaves for both stimulation and analgesia. The leaves are extremely bitter, and require a large amount of leaves to achieve the effects. Therefore, kratom is often served as a tea, steeped in hot water for extraction of the alkaloids, and addition of honey, peppermint oil, or lemon juice to cover the bitter taste. Some grind the leaves into a powder, which can be steeped as a tea, “tossed and washed” (placed in the back of the mouth and swallowed) to avoid taste buds, or mixed with olive oil. Powder may also be compressed into tablets or placed inside gelatin capsules for easy oral administration. Alkaloids may also be extracted with several multisolvent, heatless techniques available online.14

Distribution and Value

Kratom can be found in a variety of settings, from gas stations and head shops to bars and boutique tea shops, with all varieties of dosage forms.15 Inthe United States, it is most common to find kratom powder or extract for sale. There are a number of online retailers selling diverse varieties of kratom powder for approximately $7 to $12 for 25 grams to 28 grams, offering discounts on bulk orders, discount codes for repeat shoppers, and free shipping over a certain weight.18,19

Risk vs Benefit

Kratom’s General Effects

It should be stated that the effects of kratom have little evidence in primary literature and are primarily reported in anecdotal evidence.

Kratom has a detailed entry on PsychonautWiki, a user-generated site,where users have reported anecdotal effects using the Subjective Effect Index (SEI).14Many users take to forums and message boards, such as Erowid,20 to report and explore alternative methods and reasons for use.

Some of the most commonly reported benefits according to a review by Singh, et al, include:

  • euphoria
  • a sense of wellbeing,
  • relaxation
  • enhanced sociability
  • more energy
  • analgesia
  • sensory enhancement
  • a warm and tingly feeling.2

Those using kratom for pain management report preference for its stimulant effects rather than the sedation that often comes with using traditional opioids.  However, to achieve opioid-like analgesic effects, higher doses of kratom are needed, which can then lead to constipation, sedation, and euphoria.6

Although used as a drug of abuse for its euphoric effects, users tend to report this requires higher kratom doses, and is generally less intense than that of opioids. Some users also report dysphoric effects at higher doses, rather than desired euphoric effects.6

Kratom’s Relation to Opioid Addiction & Respiratory Depression

Although lacking clinical support, evidence of kratom’s use as a treatment for opioid use disorder (OUD) was documented as early as 1836. More recently, in 2005, this use was described on popular health information websites.15

In Southeast Asia, chronic kratom use generally had no significant impact on social, professional, or familial functioning, as well as low instances of criminal behavior or precarious drug use. This suggests its use may demonstrate similar benefits to current opioid replacement therapy for opioid dependence and/or addiction with intent to see improvement in psychosocial functioning.2  

As noted, most noted benefits of kratom use come from subjective reports as there are a few published animal and human trials. Animal studies in mice, rats, cats, and dogs, utilizing hot plate, tail flick, writing, and pressure and inflammation tests have confirmed analgesic properties of kratom.6,15 Interestingly, these antinociceptive properties were bolstered by caffeine as well as acetaminophen,15 suggesting a potential role for headache management. Isolation of kratom alkaloids demonstrated opioid-like activity in ligand-binding studies as well as in smooth muscle systems. (6) Importantly, these opioid-like effects, both central and peripheral, have also shown sensitivity to inhibition by opioid antagonists, such as naloxone.6,15

Perhaps the most impressive clinical finding is that oral kratom doses as high as 920 mg/kg did not induce respiratory depression.15 This reduced risk of respiratory depression is thought to be due to a lack of beta-arrestin-2 recruitment.6 Doses as low as 5 grams may induce analgesia, which equates to 71.4 mg/kg in a 70 kg individual. This suggestive safety profile partnered with sensitivity to reversal by naloxone, make kratom an appropriate candidate for further investigation into clinical utility of these already prominent uses. It has been noted that a significant amount of kratom use is as a substitute for more harmful substances, such as opioids, which may serve as a risk mitigation strategy or replacement therapy.7

Adverse Effects of Kratom

Of course, kratom use is not free of adverse effects. Commonly-experienced adverse effects are also reported on Erowid,20 and include nausea/vomiting and stomach aches, itching, dizziness or unsteadiness, alternating chills and sweats, visual alterations, sedation, and numbness in the mouth and throat.6,15

In those with chronic use, tremor, weight loss, anorexia, psychosis, and hyperpigmentation of the cheeks has been observed.6 Although low doses (< 5 grams) are used with goals of increased alertness, energy, and talkativeness, some users instead experience anxiety and agitation.6 Constipation may also be experienced as it has been linked to both opioid and non-opioid mechanisms; these include slowed intestinal transit (only partially resolved with naloxone administration), reduced intestinal smooth muscle function, reduced acetylcholine release from presynaptic nerves, and inhibiting muscarinic receptors in ileal smooth muscles.15

More serious documented adverse effects include hypothyroidism, seizure, coma, liver injury, and death in kratom toxicity.2,6

As concern for risks associated with kratom have risen, so has the number of investigations and preclinical trials. Animal studies have demonstrated cognitive impairment, addiction, toxicity, punishment tolerance, and reward-seeking behavior. However, they have also demonstrated benefits, such as the potential to slow the development of opioid tolerance when co-administered with morphine.7

A 2018 study aimed to assess the cognitive impact of long-term use. Researchers created a simulated environment where chronic kratom users and non-users underwent the Cambridge Neuropsychological Test Automated Battery. They found statistically significant deficits in chronic users compared to control in visual episodic memory and new learning, as well as an insignificant deficit (although trending towards significance) in reaction time.21

Kratom’s Dependence and Addiction Potential

Although it has been used to manage symptoms related to use disorders of other substances, kratom is not without risk of dependence and addiction of its own. One study found dependence in more than 50% of kratom users.2 In a Malaysian survey, where 90% of chronic users surveyed were using kratom to reduce addiction to other substances, and 84% to manage withdrawal symptoms from opioids, 78% of users reported previous attempts at discontinuing kratom without success.15

In another Malaysian study in 2014, where the majority of users were aiming to enhance their work performance, 31% reported using due to curiosity or peer pressure, and only 15% to wean themselves off other substances. Of these patients, 89% had previously attempted to wean themselves from kratom, and all had relapsed.15

Another study on these same individuals was completed in 2015 assessing their social functioning. While none of them required medical attention related to kratom use, used other illicit drugs, or felt they needed treatment for their kratom use, several reported:

  • memory or concentration deficits (17%)
  • anxiety (14%)
  • depressive symptoms (13%)
  • violent behavior (6%)
  • and a few patients reported suicidal attempts or hallucinations.

The subjects felt they had control of their use, however none maintained abstinence, with only 18% maintaining sobriety for longer than 3 months.15

Despite this evidence, proponents of kratom use, such as the American Kratom Association, maintain that kratom does not cause “addicting brain rewarding effects” like traditional opioids.22

Kratom Withdrawal

In zebrafish and rat studies, conflicting evidence exists between amelioration or induction of opioid withdrawal symptoms.15 Common kratom withdrawal symptoms are similar to those of traditional opioids, including: lethargy, yawning, runny nose, diarrhea, arthralgias, cramps, joint pain, hot flashes, restlessness, aggression, anxiety, dysphoria, hallucinations, and cravings.2,6,15,23

Kratom withdrawal symptoms have been reported to be less severe than those of traditional opioids, onset within about 12 to 16 hours, and have a typical duration of 1 to 3 days.2,15,21 As one might expect, users with more substantial kratom use are five to seven times more likely to experience kratom withdrawal symptoms.15

Due to inconsistencies in prevalence of withdrawal symptoms, authors from Malaysia, Germany, and the US came together to perform a multicenter retrospective review in Malaysia. All participants were male, 99% Malays, and more than half were between 18 to 32 years old, significantly limiting the applicability of their findings. However, they found that long-term consumption of kratom tea resulted in only mild to moderate anxiety and depression on cessation.24

A number of withdrawal management recommendations are available. The Clinical Opioid Withdrawal Scale (COWS) protocol utilizing clonidine or buprenorphine can be used with hydroxyzine and gabapentin as potential adjuncts. Some patients have been maintained on buprenorphine/naloxone after discharge.21 In another instance, opioid-agonist dihydrocodeine was used alongside alpha-2 agonist lofexidine with success.6,21 It may be reasonable to utilize other symptomatic treatments, such as pain with non-opioid adjunct therapies, diarrhea with non-opioid antidiarrheal medications, or benzodiazepines for anxiety and/or spasms.21

Kratom Toxicity

While prevalence of kratom toxicity has remained relatively rare in the medical literature, especially in the absence of polysubstance use, it is important to be aware of potential toxic symptoms and how to manage them. In a 2019 review of the National Poison Data System and New York City Office of the Chief Medical Examiner, it was found that toxicity appears to be dose-related, with notable concern when doses exceeded 8 grams.7

Due to the relatively recent emergence of domestic kratom use, a lack of evidence cannot be directly associated with safety, and the potential for lack of recognition by responders must be considered.15

Calls to US poison control centers regarding kratom use increased more than 50 times in the past 10 years, with the sounding majority being placed by healthcare providers, and typically minor or moderate in severity. It is important to note that less than 1% of users ever seek treatment related to consumption.15,23,25

Worse outcomes, including increased hospital admissions, were observed when multiple substances were reported versus kratom alone.26 Ethanol, benzodiazepines, narcotics, other botanicals, and acetaminophen are the most commonly reported substances used in combination with kratom leading to poison center calls.27 A case series of poison control center data following kratom exposure reported no requirement of intensive care when using kratom monotherapy.28 Current management methods are primarily symptomatic, based on the patient’s presentation. In addition to the common adverse effects seen with kratom use, toxicity can also result in tremor, diaphoresis, seizures, delirium, torsades de pointes, liver injury, rhabdomyolysis, and coma.2,7,15,21

Some suggested management options include naloxone, laxatives, benzodiazepines, magnesium IV fluids, antiemetics, antihypertensives, and supplemental oxygen.15,21

Overdose Deaths

Despite the known possibility that kratom toxicity can result in coma and death, reports of single-substance related deaths involving only kratom are relatively rare. In Southeast Asia, there have been zero reports of toxicity or death; this is thought to be related to either significant tolerance due to the long history of use, or potential underreporting as a result of widespread use in rural communities, and a low likelihood of presentation for medical attention.2

Of the 27,338 US overdose-related deaths occurring between July 2016 and December 2017 that were reported to the State Unintentional Drug Overdose Reporting System (SUDORS), only seven tested positive for kratom alone, and toxicologists noted that this could not rule out the presence of other substances.29 Low reports of kratom association may be due to poor recognition by front-line respondents, such as law enforcement or medical personnel,21 or inconsistent standards for post-mortem testing. Alternatively, the overwhelming majority of polysubstance-related deaths may suggest contamination of kratom-containing products.7,15 This has been reported numerous times in medical literature, including, as noted above, nine deaths related to krypton, or deaths related to kratom products found to be laced with hydrocodone.15

Monitoring Kratom Use

It is important to note that kratom is not detected on routine urine drug screen in the US; its use should not be ruled out due to a negative opioid screen. Kratom, or more specifically mitragynine and 7-hydroxymitragynine, may be detected through more specialized screening using liquid or gas chromatography-mass spectrometry where available. When available, a turnaround time for results of several days should be expected, limiting the clinical utility depending on treatment setting. There are varying thresholds for detection, further complicating interpretation of results.

Legality: Kratom on the International Stage

The legal status of kratom varies from region to region, country to country, and state to state. Despite its long-standing history in Southeast Asian countries, a variety of sanctions have been established against kratom’s use.

A 2008 survey in Thailand estimated more than 1 million kratom users, and in some districts, up to 70% of males used kratom daily.15 Its benefits for diarrhea and muscle spasms continue to make it a household staple in communities of southeast Asia.1

The European Union does not share a unified stance on the legality of kratom; while it remains a legal substance in Germany, it is illegal in Ireland and Latvia, and is classified as a controlled substance in Lithuania, Poland, Romania, Denmark, Finland, and Sweden.1,2,15

Kratom remains an illegal substance in Australia.2

In the US and Europe, over the past two decades, kratom’s popularity has grown, primarily among middle-aged, blue collar, insured individuals.1 The American Kratom Association estimates there are approximately 3 million to 5 million kratom users in the US.1,15 Kratom’s promotion for a “legal high” under the guise of “safe” and “natural” has led to increased use in countries practicing Western medicine.

In the US, the most common reasons for use include treatment of chronic pain, mood disorders, or withdrawal from prescription or illicit opioids.1 A 2020 study estimates that US prevalence of kratom use in the year prior is 0.8%, and in demographics of those kratom users, there was a tendency toward more serious substance abuse profiles than non-users or users of cannabis, alcohol, or cigarettes.30 This comes as a considerable variation to the trends noted in Southeast Asia, where kratom users maintain employment, are not high utilizers of healthcare, and maintain family relationship and structure.1

As an herbal supplement, kratom cannot be legally promoted in the US as a treatment for any medical condition. As a result, there is a lack of strict oversight of kratom and there is wide concern regarding variations in potency and contamination of available products.

Kratom was recalled by the CDC as a result of contamination with salmonella in February 2018. In 2010, the DEA listed kratom on the Drugs and Chemicals of Concerns list, stating “there is no legitimate medical use for kratom in the US.”6  In April 2019, the FDA released an analysis of kratom products confirming the presence of heavy metals.27,31

With the steep increase in domestic use as well as reported toxicity and deaths, regulatory action has been attempted. In 2016, the DEA recommended listing kratom and its metabolites as Controlled Substances Act Schedule I drugs, however this was met with substantial public and political outcry by researchers, interest groups, and 51 legislators.1,2,15 Despite resistance, the FDA has classified mitragynine and 7-hydroxymitragynine as opioids and kratom remains on the Drugs and Chemicals of Concern list.2

The DEA currently recognizes no legitimate medical uses of kratom, and the current FDA stance is that there is no evidence that kratom is safe, warning that it “should not be used to treat medical conditions, nor should it be used as alternative to prescription opioids.”1

The Future of Kratom

The variability of kratom’s effects – and lack of science-backed data – make it difficult to evaluate the potential utility of kratom going forward, whether for pain management or any ailment. Additional studies are warranted to determine the appropriateness of clinical use and current regulatory status, including questions around dosing, purity, strength, and packaging

There is evidence to support the claim that kratom has an improved safety and tolerability profile compared to traditional opioids. Although overdoses have been reported, they typically occurred in the setting of multiple substances versus kratom alone. Kratom could therefore represent an alternative to traditional opioid medications, however, its inconsistent response to naloxone reversal is concerning.

If kratom is scheduled as a Schedule I drug in the near future, necessary studies could be hindered32 and lead to current users to seek out other substances, potentially resulting in further harm.

However, we know that the regulation of plant-based products and standardized dosage forms (much like with cannabinoids) is difficult. Perhaps the most promise lies in the identification of our most-utilizable alkaloids, allowing for synthetic production capable of being replicated, mass-produced, and most importantly, studied in a standardized manner.

Based on the limited available data, there is reason to believe that kratom could be clinically beneficial in the settings of pain management, substance use disorders, and headache management. The safety profile appears to be safer than that of traditional opioids, due to a reduced risk of respiratory depression, and some studies suggest sensitivity to reversal by opioid antagonists. Although it is clear that further research is needed to validate these claims, it remains reasonable to believe that kratom, in some form, could have clinical utility in the coming years.

 

Source- https://www.practicalpainmanagement.com/treatments/pharmacological/non-opioids/kratom-primer-miracle-medicine-herb-abuse



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