Kratom is a plant gaining popularity as an alternative painkiller and recreational drug.
But how much do we really know about its risks and benefits?
About Kratom:
- Kratom is a tropical tree in the coffee family, native to Southeast Asia.
- People ingest its leaves to produce stimulant and opioid-like effects.
- Use is rising in the U.S., with an estimated 3-5 million current users.
- Kratom is unregulated in most places, raising concerns about purity and safety.
- Evidence suggests it may help chronic pain, but with risks like addiction and toxicity.
- More research is needed to determine if kratom could yield safer opioid medications.
Source: Pain Ther. 2020
Kratom: An Alternative to Prescription Opioids?
Kratom contains compounds that act on the same brain receptors as opioids.
This gives it painkilling properties similar to narcotic medications like morphine or oxycodone, but with a lower risk of respiratory depression and overdose.
No wonder then that people have begun using kratom to self-medicate chronic pain and opioid withdrawal.
Especially amidst the opioid epidemic, many view it as a safer, natural remedy for those struggling with addiction.
Kratom Pharmacology: Mu-Opioid Receptor Effects
Kratom’s main active ingredients are mitragynine and 7-hydroxymitragynine.
These bind to mu-opioid receptors, the same target for traditional opioid painkillers.
But their chemical structure is slightly different, making them “atypical opioids.”
This difference means they don’t fully activate one of the cell signaling pathways, beta-arrestin, triggered by classic opioids.
And beta-arrestin seems responsible for many of those drugs’ dangerous side effects.
So in theory, kratom may offer pain relief without as many downsides.
But that’s not the whole story.
Mitragynine also activates other receptors involved in pain, addiction, and mood.
So its effects are complex and dose-dependent:
- Low doses produce stimulant-like effects.
- Moderate doses have mixed stimulant and opioid properties.
- High doses bring on primarily opioid-like analgesia and euphoria.
The Health Risks of Kratom Use
Despite promising beginnings, there are good reasons for caution regarding kratom.
First, regulations on kratom products are minimal or nonexistent in most countries, including the U.S.
That means concentrations of active compounds can vary wildly between different preparations.
And without oversight, contamination or adulteration are real risks.
Second, emerging evidence suggests kratom carries its own risk of addiction and toxicity:
- Animal studies show withdrawal and drug-seeking behaviors with chronic high-dose mitragynine.
- Case reports have linked kratom to seizures, psychosis, liver damage, coma, and deaths (though often in combination with other substances).
- According to the CDC, kratom was involved in 91 overdose deaths in 27 states from July 2016 to December 2017.
So while kratom may be safer than traditional opioids, it can still be abused.
And its legal status means using it without medical supervision poses unpredictable dangers.
Kratom Addiction & Withdrawal Potential
For those with emerging kratom dependence, withdrawal can cause drug cravings, nausea, sweating, mood swings, and more.
There are currently no specific guidelines for treating kratom addiction, but typical opioid replacement therapies seem to help:
- For acute withdrawal, buprenorphine-naloxone and supportive medications can ease symptoms.
- Long-term maintenance may require methadone, buprenorphine, or extended release naltrexone.
- Adjunct treatment with counseling reduces relapse in those with substance use disorders.
The takeaway is that while kratom may hold promise as a painkiller, more controlled trials are needed.
Using unregulated products to self-medicate is risky without medical monitoring.
Along with counseling for underlying issues, existing treatments can aid those with problematic kratom use.
Kratom’s 2 Most Active Compounds
The chemical intricacies of kratom highlight why this botanical drug is so divisive.
Dozens of active compounds have been isolated from kratom leaves, but two are most important:
Mitragynine
This makes up about 2% of kratom powder by weight.
Though it binds to mu, delta, and kappa opioid receptors, it’s only a partial agonist.
This means it doesn’t fully activate them like opioid painkillers do.
Mitragynine also attaches to serotonin and adrenergic receptors.
This further explains its complex, dose-dependent stimulant and depressant properties.
7-Hydroxymitragynine
This is a minor kratom compound, but it’s 13 times more potent than morphine.
It acts mainly on mu receptors, making it primarily an analgesic.
Interestingly, 7-hydroxymitragynine appears absent in raw kratom.
It’s theorized that the plant produces mitragynine, which the body then oxidizes into the more active 7-hydroxy form.
If true, it resembles how codeine is activated into morphine in the liver.
In addition to these main players, kratom contains traces of numerous other alkaloids.
Their combined effects likely contribute to the overall pharmacology of ingested kratom leaf.
Kratom Effects at Opioid Receptors
Mitragynine and 7-hydroxymitragynine’s complex opioid receptor interactions:
- At mu receptors, they are only partial agonists, with 7-hydroxymitragynine having stronger binding. This matches mu’s role in producing analgesia.
- Counterintuitively, they are competitive antagonists at delta receptors. The significance here is still unclear.
- Their action at kappa receptors is negligible — unexpected since kappa mediates opioid side effects like dysphoria.
This nuanced receptor profile makes their effects distinct from classical opioids derived from the poppy plant.
How these differences translate into therapeutic potential and risks requires more study in humans.
Other Kratom Effects in the Brain & Body
Beyond direct opioid receptor activation, mitragynine and related chemicals seem to interact with numerous other systems:
- Serotonin receptors, implicated in mood and appetite
- Dopamine receptors, targeting the brain’s pleasure centers
- Adrenergic receptors, involved in arousal and pain modulation
- Neuronal calcium channels, which regulate nerve impulse firing
- Inflammatory pathways like COX-2, linked to pain sensitivity
The consequences of all these actions aren’t fully defined.
But they likely augment kratom’s analgesic and possibly anti-addictive properties.
These other targets may also contribute to side effects.
Kratom: Metabolism & Elimination Half-Life
Like other drugs, kratom compounds undergo hepatic metabolism to be inactivated.
Cytochrome P450 enzymes like CYP3A4 break them down into molecules that are more easily excreted.
This process is essential for converting mitragynine into 7-hydroxymitragynine.
But it can also lead to hazardous interactions with medications using the same metabolic pathways.
Following oral ingestion, mitragynine’s half-life is around 3-5 hours.
Its metabolites are then cleared from the blood within 24 hours.
This rapid elimination may help prevent excessive buildup and toxicity.
Preclinical Kratom Research: Mice, Rats, and Monkeys
Animal studies suggest kratom’s abuse potential is generally lower than that of traditional opioids:
- Mice self-administer mitragynine, but only at high doses.
- Dependence develops in rats after chronic exposure, causing withdrawal.
- Monkeys demonstrate dose-dependent effects ranging from stimulation to sedation.
But important questions remain, like the role of 7-hydroxymitragynine versus its parent compound.
One monkey study found 7-hydroxy to have much higher addiction potential.
Human trials are essential to clarify the balance between therapeutic potential and abuse risk.
But the current preclinical data at least provide a starting point to guide future research.
Kratom Needs More Research & Quality Control
Considering all these complexities, what conclusions can we draw about this enigmatic plant?
First, kratom products require manufacturing standards and quality control to improve their safety.
Reports of contamination and adulteration are troubling.
Regulation could help curb these issues and ensure users get predictable concentrations of active compounds.
Second, more rigorous clinical trials are needed to weigh kratom’s benefits against its risks in a controlled setting.
Researchers should investigate interactions with other drugs, optimal dosing, long-term side effects, toxicity thresholds, withdrawal management, and more.
These safety and efficacy data could inform medical guidelines for kratom going forward.
And third, understanding mitragynine’s structure and receptor effects might spur development of improved synthetic opioids that retain analgesic potency while minimizing negative outcomes.
Kratom likely has therapeutic potential, but realizing that in a safe, controlled way will take years of intensive study.
In the meantime, those using kratom to self-medicate should exercise extreme caution.
Unregulated products taken without medical oversight pose unpredictable health hazards.
Getting proper addiction treatment is a much safer path forward.
The Bottom Line: Kratom’s Medicinal Potential
Kratom offers a glimpse into the possibilities of tapping opioid receptors while avoiding classical drugs’ pitfalls.
But the research is still early, so for now, this plant remains controversial.
With further research, kratom may one day serve as another weapon against the prescription opioid epidemic.
References
- Study: Kratom – pharmacology, clinical implications, and outlook: a comprehensive review
- Authors: Steven C. Eastlack et al. (2020)
