How Kratom’s Primary Alkaloids Work in the Body

Kratom, or Mitragyna speciosa, is a tropical evergreen tree native to Southeast Asia. Its leaves have long been chewed, smoked, or brewed into a tea by people in Southeast Asian countries, such as Malaysia and Thailand [1].

Kratom contains a complex mixture of bioactive compounds called alkaloids. These alkaloids are unique and interact with opioid, adrenergic, serotonergic, and other receptors to induce numerous reported effects, including analgesia, improved mood, and relaxation, among others [2].

Among more than 40 identified alkaloids, mitragynine and 7-hydroxymitragynine (7-HMG) are the most prevalent and pharmacologically active, respectively [3,4].

Interest in kratom has grown in recent years due to reports of its analgesic (i.e., pain-relieving), stimulant, and opioid-like effects [5]. These effects are largely attributed to how kratom’s alkaloids interact with receptors in the central and peripheral nervous systems, and particularly opioid receptors implicated in pain signaling.

This article examines how kratom’s primary alkaloids work in the body, how they influence pain pathways, and what current research suggests about their mechanisms and limitations.

The Major Alkaloids in Kratom

Mitragynine is the most abundant alkaloid in kratom leaves [6], often comprising up to 60-70% of total alkaloid content. It is structurally distinct from classical opioids such as morphine but interacts with some of the same receptor systems.

7-HMG is present in much smaller quantities in raw plant material but exhibits significantly greater potency at certain opioid receptors. Some evidence suggests that a portion of 7-HMG may also be formed metabolically from mitragynine in the body [7].

Opioid Receptors and Pain Signaling

To understand how kratom alkaloids influence pain perception and signaling, it’s helpful to review the body’s opioid system.

There are three primary opioid receptors, comprising mu (μ), delta (δ), and kappa (κ) receptors, and these are located throughout the brain, spinal cord, and peripheral sensory neurons [8,9].  

When these opioid receptors are activated, they reduce the transmission of pain signals by inhibiting neurotransmitter release, hyperpolarizing neurons, and dampening ascending pain pathways.

Conventional opioids like morphine strongly activate μ-opioid receptors, producing analgesia but also side effects such as respiratory depression and dependence [9].

Kratom and the μ-Opioid Receptor

One of the most studied features of mitragynine and 7-HMG is their activity at the μ-opioid receptor (MOR).

A partial agonist activates a receptor, but not to the same degree as a full agonist (such as morphine). This distinction matters because receptor activation intensity often correlates with both therapeutic effects and adverse effects.

Research suggests that 7-HMG acts as a partial agonist at the MOR, whereas mitragynine might be a weaker partial agonist or modulator. The signaling of both these alkaloids may be “biased” towards certain intracellular pathways [10].

This phenomenon, referred to as G-protein-biased agonism [10], means the compound preferentially activates intracellular signaling pathways associated with analgesia while potentially producing less activation of pathways associated with respiratory depression, such as that seen with β-arrestin signaling [10]. However, this hypothesis remains under investigation and has not been conclusively demonstrated in humans.

Inhibition of Pain Transmission in the Spinal Cord

Pain signals from injured tissue travel through peripheral nerves to the spinal cord and then ascend to the brain. Activation of μ-opioid receptors in the spinal cord reduces the release of substance P and glutamate, while blunting the transmission of pain-related signals.

Animal studies show that kratom alkaloids reduce pain behaviors in rodent models, supporting the idea that they modulate spinal nociceptive processing [11], but the degree of translation of these research findings from animals to humans is uncertain.  

Effects on Descending Pain Modulation

Pain perception is not purely a bottom-up process. The brain also transmits descending inhibitory signals that regulate spinal pain transmission.

Opioid receptor activation in regions such as the periaqueductal gray (PAG) and the rostroventral medulla can amplify the descending inhibition of pain [12].

By interacting with opioid receptors in these areas, kratom alkaloids may influence both ascending and descending pain pathways, altering how pain is processed centrally by the body.

Kratom Activity Beyond Opioid Receptors

Kratom alkaloids are pharmacologically complex and do not act solely on opioid receptors.

Mitragynine appears to interact with α2-adrenergic receptors [13], which are involved in pain modulation and sedation. Drugs like clonidine reduce pain in part due to this mechanism.

Adrenergic activity may contribute to analgesic effects and mild stimulant or calming properties, depending on the dose and context.

Preclinical studies indicate interactions with serotonin receptors and dopamine pathways, which could influence the mood and reward circuits, potentially contributing to perceived benefit and misuse potential.

Anti-Inflammatory Properties

Some laboratory/cell studies indicate that mitragynine may exert anti-inflammatory effects by modulating cytokine production [14]. Since inflammation contributes to certain types of pain (e.g., musculoskeletal injury), this mechanism could theoretically play a role in analgesia. However, human data confirming meaningful anti-inflammatory effects are limited.

Pharmacokinetics of Kratom: What Happens After Ingestion?

Once orally consumed, mitragynine is rapidly absorbed (peak concentration reached within 90 mins [15]) and metabolized in the liver. Cytochrome P450 enzymes (particularly CYP3A4) appear to be involved in its metabolism [16]. Important considerations include its variable bioavailability, differences in individual metabolism, and potential drug-drug interactions. As kratom products vary widely in alkaloid content, predicting systemic exposure is difficult.

Tolerance, Dependence, and Neuroadaptation

The repeated activation of opioid receptors can lead to receptor downregulation, reduced responsiveness (tolerance), and withdrawal symptoms upon cessation.

Reports of kratom withdrawal suggest neuroadaptation similar to other opioid-like substances, though this is typically described as milder than classical opioid withdrawal [5]. Nonetheless, dependence potential is an important safety consideration for kratom.

Also of note is the legal status of kratom, which can vary by state and jurisdiction [17,18].

How Does Kratom Differ from Classical Opioids?

While kratom alkaloids interact with opioid receptors, they differ from classical opioids in several ways.

There are structural differences; for example, mitragynine is an indole alkaloid, not a phenanthrene derivative like morphine. As partial agonists, they have a lower maximal activation of particular receptors. The proposed preferential G-protein-biased signaling over β-arrestin recruitment in preclinical models also distinguishes kratom from classical opioids.

These differences have led some researchers to explore whether kratom alkaloids could inform the development of novel analgesics with fewer adverse effects. However, this remains an area of potential investigation.

Limitations of the Current Evidence

Despite increasing mechanistic research, major gaps remain in the evidence base. There are very few controlled human clinical trials [19], limited long-term safety data, coupled with inconsistent product standardization and variability in alkaloid concentrations across preparations.

Most evidence regarding pain relief comes from animal models or self-reported surveys rather than randomized controlled trials.

Conclusion

Kratom’s primary alkaloids, mitragynine and 7-hydroxymitragynine, influence pain pathways primarily through partial activation of μ-opioid receptors. They also appear to interact with adrenergic, serotonergic, and possibly inflammatory signaling systems.

Through modulation of spinal nociceptive transmission and central pain processing circuits, these compounds may alter pain perception. However, the current scientific evidence is largely preclinical, and robust human clinical trials are virtually non-existent.

While mechanistic plausibility exists for analgesic effects, questions remain regarding safety, standardization, long-term impact, and dependence potential. Continued research is needed to clarify whether kratom alkaloids have a defined therapeutic role in pain management or primarily represent a pharmacologically complex botanical with both potential and risk.

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