The Complex Pharmacology of Kratom
Kratom (Mitragyna speciosa) is a tropical tree from Southeast Asia whose leaves contain psychoactive alkaloids [1.6.1]. For centuries, it has been used in traditional medicine for its dose-dependent effects: stimulant properties at low doses and sedative-narcotic effects at higher doses [1.6.1, 1.6.4]. The central question for many users and researchers is, is kratom serotonin or dopaminergic? The answer isn't a simple choice between the two. While its most prominent action is on opioid receptors, kratom's diverse alkaloid profile allows it to influence dopamine and serotonin pathways, contributing to its complex effects [1.2.1, 1.3.3].
Primary Mechanism: Atypical Opioid Activity
The most significant pharmacological action of kratom's main alkaloids, mitragynine and 7-hydroxymitragynine (7-HMG), is their interaction with opioid receptors, specifically the mu-opioid receptor (MOR) [1.2.1, 1.5.8]. This binding is responsible for the opioid-like analgesic (pain-relieving) and euphoric effects reported by users [1.5.4].
However, these alkaloids are considered "atypical opioids" [1.2.5]. Unlike classical opioids like morphine, they act as partial agonists and do not appear to strongly recruit a protein called beta-arrestin 2 [1.2.2, 1.2.5]. The lack of beta-arrestin recruitment is significant because this pathway is associated with many of the negative side effects of opioids, including respiratory depression, which is the primary cause of overdose deaths [1.2.5]. This unique mechanism may contribute to kratom's comparatively lower risk of respiratory depression than traditional opioids [1.3.6]. 7-HMG is a much more potent MOR agonist than mitragynine, although it is present in much smaller quantities in the plant's leaves [1.4.1, 1.4.4].
Kratom's Influence on the Dopaminergic System
The dopaminergic system is crucial for regulating mood, motivation, and the brain's reward system [1.2.5]. Research into kratom's effect on this system has produced some conflicting results. Some studies suggest that mitragynine may act as a D1 and D2 dopamine receptor agonist, which could explain some of its anxiolytic (anti-anxiety) and stimulant effects [1.2.5]. For example, low doses of mitragynine appeared to increase dopamine release in male mice [1.2.6].
Conversely, other research indicates potential antidopaminergic activity, where a kratom leaf extract diminished behaviors induced by dopamine agonists [1.2.5]. This contradiction might be due to the use of whole-leaf extracts versus isolated mitragynine, suggesting other alkaloids in the plant influence dopamine receptor activity in a complex manner [1.2.5]. Chronic kratom use may also alter the regulation of the dopaminergic system, potentially leading to sensitization [1.2.5].
Kratom's Interaction with the Serotonergic System
The serotonergic system influences mood, anxiety, and sleep [1.2.5]. Kratom and its alkaloids have demonstrated clear interactions with serotonin (5-HT) receptors. This interaction is believed to contribute to kratom's reported mood-enhancing effects [1.2.4].
Specifically, certain alkaloids like paynantheine and speciogynine (but not mitragynine itself) show a high affinity for 5-HT1A receptors [1.2.4]. Activation of these receptors is linked to antidepressant and anxiolytic effects [1.2.5]. Furthermore, some research suggests that the analgesic effects of kratom are mediated not just by opioid receptor activation but also by a subsequent increase in serotonin transmission [1.2.7]. Mitragynine also binds to 5-HT2A receptors, which may be related to potential antipsychotic-like actions [1.3.4]. Research from June 2025 indicates that kratom alkaloids may directly interact with tryptophan hydroxylase (TPH), the enzyme responsible for serotonin production, potentially enhancing its activity and leading to increased serotonin levels [1.2.7].
Comparison of Effects
| Feature | Dopaminergic Interaction | Serotonergic Interaction |
|---|---|---|
| Primary Alkaloids | Mitragynine's effects are debated; some studies show agonist activity, others antidopaminergic effects [1.2.5]. | Paynantheine and speciogynine show high affinity for 5-HT1A receptors. Mitragynine binds to other 5-HT receptors [1.2.4, 1.3.4]. |
| Associated Effects | Potential stimulant, mood-elevating, and anxiolytic properties [1.2.5, 1.3.4]. | Mood-enhancing, antidepressant, and anxiolytic effects. May also contribute to analgesia [1.2.4, 1.2.7]. |
| Receptor Targets | Primarily D1 and D2 receptors, though findings are conflicting [1.2.5, 1.3.8]. | 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT7 receptors [1.2.2, 1.2.4]. |
| Mechanism | Evidence points to both direct receptor agonism and more complex modulation of the dopamine system [1.2.5, 1.2.6]. | Agonism at certain receptors and potential enhancement of serotonin biosynthesis via the TPH enzyme [1.2.4, 1.2.7]. |
Conclusion
Kratom is neither exclusively serotonergic nor dopaminergic; it is a pharmacologically complex substance that engages multiple neural systems simultaneously. Its primary and most well-understood mechanism is atypical agonism at mu-opioid receptors, which accounts for its main pain-relieving and euphoric effects [1.2.1]. However, its alkaloids also bind to and modulate both dopamine and serotonin receptors, contributing to its wide range of effects, from stimulation and mood enhancement to sedation and anxiety relief [1.2.2, 1.2.5]. The conflicting data, especially regarding dopamine, highlights the need for further research to fully untangle the contributions of each of the dozens of alkaloids present in the Mitragyna speciosa plant.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Kratom is not approved by the FDA for any medical use [1.6.4]. Consult with a healthcare professional before using any herbal supplement.
