What is Tetrahydroalstonine? How this Kratom Alkaloid Works

The more that we learn about kratom and its alkaloids, the more we will understand the best and most responsible potential uses of this popular and controversial herbal supplement. 

Kratom is most well known for its most researched alkaloid: mitragynine. Mitragynine is what gives the kratom plant its scientific name: Mitragyna speciosa. However, there are many other alkaloids in kratom, some of which haven’t been studied in great detail. This includes Tetrahydroalstonine, which is found in small concentrations in kratom. 

What are kratom’s core alkaloids? 

Some of kratom’s alkaloids include:

• Mitragynine
• Speciociliatine
• Speciogynine
• Mitraciliatine
• Paynantheine
• Isopaynantheine
• 7-hydroxymitragynine
• Corynantheidine
• Speciociliatine n-oxide
• Mitragynine n-oxide
• Tetrahydroalstonine
• Ajmalicine
• Corynoxine
• Corynoxine B
• Mitragynine oxindole B
• Isorynchophylline
• Isospeciofoline
• Speciofoline
• Mitraphylline
• Mitragynine pseudoindoxyl

There are dozens more alkaloids in kratom. Although each alkaloid has been studied independently, many have not been studied within the context of kratom. Even though the biological mechanisms of the alkaloid may be understood on their own, there is a lot to be learned about the ways that it affects (or does not affect) kratom users. 

Understanding Tetrahydroalstonine

Tetrahydroalstonine is a monoterpene indole alkaloid that is found in plants of the Apocynaceae family. Monoterpenes are common in essential oils and play a significant role in creating aromas. 

This alkaloid exhibits high binding affinity for alpha-2 adrenergic receptors and serotonin receptors. This suggests that tetrahydroaltonine may have the potential to provide pain-relieving effects on the central nervous system. Other potential effects include a positive impact on blood pressure, re-oxygenation, and circulation. 

Plants that contain tetrahydroalstonine have been used in traditional herbal medicine in both Asia and Africa. 

Tetrahydroalstonine may co-occur with other complementary alkaloids, such as ajmalicine and serpentine. Ajmalicine is found in kratom.

What do we know about tetrahydroalstonine’s properties in kratom 

Tetrahydroalstonine is a minor kratom alkaloid that is present in much smaller quantities than other alkaloids. It shows weaker binding affinity to the brain’s opioid receptors, but 

Studies have shown that it exhibits high binding affinity for alpha-2 adrenergic receptors (subtypes A, B, and C) with Ki values in the submicromolar range (18-65 nM).

In simpler terms, tetrahydroalstonine binds very strongly to all three subtypes of alpha-2 adrenergic receptors, which typically respond to norepinephrine and epinephrine (adrenaline). Adrenergic receptors are involved in a number of physiological responses in the body, including the regulation of blood pressure, attention, and pain perception. 

The binding is so strong that it occurs at very low concentrations of the compound (between 18 and 65 billionths of a mole per liter). All of this suggests that tetrahydroalstonine in kratom could potentially have effects on the physiological processes that are regulated by these adrenergic receptors. 

However, binding affinity alone doesn’t tell us whether the alkaloid activates or inhibits these receptors. More research is necessary to understand how tetrahydroalstonine in kratom can impact the body. 

Tetrahydroalstonine and serotonin

Tetrahydroalstonine also shows a moderate binding affinity for the serotonin 5-HT1A receptor with a Ki value < 0.5 μM. This leaves kratom advocates wondering if tetrahydroalstonine could influence mood, cognition, and other physiological functions that are regulated by the serotonergic system.

 Serotonin is an important neurotransmitter that affects many aspects of our daily lives, including: 

• Mood regulation (contributes to feelings of well-being)
• Sleep-wake cycle (regulates sleep patterns and influences melatonin production)
• Appetite and digestion (controls appetite and satiety; stimulates intestinal movements)
• Cognitive function (affects memory, learning, attention, and decision-making processes)
• Pain perception (moderates pain sensitivity)
• Cardiovascular function (influences heart rate and blood pressure)
• Blood clotting (contributes to the clotting process)
• Endocrine system (influences the release of some hormones)
• Temperature regulation (plays a role in controlling body temperature) 
• Sexual function (affects libido and sexual behavior)
• Social behavior (affects social interactions and bonding)
• Bone health (contributes to bone density and bone formation)
• Nausea and vomiting (involved in the vomiting reflex)
• Neuroplasticity (influences growth and reorganization of neural connections)
• Immune system function (modulates immune responses)

Importantly, there is not currently any evidence that tetrahydroalstonine’s binding with serotonin receptors causes kratom to influence these physiological responses in the human body. Although researchers have studied tetrahydroalstonine and its binding with serotonin receptors, that does not mean that they have determined how this alkaloid affects consumers of kratom.

Potential therapeutic implications of kratom

Kratom is currently used by individuals all over the US and the world for a number of desired results. Although more research will help us confirm the anecdotal reporting of these results, several studies have confirmed that there is consistency among kratom users about what it does for them. 

For example, a 2019 study found, “Respondents predominantly identified Kratom use to relieve acute or chronic pain followed by use for an emotional or mental condition. Respondents identified increased energy, decreased pain, increased focus, less depressed mood, lower levels of anxiety, reduced or stopped the use of opioid painkillers, reduction of PTSD symptoms, and elevated mood as beneficial effects of their Kratom consumption.”

Tetrahydroalstonine’s presence in kratom brings to light some potential therapeutic benefits, including: 

• Mood-modulation
• Anxiety reduction 
• Pain perception

Potential research on tetrahydroalstonine and kratom 

That said, tetrahydroalstonine shows weaker binding to opioid receptors than other kratom alkaloids, prompting research questions like these: 

• How does tetrahydroalstonine contribute to the overall effects of kratom?
• What is the specific mechanism by which tetrahydroalstonine interacts with serotonin receptors, and how does this compare to other kratom alkaloids?
• Given tetrahydroalstonine’s weaker binding to opioid receptors, what role does it play in kratom’s pain-relieving effects?
• What is the potential for developing targeted therapies based on tetrahydroalstonine’s receptor binding profile?
• How does tetrahydroalstonine’s interaction with alpha-2 adrenergic receptors contribute to kratom’s reported effects on energy and focus?
• What are the long-term effects of tetrahydroalstonine on serotonin and adrenergic systems with regular kratom use?
• How does the concentration of tetrahydroalstonine vary among different kratom strains, and how does this variation correlate with reported effects?
• What potential does tetrahydroalstonine have for treating specific conditions like PTSD or depression?
• How does tetrahydroalstonine’s pharmacological profile compare to existing medications for mood disorders or pain management?
• What are the potential risks or side effects associated with tetrahydroalstonine’s interactions with multiple receptor systems?
• How might tetrahydroalstonine contribute to kratom’s reported ability to help reduce opioid use?

Kratom is currently understudied, and tetrahydroalstonine is one of its lesser-studied alkaloids. That is a big part of why we don’t have a lot of information about how tetrahydroalstonine affects kratom users. 

The kratom industry supports additional research 

Ethical kratom vendors and advocates support additional research into the alkaloids, effects, and mechanisms of kratom. The more that we understand about kratom and its physiological components, the safer it becomes to use kratom appropriately and minimize potential negative impacts.  Tetrahydroalstonine, alongside other alkaloids in kratom, may contribute to the overall effects of kratom, but more research is necessary for us to understand its role. 

Sources

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• Hanapi, Nur Aziah et al. “Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers.” Frontiers in Pharmacology vol. 12 751656. 17 Nov. 2021, doi:10.3389/fphar.2021.751656
• Liao, Yumei et al. “The Protective Effect of (-)-Tetrahydroalstonine against OGD/R-Induced Neuronal Injury via Autophagy Regulation.” Molecules (Basel, Switzerland) vol. 28,5 2370. 4 Mar. 2023, doi:10.3390/molecules28052370
• Loza-Tavera, H. “Monoterpenes in essential oils. Biosynthesis and properties.” Advances in Experimental Medicine and Biology vol. 464 (1999): 49-62. doi:10.1007/978-1-4615-4729-7_5
• Mahomoodally, M Fawzi. “Traditional medicines in Africa: an appraisal of ten potent african medicinal plants.” Evidence-based Complementary and Alternative Medicine : eCAM vol. 2013 (2013): 617459. doi:10.1155/2013/617459
• “Serotonergic.” Science Direct. Aging Research Reviews, 2023.