Mitragyna Speciosa Alkaloids and Kratom

Mitragyna speciosa alkaloids are the most well-known of these opioid-like molecules, as their use has become more prevalent throughout the United States in the past decade (most recent estimates are around a 0.7% to 0.8% rate of use).¹˒² These alkaloids are derived from an evergreen tree in the coffee family, and often go by the name of kratom or biak-biak, depending on the country of origin (Thailand or Malaysia, respectively).³˒⁴ The pharmaceutically active components of the plant include mitragynine (MG), 7α-hydroxyl-7H-mitraynine (7-OH-MG), and mitragynine pseudoindoxyl, all of which have high binding affinity for various opioid receptors.⁵˒⁶

Additionally, different Mitragyna plants seem to have varying concentrations of MG and 7-OH-MG, which further complicates a complete evaluation of the entire species.

Figure 1. Differences in Chemical Structure Between Non-Opiate, Opioid Peptides. Chemical structures derived from

Given the above mechanisms, kratom has been used for a variety of medical ailments. These compounds are increasingly being used to self-treat pain and to mitigate opioid withdrawal in lieu of traditional opioids.⁸⁻¹⁰ There are also reports of use to self-treat mood-related disorders including depression and anxiety.¹⁰˒¹¹ Unfortunately, clinical trial evidence supporting therapeutic use and safety is rather lacking, making it difficult to discern absolute benefit versus risk profiles for this substance in patient populations.

Table I: Benefits Versus Risks of Non-Opiate, Opioid Peptides.
Benefits Risks
Mitragyna spp • Less emesis and respiratory depression
• Responds to naloxone
• 7-OH-MG is less constipating
• Can mitigate opioid withdrawal
• Abuse potential
• At low doses has a cocaine-like effect
• Widely available with no regulation
• Risk of seizures
Salvinorin A • Quick onset, short duration
• Inactive metabolites
• Interacts with kappa receptor
• Oral ingestion mitigates psychoactive effects
• Aversive
• Not detected in urine drug screens
• Potential for hallucinations
• CYP450 substrate
• Legal status depends on location
• Sparse literature available
Collybolide • Structure could be used for new therapeutics targeting the kappa receptor
• Shows antinociception in mice
• Aversion in mice
• Potential antipruritic effect
• Potential antidepressant activity
• Poorly water soluble
• Preliminary data based on animal studies
• Potentially anxiogenic
• Unclear psychotropic effects
Beta-casomorphin • Promotes analgesia
• Antidiarrheal
• Potential antihypertensive
• Potentially cardioprotective
• Showed improvement in memory and learning in mice
• Potential for depressive effects in the CNS
• Minimally studied
• Potential risk factor for ischemic heart disease
• Potentially related to apnea

Despite increasing patterns of use and self-reported benefits, kratom can be associated with significant adverse events and drug-drug interactions. Seizures, agitation, CNS depression, respiratory depression, and constipation have all been reported as side effects from use.¹²⁻¹⁴ High dose and long-term use may also be associated with development of tolerance, dependence, and withdrawal, all of which can present as dangers to patient populations unaware of such effects.¹⁵ Due to interactions with multiple receptor systems, combined use of kratom with other compounds may produce a variety of potentially serious adverse effects. For example, its opioid mechanisms combined with other CNS depressants may increase risk of respiratory depression, its adrenergic effects combined with stimulants may increase cardiovascular risk, and its serotonergic activity combined with other serotonergic drugs may elevate risk of serotonin syndrome and seizure activity. All of these are important facets of the substance to consider prior to self-using.

Selective Kappa-Opioid Receptor Agonists: Salvinorin A and Collybolide

The kappa-opioid receptor is one of four opioid receptors found throughout the central and peripheral nervous systems and has been a receptor of great pharmaceutical interest for development of novel compounds modulating its activity. Similar to mu-opioid receptors, kappa-opioid receptors are also G-protein coupled receptors found along various neuronal membranes throughout pain pathways of the human body.

Salvinorin A (Sage Bush)

Salvinorin A (Sal A) is the active metabolite of Salvia divinorum, a species of Mexican sage bush.²⁰ Salvia divinorum is a recreational hallucinogen that was brought to the US in the 1990s, though one that acts quite differently than traditional hallucinogens. Chemically, the metabolite, Sal A, is a non-nitrogenous diterpene that requires semi-synthetic modification for development and optimization.²¹ In vitro analysis has shown that Sal A has an ability to agonize the kappa-opioid receptor with high selectivity compared to other opioid receptors, and is highly lipophilic, which makes it easy for this molecule to pass through the blood brain barrier.²²

Sal A also has shown to be aversive and can diminish cocaine-induced drug seeking behavior in mouse models.²⁵˒²⁶ Sal A also has demonstrated potential to induce behavioral effects, including potential anxiolytic effects, and depressive effects by increasing immobility in the forced swim test.²⁷˒²⁸ One advantage of Sal A is that it is not broken down into any active metabolites, which results in a relatively clean pharmacokinetic profile. Sal A is a substrate of the CYP450 enzyme system and could still be prone to potential drug-drug interactions, however, there is minimal literature describing potential interactions, which increases difficulty to predict which drug classes to avoid.

Collybolide Mushroom

Collybolide is an opioid peptide that is derived from the Collybia maculata mushroom.²⁹ It was first isolated in 1974, but it appears to have limited recreational use historically, and has been studied more because of its unique effects. Interestingly, this molecule is extremely similar in structure compared to Sal A, as both share a common furyl-delta-lactone motif (see Figure 1).²⁹

Despite similarity in chemical structure, there are some major differences in overall potency and potential effects. Specifically, in vivo studies have shown collybolide to exhibit functional bias toward kappa-opioid receptor activation, with as much as a 10- to 50-fold higher potency in activating mitogen-activated protein kinase pathways compared to Sal A and equipotent ability to inhibit adenylyl cyclase activity.²⁹

Practical Takeaway: Given the noted potential advantages of this compound, collybolide could represent a relatively ideal candidate for development of novel therapeutics that target the kappa-opioid receptors.

Beta-casomorphin or Exorphins

Beta-casomorphin belongs to a group of exogenous opioid peptides that are bioactive in nature. This class of opioid peptides (also specifically known as exorphins) are exogenously derived from outside food sources and various external or food-derived origins including human and bovine milk, soy, and wheat sources.¹ Key characteristics of these compounds include their production in the GI tract (enzymes throughout the GI tract transform specific proteins into amino acid chains that can activate and modulate mu-opioid receptors), their resistance to complete breakdown by intestinal enzymes, and their absorption into the bloodstream and across the blood brain barrier allowing them a chance to interact with central opioid receptors.³⁰

Beta-casomorphin, specifically, is an opioid peptide that is derived from digestion of beta-casein in human and bovine milk.³⁰˒³¹ Milk was first discovered to have mu-opioid activity in 1979, however further studies revealed that it was selective and downstream by-products of milk that allowed for such activity. There are several subtypes of beta-casomorphin, all with varying intrinsic activities and binding affinities toward mu-opioid receptors (studied using animal tissue).³²˒³³ This molecule has been shown to promote antinociception and analgesia, and perform antidiarrheal action by enhancing net water and electrolyte absorption in the small and large intestines in animal studies.³⁴˒³⁵ There appears to be a potential for antihypertensive activity and cardioprotective functions.³⁰

Further, beta-casomorphin has shown to modulate prolactin and oxytocin production and release during lactation, and potentially plays a role in insulin and somatostatin secretion.³⁰˒³⁶ Mouse models have also demonstrated improvements in memory and learning.³⁷


There are several naturally occurring non-opiate opioid peptides and substances available worldwide with varying activity on different components of the endogenous opioid system. Some of these have been more traditionally used for both recreation and medical purposes, while others are hardly reported at all.

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