Kratom Alkaloids, Cannabinoids, and Chronic Pain: Basis of Potential Utility and Role in Therapy

Abstract

Introduction:

Chronic neuropathic pain is as a severe detriment to overall quality of life for millions of Americans. Current pharmacological treatment options for chronic neuropathic pain are generally limited in efficacy and may pose serious adverse effects such as risk of abuse, nausea, dizziness, and cardiovascular events. Therefore, many individuals have resorted to methods of pharmacological self-treatment. This narrative review summarizes the existing literature on the utilization of two novel approaches for the treatment of chronic pain, cannabinoid constituents of Cannabis sativa and alkaloid constituents of Mitragyna speciosa (kratom), and speculates on the potential therapeutic benefits of co-administration of these two classes of compounds.

Methods:

We conducted a narrative review summarizing the primary motivations for use of both kratom and cannabis products based on epidemiological data and summarize the pre-clinical evidence supporting the application of both kratom alkaloids and cannabinoids for the treatment of chronic pain. Data collection was performed using the PubMed electronic database. The following word combinations were used: kratom and cannabis, kratom and pain, cannabis and pain, kratom and chronic pain, and cannabis and chronic pain.

Results:

Epidemiological evidence reports that the self-treatment of pain is a primary motivator for use of both kratom and cannabinoid products among adult Americans. Further evidence shows that use of cannabinoid products may precede kratom use, and that a subset of individuals concurrently uses both kratom and cannabinoid products. Despite its growing popularity as a form of self-treatment of pain, there remains an immense gap in knowledge of the therapeutic efficacy of kratom alkaloids for chronic pain in comparison to that of cannabis-based products, with only three pre-clinical studies having been conducted to date.

Conclusion:

There is sufficient epidemiological evidence to suggest that both kratom and cannabis products are used to self-treat pain, and that some individuals actively use both drugs, which may produce potential additive or synergistic therapeutic benefits that have not yet been characterized. Given the lack of pre-clinical investigation into the potential therapeutic benefits of kratom alkaloids against forms of chronic pain, further research is warranted to better understand its application as a treatment alternative.

Introduction

Chronic pain, which is defined by the International Association for the Study of Pain as pain that lasts more than 3 months, is a significant burden and a leading cause of disability. ^1,2 The U.S. Centers for Disease Control and Prevention (CDC) estimated that 20.4% of U.S. adults had chronic pain in 2019. ³ More so, an estimated 10% of adults are additionally diagnosed with chronic pain per year globally. ⁴ The impact that chronic pain has on public health can be difficult to interpret, given the diversity in chronic pain condition subtypes, which vary in their etiology and pathophysiological mechanisms, some of which remain unknown or can occur idiopathically. ⁵

As such, chronic pain is structured into several top-level diagnoses such as chronic primary pain, chronic cancer-related pain, chronic post-surgical or traumatic pain, and chronic neuropathic pain. ² Furthermore, chronic pain has only been officially recognized as a disease on its own right as of 2019, rather than a secondary symptom of a separate condition. ² As such, pharmacological management of chronic pain is of great clinical significance. In this review, we aim to summarize and compare the current body of knowledge pertaining to the established efficacy, motivations, and patterns of use of both cannabis and kratom products for treating chronic pain.

Given the complexities in the classification, etiology, and clinical presentation of chronic pain, there is a diverse range in recommended pharmacotherapies. The two major classes of compounds most often used for treatment include antidepressants (tricyclic antidepressants [TCAs] and serotonin-norepinephrine reuptake inhibitors [SNRIs]) and anti-epileptic drugs (AEDs). The TCA amitriptyline and AED gabapentin have roughly equivalent clinical success rates, as indicated by the number needed to treat. ^6,7

However, gabapentin is generally more prescribed due to less adverse effects compared to amitriptyline, which produces antimuscarinic effects such as dry mouth and blurred vision. ^6,7 Overall, recommended first-line treatments for chronic pain conditions include TCAs, the gabapentinoids pregabalin and gabapentin, and the SNRIs duloxetine and venlafaxine. ^8,9 Despite this recommendation, TCAs and AEDs are associated with significant adverse effects such as dizziness, drowsiness, blurred vision, and gait disturbances when giving chronically, in addition to only achieving partial efficacy. ¹⁰

Controlled-release opioids and tramadol are recommended as second-line treatments; however, μ-opioid receptor (MOR) agonists are highly advised against for the treatment of chronic pain, given their abuse liability and tolerance susceptibility. ¹¹ Despite this, the National Health Interview Survey of the CDC reported that 22.1% of individuals with chronic pain used prescription opioids for pain management in 2019. ¹² For certain chronic pain conditions such as chemotherapy-induced peripheral neuropathy (CIPN), opioids are estimated to be used as a form of treatment in up to 97% of patients. ^13,14 Other notable pharmacotherapies include topical capsaicin and lidocaine, and various other compounds such as methadone, lamotrigine, lacosamide, tapentadol, and botulinum toxin. ^8,15,16

Other classes of agents under investigation include nerve-protecting agents, ion channel targets, antioxidants, and anti-inflammatory agents. While most of these drugs demonstrated efficacy pre-clinically, their clinical efficacy remains largely inconclusive. ¹⁷ Furthermore, the therapeutic efficacy of these pharmacological agents are largely dependent upon the type of chronic pain condition. Consequently, chronic pain persists as an immense economic burden, with an estimated annual range of $560–635 billion in the United States as a result of health care and lost productivity. ¹⁸ Therefore, there is a clear unmet need for novel pharmacological interventions for chronic pain, which maintain efficacy without the risk of severe adverse effects.

Given the significant burden of chronic pain both physically and financially, and the concerns with current pharmacological treatment options, many resorted to self-treating their symptoms using novel pharmacological approaches. One of the major products that emerged as a self-treatment of pain is kratom (Mitragyna speciosa), a plant endogenous to Southeast Asia and a member of the Rubiaceae family. ¹⁹ Kratom has been used for centuries in its native region, where it is most often consumed orally either by directly chewing raw plant material or as a tea.

In the United States, kratom products are typically sold as dried or powdered plant material in capsule, tablet, or bulk form, where they are readily available through online and retail outlets. ^{20 –22} To date, kratom remains uncontrolled by the Controlled Substances Act, yet is listed as a “Drug of Concern” by the Drug Enforcement Administration and remains unapproved for any therapeutic use by the U.S. Food and Drug Administration (FDA). ²³

Concerns surrounding the unregulated status of kratom in the United States largely stem from the potential adverse effects associated with its use, its opioid pharmacology, and potential of consuming adulterated products. ²⁴ Given that the FDA does not recognize kratom as a dietary supplement in the United States, there is no official regulatory standard on kratom packaging, labeling, product contents, or alkaloid concentrations. ^24,25 However, the World Health Organization Executive Committee on Drug Dependence determined in 2021 that there is presently not enough available evidence to warrant banning or restricting access to kratom, choosing instead to keep kratom under surveillance. ²⁶ The regulation of kratom would undoubtedly affect the lives of the estimated 1–16 million people who use kratom in the United States, with several reports suggesting that this number may be even higher. ^{21,24,27 –31}

Despite the growing user base, there remains a great degree of uncertainty regarding potential benefits and risks of kratom among both users and health care providers. While largely anecdotal, people report differences in the therapeutic effect of kratom that are dose dependent, with low doses producing stimulant and mood-elevating effects, and higher doses producing opioid-like effects such as analgesia and mitigation of opioid withdrawal. ³² Further research is required to better understand the potential benefits of kratom use and to validate or disprove these anecdotal reports, which is heavily reliant on its legal standing.

Cannabis sativa and cannabis-based products, specifically agonists of the cannabinoid type 1 (CB1R) or cannabinoid type 2 (CB2R) receptors, have also emerged as a frontrunner for the self-treatment of chronic pain, which may overlap with kratom use clinically. In this narrative review, we will analyze the prevalence of pain as a primary motivator for use of both kratom and cannabis-based products and correlate these findings with pre-clinical characterizations of each class of compounds in the context of chronic pain. In addition, we will synthesize existing data regarding the pharmacology of kratom and cannabis' primary constituents to address the potential therapeutic benefits of the co-administration of these plants (kratom and cannabis) and respective compounds for the treatment of chronic pain.

Prevalence of Concurrent Cannabis and Kratom Use and Motivations for Use

Given the growing popularity of kratom use in the United States and the speculation of its therapeutic benefits in humans, many have sought to characterize the demographics and intentions of use among adults who use kratom in the United States to better understand its potential therapeutic purposes (Table 1). Across four online anonymous cross-sectional surveys, 48.4–91.3% of survey respondents in the United States cited kratom use primarily for acute or chronic pain, or a medical condition leading to or associated with pain. ^25,31,33,34 In these same surveys, kratom use for the self-treatment of pain was reported as beneficial in 15.2–98.7% of survey participants. ^25,31,33,34

Table 1.

Prevalence of Self-Reports of Pain as a Primary Motivator and Benefit of Kratom Use

Self-reports of pain as a motivator of kratom use		Self-reports of treating pain as a benefit of kratom use		Prevalence of previously diagnosed form of chronic pain		Prevalent pain conditions	Total sample (N)	Reference
Frequency	%	Frequency	%	Frequency	%
1,388	48.4	1,259 current users; 38 past users	90.7% of current users; 60.3% of past users	NR	NR	Spine or back (N=596); fibromyalgia (N=165); injury related (N=138)	3,024	25
4,811	68.1	6,466	85.0	4,811	68.1	NR	8,049	31
2,544	91.3	2,762	98.7	1,924	68.8	Back (N=2,028); muscle (N=1,760); neck (N=1,540)	2,798	33
3,761	73.0	4,446	15.2	2,587	50.2	Back (N=2,680); acute (N=1,184); fibromyalgia (N=791)	5,152	34

Across all studies, percentages do not add to 100% due to multiple selection of effects.

NR, not reported.

Common pain conditions listed among survey respondents include fibromyalgia, spine or back, muscle, neck, or injury-related pain. ^25,33,34 Chronic pain was reported across 50.2–68.8% of survey respondents. ^25,31,34 In a separate study, chronic pain was much more prominent among people who used kratom in their lifetime (25.0%, N=112) compared to people who have never used kratom (14.6%, N=1,730). ³⁵ Furthermore, 97.6% of people who use kratom for pain reported using kratom as an alternative to other, unsuccessful interventions. ²⁵ Overall, these self-report surveys illustrate that the self-treatment of pain is a primary motivator of kratom use among American adults with chronic pain, and that most individuals report using kratom due to a lack of pain relief with other pharmacological interventions.

In addition to its use for pain relief, there are a substantial number of self-reports of kratom use for reduction of opioid use and mitigation of opioid withdrawal. ^{24,25,31,33,34,36} This is crucial to consider, given the prominence of opioid use for treating chronic pain, despite limited therapeutic efficacy and abuse liability. Furthermore, it raises the question of what other drugs or substances people who use kratom may use concomitantly. Concurrent use of two or more analgesics is seen in up to 50% of chronic pain patients depending on the condition. ³⁷ Therefore, characterizing the demographics and understanding the prevalence of polydrug use among kratom users are also of significant clinical relevance.

Surprisingly, cannabis use has been found to significantly overlap with kratom use (Table 2). In a previously mentioned study, participants were asked to report on past 12-month substance use, in which 37.2% of people who use kratom reported using cannabis within the past 12 months. ³³ Prior cannabis use was more frequently reported than opioids (33.0%), and the only two substances with higher reports of use within the past 12 months were alcohol (47.4%) and tobacco (42.2%), making cannabis the most commonly previously used substance that is federally illegal. ³³

Table 2.

Prevalence of Self-Reports of Prior or Concurrent Cannabis Use Among Kratom Users

Prevalence of prior or concurrent use of other substances with kratom		Prevalence of prior substance use disorder		Prevalence of prior cannabis use		Prevalence of prior cannabis use disorder		Total sample (N)	Reference
Frequency (N)	%	Frequency (N)	%	Frequency (N)	%	Frequency (N)	%
NR	NR	Last used kratom 30+ days ago (65); kratom used within past 30 days (17)	Last used kratom 30+ days ago (8.76); kratom used within past 30 days (4.02)	NR	NR	Last used kratom 30+ days ago (146); kratom used within past 30 days (26)	Last used kratom 30+ days ago (28); kratom used within past 30 days (24)	32,893	27
Alcohol (1,327); tobacco (1,180); opioids (922)	Alcohol (47.4); tobacco (42.2); opioids (33.0)	Kratom-related SUD (344)	Kratom-related SUD (12.3)	1,041	37.2	NR	NR	2,798	33
1,308	25.7	NR	NR	Marijuana, hashish (643); CBD (594)	Marijuana, hashish (12.5); CBD (11.5)	NR	NR	7,381	34
Monthly: nicotine (88); methamphetamine (52); heroin (49)	Monthly: nicotine (78.6); methamphetamine (46.4); heroin (43.8)	Opioids (45); alcohol (53); other (27)	Opioids (40.2); alcohol (47.3); other (24.1)	Monthly (77); lifetime (108)	Monthly (68.8); lifetime (96.4)	NR	NR	1,842	35
NR	NR	Lifetime (200); past year (899)	Lifetime (13.2); past year (59.5)	Cannabis (1,089); CBD (546); medicinal cannabis (141)	Cannabis (72.1); CBD (36.1); medicinal cannabis (9.3)	NR	NR	1,510	36

Across all studies, percentages do not add up to 100% due to multiple selection of effects.

CBD, cannabidiol; SUD, substance use disorder.

In a study comparing substance use prevalence between people who have used kratom in their lifetime (N=112) and people who have never used kratom (N=1,730), both monthly (68.8%) and lifetime (96.4%) cannabis use were significantly more common in the lifetime kratom users compared to non-kratom users. ³⁵ Similarly, in a study comparing lifetime substance use between people who have used kratom in their lifetime (N=202) and people who have never used kratom (N=1,308), lifetime use of both nonmedical and medicinal cannabis, as well as nonintoxicating constituents of cannabis such as cannabidiol (CBD) products, was found to be significantly higher in individuals who have used kratom in their lifetime compared to those who have never used kratom. ³⁶ Prior drug use was also found to be the strongest predictor of kratom use, with CBD being the strongest. ³⁶

These data suggest that not only does prior use of cannabis or CBD products appear to be a strong predictor of subsequent kratom use, but a significant number of individuals actively use both substances, which may lead to potential additive or synergistic therapeutic effects in the context of pain. Among adults who use kratom in the United States, the most common substances taken in combination with kratom are cannabis (12.5%) and CBD (11.5%). ³⁴ A recent analysis of the 2020 National Survey on Drug Use and Health dataset (N=32,893) was conducted to investigate the prevalence of co-occurring substance use disorders among a U.S. population of people who did and did not use kratom during the COVID-19 pandemic. ²⁷

Of all participants who never used kratom, 6% reported past year cannabis use disorder ranging from mild to severe, compared to being reported by 28% and 24% of individuals reporting kratom use more than 30 days ago or within the past 30 days, respectively. ²⁷ This suggests that cannabis use disorder is more prevalent among individuals actively or having recently used kratom products compared to those who have never used kratom. Overall, these findings suggest that prior use of cannabis or other cannabinoid products can serve as a strong predictor of kratom use, and that there are a substantial number of individuals who actively use both substances.

Coinciding with the incidence of prior or concurrent cannabis use among people who use kratom, the self-reported motivations for use of both substances also have significant overlap. Like kratom, the self-treatment of underlying chronic pain conditions, particularly when traditional treatment methods become ineffective or intolerable, is a primary motivator for use of cannabis products. ³⁸ Outside of treating pain, other less notable self-reported motivators for both cannabis and kratom products include the treatment of mood or psychiatric symptoms such as anxiety and depression. ^{24,25,33,34,39,40} While the self-treatment of pain remains a primary motivator for both kratom and cannabis use, it is important to note that the prevalence of certain motivators has increased as a consequence of the COVID-19 pandemic, such as increased feelings of anxiety, social isolation, boredom, and more time spent at home. ^{27,40 –42}

Consequently, these changes in motivations for use have impacted general use patterns of both substances. Significant increases in weekly and daily self-reported medical cannabis use during COVID-19 have been reported among medical cannabis users using cannabis <weekly. ⁴⁰ Moreso, significant increases in the frequency of those using nonmedical cannabis were reported in individuals who used cannabis ≤monthly or not at all before COVID-19, suggesting that changes in use patterns are not exclusive to medical or recreational users, and that increased frequency of use is most prominent among those who were not initially using cannabis regularly. ⁴³

While there is much less quantitative evidence available, several others have speculated that the kratom user base has drastically increased because of the COVID-19 pandemic, largely attributed to restrictive access to both proper health care and prescription opioids, in addition to increases in mental health issues. ^{21,27 –29,42} Given these changes in both kratom and cannabis use patterns, along with the predisposition to subsequent kratom use among prior cannabis or CBD users, there is great urgency to explore the effects concomitant use may have pharmacologically and therapeutically in the context of pain.

Kratom Alkaloid Pharmacology

To better understand the rational for using kratom as a therapeutic alternative for chronic pain, it is important to understand the pharmacological profile of its individual alkaloid constituents. To date, more than 40 unique kratom alkaloids have been identified, the most prevalent and well-studied being mitragynine (MG) and its biologically active metabolite 7-hydroxymitragynine (7-HMG). ^32,44,45 MG accounts for roughly 66% of the crude base alkaloid content of kratom and 6% of dried plant weight. ⁴⁶

As previously described, kratom products are commonly used to reduce or cease the use of other opioids, including both prescription opioid medications and illicit opioids such as heroin. ^{24,25,31,33,34,36} Consequently, much of the attention received by MG and 7-HMG is attributed to their opioid pharmacology, which has been thoroughly investigated in vitro. ^{45,47 –51} Most recent data demonstrate MG displays 2.4-fold higher binding affinity at MOR (K _i=709 nM) than at kappa opioid receptor (KOR) (K _i=1,700 nM) and 9.6-fold higher binding affinity than at delta opioid receptor (DOR) (K _i=6,800 nM). ⁴⁸

The binding affinity of MG at MOR is 89-fold lower than the potent analgesics fentanyl (K _i=7.96 nM) and morphine (K _i=4.19 nM). ⁴⁸ Compared to MG, 7-MHG displays roughly 10-fold greater binding affinity at MOR sites (K _i=77.9 nM). ⁴⁸ Functional assessments of MG at MOR have produced mixed results, with reports of both competitive antagonist and partial agonist activity, contrasting with the routinely observed partial agonist activity of 7-HMG. ^{48 –51} MG and 7-HMG are also believed to behave at MOR sites in a G-protein biased manner with minimal β-arrestin recruitment, suggesting a safer therapeutic profile and lower risk of adverse effects associated with classical opioids such as respiratory depression. ^50,51

In addition to opioid signaling, adrenergic properties of MG have also been described in vitro, as MG displays micromolar affinity for both α₁- and α₂-adrenergic receptor subtypes. ^47,49 MG also interacts with serotonin receptor subtypes in vitro, displaying moderate inhibition of radioligand binding at 5HT_2C (58.77%) and 5HT₇ receptors (64.41%). ⁵² Interactions with 5HT_2AR have also been proposed, as MG suppresses 5HT-induced head-twitch in mice. ⁵³ However, other kratom alkaloids such as paynantheine and speciogynine, but not MG, exhibit high affinity for 5HT_1AR and 5HT_2BR in vitro, despite all three alkaloids producing antinociception in a 5HT_1AR-dependent manner. ⁵⁴ Cannabinoid mechanisms have also been demonstrated for MG, as chronic high-dose exposure induces cognitive deficits and increases hippocampal CA1 and ventral tegmental area mRNA expression of CB1R, which are both reversed by the CB1R antagonist NIDA-41020. ⁵⁵

Overall, the primary kratom alkaloid MG possesses a mixed pharmacological profile combining opioid, adrenergic, serotonergic, and potentially cannabinoid mechanisms, while the primary metabolite 7-HMG possesses a more stringent MOR profile. Given the unique mixed pharmacology of kratom alkaloids such as MG, which encompasses the pharmacological profiles of multiple first- and second-line treatment options for a variety of chronic neuropathic pain conditions, there is considerable reason to suspect that kratom alkaloids would exhibit additional efficacy in pre-clinical models of chronic pain. Yet, much of our understanding on the behavioral pharmacology of individual kratom alkaloids in the context of rodent models of pain is limited to the scope of acute pain.

Therapeutic Efficacy of Kratom Alkaloids in Pre-clinical Pain Models

Given the shared opioid pharmacological profile of the major kratom alkaloids and the well-established efficacy of opioids for the management of acute pain, most of our understanding on the efficacy of kratom alkaloids in combating pain originates from rodent models of acute pain. An early study reported that the antinociceptive properties of MG is 2.6 times less potent than codeine in a mouse hot-plate test. ⁵⁶

Future studies have demonstrated that both MG and 7-HMG produce robust antinociception in hot-plate and tail-flick assays in a MOR-dependent manner, as MG and 7-HMG antinociception are diminished by pre-treatment with MOR antagonists naloxone and cyprodime. ^{57 –61} This effect has been confirmed through genetic approaches, as the analgesic activity of both MG and 7-HMG are lost in MOR-, but not KOR- or DOR-KO mice in the tail-flick test. ⁶² Adrenergic and serotonergic mechanisms also contribute to MG-induced antinociception, as intrathecal administration of the α₂-adrenergic antagonist idazoxan abolishes the antinociceptive effect of supraspinal MG administration in response to thermal noxious stimuli, as does monoamine depletion. ⁶³

However, more recent findings show that the α₂-adrenergic receptor antagonist yohimbine is insufficient to block MG or 7-HMG antinociception, despite both alkaloids obtaining potential antinociceptive synergism when co-administered with α₂-adrenergic receptor agonists. ⁴⁹ To date, a single publication has investigated cannabinoid mechanisms of a kratom alkaloid in a rodent model of acute pain, which demonstrated that the CB1 inverse agonist AM251 does not block MG-induced antinociception in the hot plate assay. ⁶⁴ Overall, both MG and 7-HMG produce robust antinociception in acute models of pain, which is primarily dependent on MOR activation, with additional evidence of α-adrenergic mechanisms. For a systematic review of all pre-clinical characterization of the therapeutic potential of kratom in acute pain, see review Prevete et al. ⁶⁵

Comparatively, much less has been described regarding the efficacy and pharmacological mechanisms of kratom alkaloids in the context of chronic or neuropathic pain (Table 3). For the first time, our laboratory characterized the therapeutic efficacy of a kratom alkaloid in an animal model of CIPN. ⁶⁶ In this study, MG dose-dependently inhibited the development of oxaliplatin-induced mechanical hypersensitivity in rats through adrenergic and opioid mechanisms, as this effect was blocked by pre-treatment with the α₁-adrenergic receptor antagonist prazosin, the α₂-adrenergic receptor antagonist yohimbine, and the MOR antagonist naltrexone.

Table 3.

Summary of the Pre-clinical Characterization of Therapeutic Efficacy of Kratom Alkaloids in Chronic Neuropathic Pain

Species	Strain	Sex	Alkaloid tested	Dosing	Pain model	Behavioral assay	Effects of alkaloid on pain outcomes	Mechanisms	Reference
Rat	Sprague-Dawley	M	Mitragynine	1–10 mg/kg i.p., once daily for 5–7 days	Oxaliplatin CIPN	Von-Frey monofilaments	Dose-dependent inhibition of mechanical hypersensitivity	Effect blocked by μ-opioid, α1- and α2-adrenergic receptor antagonists	66
Mouse	C57BL/6J	M/F	Mitragynine	1–10 mg/kg i.p., once daily for 6 days	Oxaliplatin CIPN	Von-Frey monofilaments	Dose-dependent inhibition of mechanical hypersensitivity greater in males than females	Effect blocked by μ-opioid, α1- and α2-adrenergic receptor antagonists	67
Mouse	ddY	M	MGM-16	Single treatment of 0.1–0.4 mg/kg s.c. or 0.5–2.0 mg/kg p.o.	Sciatic nerve ligation	Von-Frey monofilaments	Dose-dependent inhibition of mechanical hypersensitivity	Effect blocked by μ- and δ-opioid receptor antagonists	68

CIPN, chemotherapy-induced peripheral neuropathy; F, female; i.p., intraperitoneal; M, male; MGM-16, (E)-methyl 2-((2S,3S,7aS,12aR,12bS)-3-ethyl-9-fluoro-7a-hydroxy-8methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3a]quinolizin-2-yl)-3-methoxyacrylate; p.o., per os.; s.c., subcutaneous.

More recently, these opioid and adrenergic-dependent effects of MG have been confirmed in a mouse model of oxaliplatin-induced mechanical hypersensitivity, findings that are the first to demonstrate the antiallodynic efficacy of MG is greater in male mice compared to females. ⁶⁷ To date, only one other publication has demonstrated the antiallodynic efficacy of kratom alkaloids. However, this was demonstrated in a sciatic nerve ligation model of neuropathic pain, and used the synthetic derivative of MG, (E)-methyl 2-((2S,3S,7aS,12aR,12bS)-3-ethyl-9-fluoro-7a-hydroxy-8methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3a]quinolizin-2-yl)-3-methoxyacrylate (MGM-16). ⁶⁸ Here, MGM-16 dose-dependently increased mechanical thresholds when administered either subcutaneously or orally. Furthermore, MGM-16 produces an antiallodynic effect ∼100 times more potent compared with gabapentin when orally administered. ⁶⁸

The antiallodynic effect of MGM-16 was dependent on opioid signaling, as pre-treatment with the opioid receptor antagonists β-funaltrexamine and naltrindole completely blocked its effect. ⁶⁸ However, a major limitation of these studies is that their study designs are exclusive to assessing stimulus-evoked nociceptive behaviors, meaning kratom alkaloids have yet to be tested against spontaneous behaviors such as locomotion in the context of pain. Also, the effects of kratom alkaloids on peripheral nerve function in the context of pain, such as intraepidermal nerve fibers density and caudal nerve conduction velocity, have yet to be explored. Therefore, much more research is required to fully understand the efficacy and pharmacological mechanisms of kratom alkaloids in treating forms of chronic pain.

Targeting the Endocannabinoid System in Pre-clinical Models of Chronic Neuropathic Pain

In contrast to that of kratom alkaloids, the role of the endocannabinoid system (eCS) in the physiological processing of pain in rodents has been well characterized. In brief, the eCS comprises of two G protein-coupled receptors, CB1R and CB2R, the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG), and the enzymes that regulate their metabolism such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), for AEA and 2-AG degradation, respectively. ^{69 –71} While beyond the scope of this review, imbalances in eCS signaling during the processing of physiological pain can increase susceptibility to the development of symptoms underlying conditions such as chronic neuropathic pain. ^72,73

Therefore, targeting the eCS for the treatment of chronic pain symptomology in rodents is of great significance. The establishment of the eCS as a suitable target for treating pain has been achieved through a variety of pharmacological approaches such as small molecule CB1R and CB2R agonists, nonselective receptor agonists, and endocannabinoid modulators such as FAAH and MAGL inhibitors. ⁷²

Recent meta-analyses have helped put into perspective the extent to which the antinociceptive efficacy of cannabinoids, cannabinoid-based medicines (CBMs) such as nabiximols, dronabinol, nabilone, and epidiolex, or eCS modulators has been studied in models of pathological or injury-related persistent pain, with a total of 374 studies identified to date. ^74,75 A total of 171 different cannabinoid-related interventions have been tested, with CB1R and CB2R agonists being the most frequently tested, accounting for 19% and 20% of all nested group comparisons made within studies, respectively. ⁷⁵

Specifically, the most tested compound has been the synthetic CB1R agonist WIN55,212, accounting for 13% of all comparisons. ⁷⁵ Other commonly used compounds include nonselective CBR agonists (18.9%), FAAH inhibitors (15.2%), and agonists at peroxisome proliferator-activated receptor alpha (10.6%). ⁷⁵ Phytocannabinoids such as CBD and Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC), the primary psychoactive constituent of cannabis, have been tested in 4.5% and 4.2% of studies, respectively. ⁷⁵

In addition to the variety of cannabinoid-related pharmacological interventions having been tested, there is also great variety in the pain model types implemented in comparison to that of kratom alkaloids, with over 20 different models of persistent or injury-related pain been utilized. ⁷⁵ Inflammatory pain models make up 30% of the comparisons made across all studies, including carrageenan, osteoarthritic, and Complete Freund's Adjuvant models. ^74,75 The most commonly reported chronic pain models used include nerve injury (26.7%), chemotherapy (8.2%), and diabetes models (4.7%). ^74,75 In these pain models, the most consistent antinociceptive efficacy has been achieved by FAAH inhibitors, CB1R and CB2R agonists, and CBD, as determined by standardized mean difference effect size. ⁷⁴

Despite the overwhelming body of pre-clinical evidence supporting the use of cannabinoid-based therapies for forms of chronic pain, there are several limitations to these data. Like kratom alkaloids, there is an overreliance on evoked limb withdrawal for the assessment of chronic pain. Specifically, meta-analyses report that evoked limb withdrawal to mechanical and thermal stimuli has been tested in 51% and 22% of comparisons, respectively. ^74,75

There is also a significant sex bias toward males, as 91% and 81% of all studies used male rats and mice, respectively. ⁷⁴ This trend severely contradicts the reality that chronic pain is more prevalent in women in the United States, and does not reflect the equal representation of male (N=3,613) and female patients (N=3,691) in clinical trials involving cannabinoids, cannabis, or CBMs. ⁷⁶ Nonetheless, there is an immense volume of pre-clinical investigation into utilizing cannabinoids and the eCS as a tool for treating chronic pain in comparison to kratom alkaloids.

Speculatory Cannabinoid-Kratom Interactions in Pain, Abuse Liability, and Withdrawal

Both kratom and cannabis products are commonly used to self-treat symptoms of chronic pain, despite the immense gap in knowledge of supporting pre-clinical evidence in favor of cannabis products. Furthermore, individuals concurrently use kratom and cannabis products, which may produce potential additive or synergistic therapeutic effects against pain. Yet, this has yet to be explored pre-clinically. With this, and the prominent opioid pharmacology of kratom, we are left to speculate on the potential therapeutic benefits of concurrent kratom and cannabinoid use based on previous pre-clinical studies of cannabinoids administered in combination with other opioids.

Cannabinoid-opioid combinations have been studied in the context of pain to identify potential opioid-sparing effects, which is clinically significant as this can reduce the required dose of opioids and reduce adverse effects associated with opioid use without diminishing pain relief. Synergistic and additive opioid-sparing effects of cannabinoids have been reported pre-clinically with mixed CB1/CB2 agonists such as CP55,940, Δ ⁹ -THC, HU-210, and WIN55,212-2 occurring much more readily than CB1- or CB2-selective ligands. ⁷⁷

Functional interactions have also been described, as heteromerization between CB1R and both μ-opioid and δ-opioid receptors has been demonstrated in vitro. ^78,79 CB1R-DOR heteromers have been detected in the cortex of rats in a model of spinal nerve ligation and in the lumbar spinal cord of both rodents and humans with paclitaxel-induced neuropathic pain. ^80,81 More recently, both CB1R-DOR and CB1R-MOR heteromer complexes have been characterized in a mouse model of diabetic neuropathy. ⁸² However, pharmacological effects of kratom alkaloid and cannabinoid combinations on pain are likely much more complex, given the adrenergic and serotonin components of MG and phytocannabinoids such as CBD. ⁸³

Aside from the demonstrated analgesic benefits of cannabinoid-opioid combinations, there remains a reasonable concern that cannabinoid-opioid combinations may also impact abuse liability. However, there is little pre-clinical evidence suggesting cannabinoid-opioid combinations exacerbate the rewarding and reinforcing properties of opioids, but suggest that cannabinoid agonists may reduce the rewarding and reinforcing properties of opioids. For example, the CB2 agonists JWH-015 and LY2828360 block morphine conditioned place preference (CPP) in rodents. ^84,85 CP55,940 and Δ ⁹ -THC suppress morphine intracranial self-stimulation (ICSS) and oxycodone self-administration in rats, respectively. ^86,87

In nonhuman primates, Δ ⁹ -THC reduces both morphine and heroin discriminative stimulus effects, while CP55,940 and WIN55,212 reduce morphine discriminative stimulus effects and heroin self-administration. ^88,89 However, clinical findings contradict these data, as Δ ⁹ -THC and dronabinol potentially enhance the abuse liability of opioids such as oxycodone and hydromorphone. ^{90 –92} The rewarding properties of endocannabinoid modulators have also been investigated in neuropathic pain states, as the MAGL inhibitor MJN110 does not possess intrinsic rewarding properties on its own, but develops a CPP in mice with paclitaxel-induced CIPN, suggesting that modulation of endocannabinoid signaling may reduce pain affect. ⁹³

Conversely, there is minimal evidence supporting the existence of rewarding or reinforcing properties of kratom products or individual alkaloids. Rats self-administer 7-HMG, but not MG at rates exceeding that of saline, and MG pre-treatment decreases heroin self-administration. ^94,95 Furthermore, neither MG or 7-HMG produces rewarding effects in an ICSS paradigm. ⁹⁶ In drug discrimination studies, MG only partially generalizes to morphine in rats, but not to Δ ⁹ -THC. ^48,97,98 Kratom products produce CPP at high doses; however, there is high variability in the alkaloid content of preparations used, the doses tested, and route of administration. ^{99 –104}

Outside of its uses for pain, kratom products are also widely used as an opioid substitute for harm reduction and to ease withdrawal for those with opioid-use disorder. ^{24,25,31,33,34,36,52,105,106} Kratom use for reducing illicit or prescription opioid use has been reported in 10–90% of cross-sectional, online survey participants. ^25,31,33,106 In general, kratom users are also more likely to have lifetime use of opioid agonist therapy such as methadone or buprenorphine compared to non-kratom users. ³⁶ Improvements in opioid withdrawal symptoms has also been self-reported in 14.5–87.3% of study participants. ^25,33,106 Kratom use has also been reported to reduce opioid cravings (79.6%) and help achieve 6 months of abstinence from opioids (74.2%) in some individuals. ³³

Several reports of evidence also suggest that cannabis may be beneficial for reducing opioid use and withdrawal, particularly Δ ⁹ -THC and dronabinol. To date, a total of 11 clinical studies have been conducted examining the association between opioid withdrawal and cannabis use, which include both observational studies and experimental, randomized placebo-controlled clinical trials. ¹⁰⁷ Improvements in opioid withdrawal symptoms have been reported across four observational studies, in addition to two experimental clinical studies following dronabinol exposure. ¹⁰⁷

However, more research is warranted before recommending cannabinoids for opioid withdrawal, as there is risk of bias and inconsistency in these studies. ¹⁰⁷ Nonetheless, these findings correlate with the extensive pre-clinical characterization of the use of cannabinoids for opiate withdrawal and dependency. ¹⁰⁸ Overall, there is justification that kratom alkaloids such as MG may achieve additive or synergistic analgesia when mixed with cannabinoids, without risk of abuse liability. Furthermore, there may be additional benefits to kratom and cannabis use for individuals seeking a substitute to other prescription opioids due to dependency or withdrawal.

Concluding Remarks

Chronic pain is a highly prevalent and debilitating detriment to public health where therapeutic needs remain unmet. In contrast to the mounting pre-clinical evidence of targeting the eCS for treating chronic pain, kratom alkaloids such as MG have emerged as novel therapeutics for pain much more recently. Given the great disparity in the body of knowledge of the use of cannabinoids for treating chronic pain compared to that of kratom products, further pre-clinical research on kratom alkaloids in this context is required. In addition, we are much further along in our clinical understanding of the efficacy of cannabinoids in the context of chronic pain, as reports on the use of kratom products to alleviate chronic pain in humans are limited to observational studies.

The safety and analgesic effectiveness of kratom products remain to be answered quantitatively under rigorous clinical trials, with the only registered clinical trial within the United States (NCT05457803) being observational. Despite this difference, there remains a significant body of epidemiological evidence highlighting the prevalence of concurrent cannabis and kratom use among adults in the United States. Given that pain is a common self-reported motivator of both classes of compounds, investigating the pharmacological and behavioral effects of cannabinoid and kratom alkaloid co-administration in animal pain models will help characterize the potential therapeutic role of concurrent use. Not only may kratom and cannabinoid produce therapeutic effects in the context of pain but may also be dually beneficial for those who use either class of compounds to reduce opioid use or mitigate opioid withdrawal.

Abbreviations Used

2-AG

2-arachidonylglycerol

7-HMG

7-hydroxymitragynine

Δ ⁹ -THC

Δ ⁹ -tetrahydrocannabinol

AEA

anandamide

AEDs

anti-epileptic drugs

CB1R

cannabinoid type 1 receptor

CB2R

cannabinoid type 2 receptor

CBD

cannabidiol

CBMs

cannabinoid-based medicines

CDC

Centers for Disease Control and Prevention

CIPN

chemotherapy-induced peripheral neuropathy

CPP

conditioned place preference

DOR

delta opioid receptor

eCS

endocannabinoid system

FAAH

fatty acid amide hydrolase

FDA

Food and Drug Administration

ICSS

intracranial self-stimulation

KOR

kappa opioid receptor

MAGL

monoacylglycerol lipase

MG

mitragynine

MGM-16

(E)-methyl 2-((2S,3S,7aS,12aR,12bS)-3-ethyl-9-fluoro-7a-hydroxy-8methoxy-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3a]quinolizin-2-yl)-3-methoxyacrylate

MOR

μ-opioid receptor

SNRIs

serotonin-norepinephrine reuptake inhibitors

TCAs

tricyclic antidepressants

Authors' Contributions

D.J.F. prepared and constructed the article with contributions from all authors. Z.D.C., A.C.H., and L.N.H. proofread and edited the article for grammatical errors and consistency. Z.D.C., S.M.R., and S.J.W. aided in article design, content, and conceptualization. All authors read and approved the final article.

Author Disclosure Statement

All authors confirm there are no conflicts of interest to declare.

Funding Information

This research was supported by NIDA awards P30DA013429 and T32DA007237.

Cite this article as: Farkas DJ, Cooper ZD, Heydari LN, Hughes AC, Rawls SM, Ward SJ (2023) Kratom alkaloids, cannabinoids, and chronic pain: basis of potential utility and role in therapy, Cannabis and Cannabinoid Research 10:2, 187–199, DOI: 10.1089/can.2023.0064.