Similarly, the pharmacokinetics of corynanthidine, a minor kratom alkaloid and perhaps a MOR antagonist, were determined after 2.5 mg/kg IV and 20 mg/kg oral doses to rats, yielding a 50% oral bioavailability, a 4.1 h Tmax and extensive distribution including in brain corpus callosum and hippocampus regions (King et al., 2020). Thirteen MG metabolites were identified in human liver microsomes and S9 fraction studies (Kamble et al., 2019), and potential MG and other kratom alkaloids drug interactions were investigated including with pharmaceutic products (Kamble et al., 2020a). Kratom alkaloids are of interest as templates for novel synthesized molecules (i.e., analogs) for new medicines. One third to one half of FDA-approved medicines are based on natural plant product substances from which novel chemical entities were developed (Newman and Cragg, 2016; Domnic et al., 2021a).
- Finally, we recommend that the US federal government and other nations consider approaches to kratom regulation as are presently being pioneered in five US states.
- Surveys and more than 20,000 comments to the DEA suggest that many kratom users fear resumption of opioid use and the need to resort to illicit kratom markets (Drug Enforcement Adm, 2016; Grundmann, 2017; Coe et al., 2019; Garcia-Romeu et al., 2020).
- Other studies of opioid or MG withdrawal suggested that specific brain proteins might serve as more sensitive biomarkers for physiological dependence in rats as compared to behavioral signs (Hassan et al., 2021).
- Factors 4–6 discuss the public health aspects of kratom use; however, many of the same studies address Factor 1 concerning evidence for abuse and are mentioned here.
- By contrast, and over the same time frame, lifetime mentions of oxycodone, heroin, cocaine, amphetamine, marijuana, and other prototypic substances of abuse were in the many thousands.
The evidence shows that millions of people in the US purchase and use kratom products for improving health and are preferred to FDA approved medicines because for them, kratom products are more effective, accessible, and tolerable. It is important to note that the benefits documented in published surveys do not constitute the basis for therapeutic claims and no kratom product or kratom alkaloid is approved for therapeutic use in the US. The FDA and other federal agencies state that there is no proven therapeutic use for kratom despite evidence that millions of people in the US and many more in SEA use kratom primarily for therapeutic, beneficial use. That evidence includes peer reviewed surveys and field studies in the US and SEA, clinical and preclinical studies showing that MG’s mechanisms of action are consistent with such effects. Moreover, several animal models used to predict efficacy for treating opioid use disorder, opioid withdrawal and pain demonstrated efficacy. In the first half-year of the COVID-19 pandemic, there was uncertainty about kratom supply by vendors and consumers, however, overall US supply was not affected.
Repeated LKT administration produced no physical dependence, but significantly decreased naloxone-precipitated withdrawal in morphine dependent mice, confirming MOR agonist activity and therapeutic LKT effect for treating pain and opioid physical dependence. MG and 7-OH-MG have some MOR mediated effects, but 7-OH-MG occurs at low concentrations in kratom leaves and is absent in many kratom product derivatives suggesting that the effects reported by kratom consumers are due primarily to MG. Some kratom effects were shown to be naloxone reversible https://rehabliving.net/ (e.g., “pain” tolerance); however, MG and 7-OH-MG mechanisms of action were diverse and mediated by non-opioid transmitters and pathways . Rates of MG self-administration were similar to those of saline, and MG pretreatment produced dose-related reductions in morphine self-administration rates (Hemby et al., 2019). The authors concluded “The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal … ”.
By contrast, and over the same time frame, lifetime mentions of oxycodone, heroin, cocaine, amphetamine, marijuana, and other prototypic substances of abuse were in the many thousands. Lifetime aspirin mentions ranged from 7 to 23 per year, while lifetime diphenhydramine mentions ranged from 11 to 46 per year. We do recommend accelerated research to address the many questions raised in this review, including support of the potential development of new medicines with potential better safety and/or efficacy profiles for a variety of diseases. Finally, we recommend that the US federal government and other nations consider approaches to kratom regulation as are presently being pioneered in five US states. None of this research meets FDA’s standard for therapeutic efficacy that is determined by evaluation of a New Drug Application .
Kratom Abuse Potential 2021: An Updated Eight Factor Analysis
Kratom and its alkaloids are not approved for any therapeutic use by the FDA, are not federally controlled in the US, nor in the International Drug Control Conventions; however some countries do control kratom and/or its two primary alkaloids, MG and 7-OH-MG (Prozialeck et al., 2019; International Narcotics C, 2020a; International Narcotics C, 2020b). Six states in the US have banned kratom, while five have passed consumer protection legislation to ensure consumer access to kratom with a framework for regulatory oversight . Maryland rejected a proposed ban and passed a minimum age of purchase law , and at this writing, several states are considering their own kratom consumer protection laws to ensure consumer access but with regulatory oversight. In December, 2021, the World Health Organization Expert Committee on Drug Dependence concluded “there is insufficient evidence to recommend a critical review of kratom mitragynine and 7-hydroxymitragynine” but should be kept under surveillance . It’s critical to consult a physician who specializes in addictive behavior if you identify the indications of kratom abstinence. A specialist can aid you in overcoming physical dependency because you can concentrate on the fundamental conditions that lead to prolonged usage, such as opioid overdose, severe pain, or depressed mood.
The opioid overdose crisis is among one of the most significant public health challenges we are facing today in North America. With over 70,327 lives lost in the United States and 3,987 in Canada in 2017, the number of deaths continue to increase from year to year with little sign of slowing. Canadian and US policy makers, people who use drugs, health professionals, and cannabis activists are increasingly suggesting that cannabis may be an effective tool for alleviating the overdose crisis. This subject has been the focus of a growing number of articles published in academic journals, which have become the subject of much debate.
The intent was to include all new studies published in English relevant to kratom abuse potential, safety and mechanisms of action published in since January 1, 2018 with some essential earlier studies mentioned and referenced to our 2018 review.1 This was by comprehensive online literature searches, and direct requests to leading kratom researchers worldwide. To be concise, factors 4, 5, and 6 are considered a single group of public health related factors.2 (Henningfield et al., 2018a; Johnson et al., 2018). In 2017, the National Institute on Drug Abuse substantially increased its active research program on kratom’s alkaloids and derivatives as potentially safer and less abusable medicines for pain and addiction and other disorders.
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Founded by Sarah Blyth, President of the Overdose Prevention Society, High Hopes offers cannabis products, which include bud, edibles, capsules, CBD, kratom, and cannabis-infused honey as an alternative to opioids for pain management and as a measure to stem the tide of fentanyl overdoses in the DTES, the epicentre of the opioid crisis in Canada. Although it is very much an emerging area of research, there is some evidence to support the cannabis-opioid-sparing hypothesis. Some of the population-level research on states with medical cannabis and recreational cannabis laws, for instance, has linked the presence of laws to decreases in opioid prescribing and harms.
If opioids prevent significant suffering, then the solution to the prescription opioid problem cannot simply be to stop using them. As the nation grapples with its opioid addiction epidemic, an understanding of how the drugs affect people is important. Now they are using these images to design “biased” opioids that block pain without the dangerous side effects. As the nation grapples with its opioid addiction epidemic, one solution for many with chronic joint pain and back pain could be physical therapy. But, when they have the merchant account with them, it is best for both customers and merchants to carry out the entire process.
4FDA never reported the results of that investigation, however, the US DHHS review that led to the 2018 withdrawal of the 2017 MG and 7-OH-MG CSA scheduling recommendation determined that the incident in question was an automobile crash not attributable to kratom use. 1The authors welcome communications from readers on abuse‐potential and safety related kratom research published since 2018 that we might have missed. JH was the primary scientist/investigator, and lead the identification eco sober house rating of articles, writing, and analysis. • A scientific determination based on data whether kratom actually serves as a gateway drug that promotes further use of more dangerous opioids . These findings are consistent with new US survey data showing relatively low self-reported kratom addiction rates, with most people describing MG use to manage pain, depression, anxiety, opioid and other drug use disorders and withdrawal, and to increase alertness, focus and work performance.
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Over time, the analgesic effect of opioids diminishes, and tolerance builds up, which requires higher doses to achieve pain relief and can result in dependence or addiction. The danger of opioids, in addition to the risk of problematic use, is their potential for producing an overdose. Opioids are central nervous system depressants and when taken in a quantity that exceeds what the body can handle, they can depress breathing and precipitate heart failure. While many health professionals are pointing to the over prescription of opioids for physical pain as the source of the current opioid crisis, this emphasis often overlooks how opioids are used to treat other forms of pain, including psychological suffering and mental illness, which can also intersect with physical pain.
Research suggests that this happens because there is a synergy in the analgesic effects between opioids and cannabinoids, given that CB1 cannabinoid receptors and opioid mu receptors are located in the same pain-signalling regions of the spinal cord and brain (Fig. 1). As the opioid crisis continues to worsen, the evidence that cannabis can have an opioid-sparing effect has made some researchers hopeful that cannabis may temper opioid use by reducing the quantities consumed and lowering the rates of physical dependence. When tetrahydrocannabinol , a primary active ingredient in cannabis, enters the body, it activates the CB1 cannabinoid receptors found throughout the nervous system and the CB2 cannabinoid receptors located primarily in the immune system, in areas such as the spleen and tonsils. The activation of these receptors engenders pain relief, muscle relaxation, and can produce a psychoactive response.
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A low priming injection of MG or morphine reinstated CPP after establishment with either drug, suggesting rewarding effects for both (Japarin et al., 2021). Baclofen pretreatment prevented the acquisition and expression of MG-induced CPP (Yusoff et al., 2018). CPP was achieved in mice with a high dose methanolic extract of kratom leaves (Vijeepallam et al., 2019). In a fourth study , lyophilized (freeze-dried) kratom tea , a potential treatment for pain and opioid dependence, did not induce CPP in mice (Wilson et al., 2020). There eco sober house cost were no animal intravenous drug self-administration , intracranial self-stimulation brain reward, or physical dependence/withdrawal studies of kratom’s alkaloids; however, other data suggested relatively low abuse potential as compared to opioids and other drugs of abuse (Henningfield et al., 2018a). There was evidence of morphine opioid receptor mediated effects, and preliminary drug discrimination and conditioned place preference studies with rats suggested abuse related effects at high intolerable human dose equivalents.
- Speciociliatine pharmacokinetics were characterized following IV and oral dosing to help understand the potential contribution of this alkaloid to in vivo kratom administration effects (Berthold et al., 2021).
- Over time, the analgesic effect of opioids diminishes, and tolerance builds up, which requires higher doses to achieve pain relief and can result in dependence or addiction.
- Lifetime aspirin mentions ranged from 7 to 23 per year, while lifetime diphenhydramine mentions ranged from 11 to 46 per year.
- Of the population that indicated that they reduced their opioid consumption after visiting High Hopes, 15% reported that they ceased use completely, and 21% noted that they reduced consumption by 6-9 fewer times each week.
The fact that we are now discussing cannabis as a possible treatment and harm reduction strategy in Canada and the US, two countries which now have some legal provisions in place for medical and recreational cannabis, signals that there has been an ideological shift in public attitudes towards cannabis use. It is measurable progress that a drug that was once considered a gateway to harder substances might now be viewed as an emergency exit from a deadly public health crisis. As a result of the war on drugs, research suggesting that cannabis is a ‘gateway drug’ to harder substance use has figured prominently in public and academic discourse and has operated as a warning to the public – and especially youth – on the dangers of cannabis use. A significant body of research has since continued to highlight the dangers of cannabis to public health. HIV, STIs and other dangerous infections are feeding off of the opioid epidemic, creating an even more complicated threat to public health. From 2010 through 2018, there were a total of nine lifetime kratom mentions (unweighted—not nationally representative), although five of those were in the last 2 years .
In a recent study that explored MC laws in states with operational dispensaries, the reduction in overdoses was found to be as high as 25% and a 38% reduction in treatment admissions was reported for heroin and other opioids. Opioids operate by binding to opioid receptors, known as mu receptors, in the brain, spinal cord and other tissues of the human body where they trigger the flow of endorphins – the body’s ‘natural’ opioids. When they attach to opioid receptors, they alter the perception of pain by stimulating dopamine release, which, in high doses, can also engender a sense of euphoria.
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Kratom’s main effects are due to the consumption of MG, but other minor alkaloids and metabolites, including 7-OH-MG, may also contribute to effects reported by consumers. Since 2018, many scientific advances improved our understanding of how these alkaloids and metabolites interact. Some alkaloids that contribute little to the effects of kratom may ultimately contribute to safer and more effective new medicines for a variety of disorders, as well as for general health and well-being. Development and approval of such products may be a decade or more in the future, but this rapidly advancing science is explaining how kratom works, and why its pain relieving, and other benefits occur with relatively low levels of abuse, dependence, and harmful decreases in respiration compared to opioids.
The new data suggest relatively low abuse potential as compared to morphine-like opioids, stimulants, and other drugs of abuse that demonstrate robust rewarding effects across all such abuse potential models. Similarly, MG’s potential to produce physical dependence and withdrawal appears relatively low, but not absent, as compared to opioids in animal models. These findings are generally consistent with human reports that MG has a relatively low abuse and withdrawal potential as compared to recreationally used opioids but can reduce opioid self-administration and withdrawal. Surveys indicate that reducing opioid self-administration and withdrawal are among the most common reasons for kratom use in the US . New studies discussed in Factors 2–7 contribute further to the understanding of kratom’s abuse potential, including its public health risks and benefits, that are part of the 8-factor abuse potential assessment.
Gutridge et al. pharmacologically characterized interactions between kratom extracts, kratom alkaloids, and synthetic carfentanil-amide opioids with G-proteins and beta-arrestin at mu, delta and kappa opioid receptors in vitro, and assessed whether they had rewarding properties and the degree to which they reduced alcohol intake (Gutridge et al., 2020). The authors concluded that “kratom alkaloids do not recruit β-arrestin 2 at the μOP, δOP, and κOP and can significantly reduce both moderate and binge alcohol intake in male and female mice. This pharmacological profile and effect on alcohol intake in rodents may explain why some find kratom useful to self-medicate for alcohol use disorder.” These findings were further supported by the findings by Todd et al. who concluded “mitragynine and 7-hydroxymitragynine demonstrate functional selectivity for G-protein signaling, with no measurable recruitment of β-arrestin. Overall, the study demonstrates the unique binding and functional profiles of the kratom alkaloids, suggesting potential utility for managing pain, but further studies are needed to follow up on these in vitro findings” (Todd et al., 2020). Kratom contains approximately 1–2% MG by weight, as well as other alkaloids (including 7-OH-MG) that typically are present at such low levels in kratom leaf material that it is uncertain if they contribute to kratom effects (Prozialeck et al., 2019).