ABSTRACT
Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product.
ABSTRACT
INTRODUCTION: The Society for Research on Nicotine and Tobacco began in the United States as a scientific organization "to stimulate the generation and dissemination of new knowledge concerning nicotine and tobacco in all its manifestations." Now in its 30th year, the Society is taking on new challenges in tobacco control, nicotine vaping, product regulation, and public policy. AIMS AND METHODS: This Review describes the formative years of the Society from the perspective of researchers who were in leadership positions during that time, documenting how biobehavioral and clinical research in the first 10 years was a continuation of the scientific mission of the 1988 United States Surgeon General's Report on Nicotine Addiction and summarizing organizational innovations during each president's term of office. CONCLUSIONS: The Society's promotion of scientific research served as a catalyst for funding, policy, and regulation, setting the stage for its influence and credibility. IMPLICATIONS: This Commentary provides context and an overview of the scientific research and the organizational innovations that occurred during the early years of the Society for Research on Nicotine and Tobacco using publications and available documentation. The Society was able to thrive because biobehavioral research on nicotine addiction provided the scientific underpinnings for the tobacco control enterprise as a whole. The objective of this Commentary is to describe formative events in the Society's history based on the accomplishments of its early leaders.
Subject(s)
Surgeons , Tobacco Use Disorder , Humans , United States , Nicotine , Public PolicyABSTRACT
OBJECTIVE: Despite kratom impacting neurobiological systems involved in psychiatric disorders, little is known about the prevalence of use among patients with severe psychopathologies. Here, we investigated the prevalence of kratom use, motives for use, and the clinical associations among inpatients with severe psychiatric disorders. METHODS: A total of 578 patients, aged 18 to 65, were evaluated by New Hampshire Hospital's Addiction Services from January 1, 2020, to February 28, 2022. The study collected demographic information and used chi-square tests, multivariable logistic regression, and subgroup analyses with 95% confidence intervals to examine trends among kratom users. A receiver operating characteristic curve analysis was also conducted. All statistical tests were performed using IBM SPSS Version 28.0.1. RESULTS: Of the patients assessed, 2.2% (n = 13) reported using kratom. The reasons for kratom use were managing withdrawal symptoms (15.4%), maintaining sobriety and reducing cravings for opioids (53.8%), improving focus and concentration (30.8%), alleviating low moods (38.5%), and managing pain (15.4%). Compared to non-kratom users, the only factor with a fair to good association with kratom use is postsecondary education (Area Under Curve, AUC = 0.77). CONCLUSIONS: Prevalence of kratom use among patients with serious mental illness at our site aligns with that reported in the general population. Users often cite self-management of cravings and sobriety from opioids, as well as treatment of low mood states, as motivations for consumption. While observations suggest a possible association between kratom use and individuals with post-secondary education, multiple substance use, and experience of substance-induced psychosis or mood disorders, it is essential to interpret these links cautiously until further rigorous studies are carried out to substantiate these findings.
Subject(s)
Mitragyna , Substance Withdrawal Syndrome , Substance-Related Disorders , Humans , Mitragyna/adverse effects , Inpatients , Prevalence , Substance-Related Disorders/complications , Substance-Related Disorders/epidemiology , Substance-Related Disorders/drug therapy , Substance Withdrawal Syndrome/complications , Substance Withdrawal Syndrome/epidemiology , Substance Withdrawal Syndrome/drug therapy , Analgesics, Opioid/therapeutic useABSTRACT
As individuals and communities around the world confront mounting physical, psychological, and social threats, three complimentary mind-body-spirit pathways toward health, wellbeing, and human flourishing remain underappreciated within conventional practice among the biomedical, public health, and policy communities. This paper reviews literature on psychedelic science, contemplative practices, and Indigenous and other traditional knowledge systems to make the case that combining them in integrative models of care delivered through community-based approaches backed by strong and accountable health systems could prove transformative for global health. Both contemplative practices and certain psychedelic substances reliably induce self-transcendent experiences that can generate positive effects on health, well-being, and prosocial behavior, and combining them appears to have synergistic effects. Traditional knowledge systems can be rich sources of ethnobotanical expertise and repertoires of time-tested practices. A decolonized agenda for psychedelic research and practice involves engaging with the stewards of such traditional knowledges in collaborative ways to codevelop evidence-based models of integrative care accessible to the members of these very same communities. Going forward, health systems could consider Indigenous and other traditional healers or spiritual guides as stakeholders in the design, implementation, and evaluation of community-based approaches for safely scaling up access to effective psychedelic treatments.
Subject(s)
Hallucinogens , Humans , Hallucinogens/pharmacology , Global HealthABSTRACT
Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.
Subject(s)
Illicit Drugs , Ketamine , Humans , Oxycodone , Receptors, N-Methyl-D-Aspartate , Dextromethorphan/adverse effects , Ketamine/adverse effects , Analgesics, Opioid/adverse effects , Cross-Over Studies , Double-Blind MethodABSTRACT
Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and a contributor to opioid overdose in the United States. For many people, pain can be satisfactorily managed by existing medicines and comprehensive psychosocial treatments. For others, available treatments are either ineffective or not acceptable, due to side effects and concerns about risks. Preliminary evidence suggests that some psychedelics may be effective for certain types of pain and/or improved quality of life with increased functionality and reduced disability and distress in people whose pain may never be completely relieved. Efficacy in these quality-of-life related outcomes would be consistent with the 'reset in thinking' about chronic pain management being increasingly called for as a more realistic goal for some people as compared to complete elimination of pain. This commentary summarizes the rationale for conducting more basic research and clinical trials to further explore the potential for psychedelics in chronic pain management. Additionally, if shown to be effective, to then determine whether the effects of psychedelics are primarily due to direct antinociceptive or anti-inflammatory mechanisms, or via increased tolerability, acceptance, and sense of spirituality, that appear to at least partially mediate the therapeutic effects of psychedelics observed in psychiatric disorders such as major depression. This commentary represents a collaboration of clinical and more basic scientists examining these issues and developing recommendations for research ranging from neuropharmacology to the biopsychosocial treatment factors that appear to be as important in pain management as in depression and other disorders in which psychedelic medicines are under development. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".
Subject(s)
Chronic Pain , Depressive Disorder, Major , Hallucinogens , Humans , United States , Hallucinogens/therapeutic use , Hallucinogens/pharmacology , Lysergic Acid Diethylamide/pharmacology , Chronic Pain/drug therapy , Quality of Life , Psilocybin/therapeutic use , Depressive Disorder, Major/drug therapyABSTRACT
RATIONALE: Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health. OBJECTIVES: This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act. RESULTS: LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks. CONCLUSIONS: LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.
Subject(s)
Orexin Receptor Antagonists , Sleep Initiation and Maintenance Disorders , Adult , Humans , Controlled Substances , Pyridines , Hypnotics and SedativesABSTRACT
BACKGROUND: Psychedelics are an increasingly active area of research and pharmaceutical development. This includes abuse potential assessment to better understand their pharmacological mechanisms and effects and guide controlled substance regulation. Psychedelics pose challenges to abuse assessments to ensure valid, reliable, and generalizable outcomes and safe study conduct. FINDINGS: Key nonclinical techniques, for example, receptor binding and functional assays in vitro, and nonclinical physical dependence determinations, are easily adaptable to psychedelics. However, the entactogens (weak reinforcers) and hallucinogens (non-reinforcers) require more flexible approaches than typically recommended by regulatory agencies. Phase 1 pharmacokinetic/pharmacodynamic safety studies and Phases 2/3 efficacy/safety trials with systematic monitoring of abuse-related adverse events are readily applicable to psychedelics. Human abuse trials require modification because supratherapeutic doses may not be safe and procedures, for example, personal monitors to manage serious adverse events, might bias outcomes. RECOMMENDATIONS: Abuse-related studies for psychedelics requiring approval by Food and Drug Administration and other agencies should take into consideration existing knowledge that will vary from extensive, for example, psilocybin, to zero for novel hallucinogens and entactogens. Many abuse assessments can be reasonably applied to animals and humans without compromising scientific integrity. Modification of existing techniques and incorporating a broader range of nonclinical tests should ensure generalizable outcomes. Human abuse studies merit reconsideration and possible modification to ensure safety and validity for psychedelic drug evaluation. Other nonclinical and clinical methods can provide evaluations of the pharmacological equivalence of test drugs to known drugs of abuse to provide context to the abuse assessment and guide drug scheduling.
Subject(s)
Hallucinogens , Substance-Related Disorders , Animals , Humans , United States , Hallucinogens/adverse effects , Controlled Substances , Psilocybin/pharmacology , Substance-Related Disorders/drug therapy , Lysergic Acid Diethylamide/pharmacologyABSTRACT
RATIONALE: Kratom derives from Mitragyna speciosa (Korth.), a tropical tree in the genus Mitragyna (Rubiaceae) that also includes the coffee tree. Kratom leaf powders, tea-like decoctions, and commercial extracts are taken orally, primarily for health and well-being by millions of people globally. Others take kratom to eliminate opioid use for analgesia and manage opioid withdrawal and use disorder. There is debate over the possible respiratory depressant overdose risk of the primary active alkaloid, mitragynine, a partial µ-opioid receptor agonist, that does not signal through ß-arrestin, the primary opioid respiratory depressant pathway. OBJECTIVES: Compare the respiratory effects of oral mitragynine to oral oxycodone in rats with the study design previously published by US Food and Drug Administration (FDA) scientists for evaluating the respiratory effects of opioids (Xu et al., Toxicol Rep 7:188-197, 2020). METHODS: Blood gases, observable signs, and mitragynine pharmacokinetics were assessed for 12 h after 20, 40, 80, 240, and 400 mg/kg oral mitragynine isolate and 6.75, 60, and 150 mg/kg oral oxycodone hydrochloride. FINDINGS: Oxycodone administration produced significant dose-related respiratory depressant effects and pronounced sedation with one death each at 60 and 150 mg/kg. Mitragynine did not yield significant dose-related respiratory depressant or life-threatening effects. Sedative-like effects, milder than produced by oxycodone, were evident at the highest mitragynine dose. Maximum oxycodone and mitragynine plasma concentrations were dose related. CONCLUSIONS: Consistent with mitragynine's pharmacology that includes partial µ-opioid receptor agonism with little recruitment of the respiratory depressant activating ß-arrestin pathway, mitragynine produced no evidence of respiratory depression at doses many times higher than known to be taken by humans.
Subject(s)
Mitragyna , Plant Extracts , Secologanin Tryptamine Alkaloids , Animals , Rats , Analgesics, Opioid/pharmacology , Mitragyna/chemistry , Oxycodone/pharmacology , Plant Extracts/pharmacology , Receptors, Opioid , Secologanin Tryptamine Alkaloids/pharmacologyABSTRACT
New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled globally. The implications of the CSA for research and medicines development, the path to approval of medicines, and their subsequent removal from Schedule I in the US are discussed. This entire process occurs within the framework of the CSA in the US and its counterparts internationally in accordance with international drug control treaties. Abuse potential related research in the US informs the eight factors of the CSA which provide the basis for rescheduling actions that must occur upon approval of a drug that contains a Schedule I substance. Abuse-related research also informs drug product labeling and the risk evaluation and mitigation strategies (REMS) will likely be required for approved medicines. Human abuse potential studies typically employed in CNS drug development may be problematic for substances with strong hallucinogenic effects such as psilocybin, and alternative strategies are discussed. Implications for research, medicinal development, and controlled substance scheduling are presented in the context of the US CSA and FDA requirements with implications for global regulation. We also discuss how abuse-related research can contribute to understanding mechanisms of action and therapeutic effects as well as the totality of the effects of the drugs on the brain, behavior, mood, and the constructs of spirituality and consciousness.
Subject(s)
Hallucinogens , Substance-Related Disorders , Controlled Substances , Hallucinogens/pharmacology , Hallucinogens/therapeutic use , Humans , Lysergic Acid Diethylamide/pharmacology , Lysergic Acid Diethylamide/therapeutic use , Psilocybin/therapeutic use , Substance-Related Disorders/drug therapy , United StatesABSTRACT
There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food and Drug Administration and may potentially receive full FDA approval with similar regulatory considerations occurring in multiple countries. At the same time, regulatory changes are poised to increase access to legal or decriminalized psychedelic use in various non-medical settings. This review provides a brief discussion on the historical use of psychedelic medicines, the status of the empirical evidence, and numerous significant policy considerations that must be thoughtfully addressed regarding standards-of-practice, consumer protection, engagement of communities, safeguarding access for all, and developing data standards, which supports the responsible, accountable, safe, and ethical uses of these medicines in clinical, faith-based, and other contexts. We provide suggestions for how public health and harm reduction can be supported through a public-private partnership that engages a community of stakeholders from various disciplines in the co-creation and dissemination of best practices and public policies.
Subject(s)
Hallucinogens , N-Methyl-3,4-methylenedioxyamphetamine , Substance Withdrawal Syndrome , Hallucinogens/therapeutic use , Humans , N-Methyl-3,4-methylenedioxyamphetamine/therapeutic use , Policy , Psilocybin/therapeutic use , Substance Withdrawal Syndrome/drug therapyABSTRACT
REL-1017 (esmethadone, D-methadone) is the opioid-inactive d-isomer of racemic D,L-methadone. REL-1017 may exert antidepressant effects via uncompetitive N-methyl-D-aspartate receptor (NMDAR) channel block. As REL-1017 is expected to exert central nervous system activity, full characterization of its abuse potential is warranted. We evaluated lack of reinforcing effect, physical dependence, and withdrawal of REL-1017 in Sprague Dawley rats. (1) Self-administration Study Rats were trained to self-administer oxycodone intravenously (IV) and then were subjected to 3-day substitution tests where saline, oxycodone, and REL-1017 were self-delivered IV by a fixed number of lever presses; (2) Drug Discontinuation Study Rats were treated for 30 days by oral gavage with vehicle, REL-1017, ketamine or morphine and evaluated for withdrawal with functional observational batteries (FOBs). In the self-administration study, rats treated with saline, vehicle, and all REL-1017 doses showed the typical "extinction burst" pattern of response, characterized by an initial rapid increase of lever-pressing followed by a rapid decrease over 3 days. Rats treated with oxycodone maintained stable self-injection, as expected for reinforcing stimuli. In the withdrawal study, REL-1017 did not engender either morphine or ketamine withdrawal signs over 9 days following abrupt discontinuation of drug exposure. REL-1017 showed no evidence of abuse potential and did not engender withdrawal symptomatology.
Subject(s)
Ketamine , Substance-Related Disorders , Animals , Methadone/adverse effects , Morphine , Oxycodone/adverse effects , Rats , Rats, Sprague-DawleyABSTRACT
PURPOSE/BACKGROUND: As part of a human abuse potential (HAP) study of lemborexant (LEM), the effects of therapeutic (LEM 10 mg), and supratherapeutic doses of LEM 20 mg and LEM 30 mg on cognition and psychomotor performance were compared with placebo (PBO) and supratherapeutic doses of zolpidem (ZOL) 30 mg and suvorexant (SUV) 40 mg. Subjects (n = 32) were healthy, nondependent, recreational sedative users able to discriminate the effects of both SUV and ZOL from PBO on subjective drug measures. METHODS/PROCEDURES: The human abuse potential study was a single-dose, randomized, double-blind, PBO-controlled, 6-way crossover study. Eligible subjects admitted to the treatment phase completed the choice reaction test (CRT) and divided attention test. The CRT included measurements of recognition reaction time (RRT) and motor reaction time. FINDINGS/RESULTS: Recognition reaction time and mean maximum change from baseline (CFB max ) scores were significantly increased (slower performance) versus PBO for all LEM doses (all P < 0.001), ZOL ( P < 0.001), and SUV ( P = 0.004), and LEM (all doses) was not statistically different from ZOL or SUV. Motor reaction time and mean CFB max versus PBO were significantly increased for all LEM doses (all P < 0.001), and ZOL ( P < 0.001) and SUV ( P < 0.001). All LEM doses showed significantly decreased (better performance) mean CFB max versus ZOL (all P < 0.001), but not SUV. Notably, all cognitive effects in the CRT and divided attention test were limited to the main treatment phase (up to 8 hours postdose). IMPLICATIONS/CONCLUSIONS: All active doses of LEM, ZOL, and SUV generally increased reaction time and reduced divided attention capabilities versus PBO. However, at therapeutic/supratherapeutic doses, LEM led to significantly less cognitive impairment than supratherapeutic doses of ZOL in some measures.
Subject(s)
Hypnotics and Sedatives , Orexin Receptor Antagonists , Azepines , Cognition , Cross-Over Studies , Double-Blind Method , Humans , Hypnotics and Sedatives/adverse effects , Orexin Receptor Antagonists/adverse effects , Pyridines , Pyrimidines , Triazoles , ZolpidemABSTRACT
BACKGROUND: Lemborexant (LEM) is a dual orexin receptor antagonist approved for the treatment of insomnia in adults in multiple countries including the the United States, Japan, Canada, Australia and several Asian countries. PROCEDURES: This was a randomized, single-dose, single-center, double-blind, active-control, 6-way crossover study to evaluate LEM abuse potential. The study assessed oral doses of LEM 10 mg (LEM10), 20 mg (LEM20), and 30 mg (LEM30) compared with placebo (PBO), zolpidem (ZOL) immediate release 30 mg, and suvorexant (SUV) 40 mg. Subjects were healthy, nondependent, recreational sedative users able to discriminate/like the effects of both SUV and ZOL from PBO during a qualification phase. RESULTS: Abuse potential endpoints were analyzed in qualified subjects who received and completed all treatments (n = 32). On the "at this moment" drug-liking visual analog scale (VAS), mean maximum (peak) effect (primary endpoint) values were 78.4, 80.5, and 83.6 for LEM10, LEM20, and LEM30, respectively, which were all significantly greater than PBO (57.8; all P > 0.05) but not different from SUV (76.1) or ZOL (78.3). Similarly, for secondary endpoints overall drug-liking VAS and take-drug-again VAS, mean maximum (peak) effect values for all LEM doses were significantly greater than PBO ( P > 0.05) but not different compared with ZOL or SUV. CONCLUSIONS: For all doses, LEM demonstrated abuse potential versus PBO and appeared to have a similar abuse potential profile to ZOL and SUV in this study population. Lemborexant was well tolerated. Lemborexant has been placed in Schedule IV, the same drug schedule as ZOL and SUV.
Subject(s)
Hypnotics and Sedatives , Orexin Receptor Antagonists , Adult , Azepines , Cross-Over Studies , Double-Blind Method , Humans , Hypnotics and Sedatives/adverse effects , Orexin Receptor Antagonists/adverse effects , Pyridines , Pyrimidines , Triazoles , Zolpidem/adverse effectsABSTRACT
This Letter to the Editor is a response to Broyan and colleagues who recently published a Case Report presenting data on 28 patients in the United States who identified kratom as their primary substance of use and who were subsequently induced on buprenorphine/naloxone for a reported diagnosis of kratom use disorder. We applaud the authors for helping to advance the science on kratom and recognize the difficulties in conducting kratom-related clinical assessment and research. However, a number of inconsistences and generalizations were identified in this Case Report, which also lacked some critical context. Importantly, such inconsistencies and generalizations can be observed throughout kratom-specific case reports. We feel this is now an important opportunity to highlight these issues that are present in the Broyan and colleagues Case report but emphasize that they are not unique to it. We do this with the hope that by acknowledging these issues it can help inform editors, clinicians, and researchers who may not be familiar with kratom and, as a result of this unfamiliarity, may inadvertently present findings in a manner that could confuse readers and even misinform clinical researchers and practitioners.
Subject(s)
Mitragyna , Opioid-Related Disorders , Analgesics, Opioid/therapeutic use , Buprenorphine, Naloxone Drug Combination/therapeutic use , Humans , Opioid-Related Disorders/diagnosis , Opioid-Related Disorders/drug therapy , United StatesABSTRACT
Kratom (Mitragyna speciosa Korth., Rubiaceae) is a plant native to Southeast Asia, where it has been used for centuries as a mild stimulant and as medicine for various ailments. More recently, as kratom has gained popularity in the West, United States federal agencies have raised concerns over its safety leading to criminalization in some states and cities. Some of these safety concerns have echoed across media and broad-based health websites and, in the absence of clinical trials to test kratom's efficacy and safety, considerable confusion has arisen among healthcare providers. There is, however, a growing literature of peer-reviewed science that can inform healthcare providers so that they are better equipped to discuss kratom use with consumers and people considering kratom use within the context of their overall health and safety, while recognizing that neither kratom nor any of its constituent substances or metabolites have been approved as safe and effective for any disease. An especially important gap in safety-related science is the use of kratom in combination with physiologically active substances and medicines. With these caveats in mind we provide a comprehensive overview of the available science on kratom that has the potential to i clarity for healthcare providers and patients. We conclude by making recommendations for best practices in working with people who use kratom.
ABSTRACT
Difelikefalin, a selective kappa-opioid receptor agonist with limited central nervous system penetration, is being developed for the treatment of chronic pruritic conditions. This randomized, double-blind, active- and placebo-controlled, four-way crossover study was designed to evaluate the abuse potential of difelikefalin in healthy recreational polydrug users. Using a 4 × 4 Williams design, nondependent adult users of opioids and hallucinogens (N = 44) were randomized to receive single intravenous (i.v.) injections of difelikefalin at supratherapeutic doses (5 and 15 mcg/kg); pentazocine (0.5 mg/kg), a schedule IV mu-opioid partial agonist and kappa-opioid receptor agonist; and placebo. The abuse potential of difelikefalin was compared with pentazocine and placebo using the maximal score (maximum effect [Emax ]) of the Drug Liking visual analog scale (VAS; primary end point), along with multiple secondary end points of subject-rated measures and pupillometry. Difelikefalin produced significantly lower Drug Liking VAS Emax , and lower peak positive, sedative, and perceptual effects compared with pentazocine. These effects of difelikefalin were small, brief, and not dose-dependent, although marginally greater than those observed with placebo. Neither dose of difelikefalin elicited significant negative or hallucinogenic effects. On end-of-session measures of overall drug liking and willingness to take the drug again, difelikefalin did not differ from placebo, indicating subjects neither liked nor disliked the effects overall and did not feel motivated to take the drug again. Consistent with its lack of mu agonist activity, difelikefalin did not induce miosis compared with pentazocine. All treatments were generally well-tolerated. This study indicates that difelikefalin presents a low potential for abuse.