Alessandro E. Vento1,2
Simone de Persis3
Sergio De Filippis4
Fabrizio Schifano5Flavia Napoletano5
John M. Corkery5
Georgios D. Kotzalidis4,6*- 1ASL (Azienda Sanitaria Locale) Roma 2, Rome, Italy
- 2Addictions' Observatory (ODDPSS), Rome, Italy
- 3ASL, Rieti, Italy
- 4Villa von Siebenthal Neuropsychiatric Clinic and Hospital, Genzano di Roma, Italy
- 5Psychopharmacology, Drug Misuse & Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, United Kingdom
- 6NESMOS Department (Neurosciences, Mental Health, and Sensory Organs), School of Medicine and Psychology, Sant'Andrea Hospital, Sapienza University, Rome, Italy
Kratom or Mitragyna speciosa (Korth.) is an evergreen tree of the coffee family native to South-East Asia and Australasia. It is used by locals recreationally to induce stimulant and sedative effects and medically to soothe pain and opiate withdrawal. Its leaves are smoked, chewed, or infused, or ground to yield powders or extracts for use as liquids. It contains more than 40 alkaloids; among these, mitragynine and 7-hydroxymitragynine are endowed with variable mu, delta, and kappa opioid stimulating properties (with 7-hydroxymitragynine having a more balanced affinity), rhynchophylline, which is a non-competitive NMDA glutamate receptor antagonist, but is present in negligible quantities, and raubasine, which inhibits α1-adrenceptors preferentially over α2-adrenceptors, while the latter are bound by 7-hydroxymitragynine, while mitragynine counters 5-HT2A receptors. This complexity of neurochemical mechanisms may account for kratom's sedative-analgesic and stimulant effects. It is commonly held that kratom at low doses is stimulant and at higher doses sedative, but no cut-off has been possible to define. Long-term use of kratom may produce physical and psychological effects that are very similar to its withdrawal syndrome, that is, anxiety, irritability, mood, eating, and sleep disorders, other than physical symptoms resembling opiate withdrawal. Kratom's regulatory status varies across countries; in Italy, both mitragynine and the entire tree and its parts are included among regulated substances. We describe the case of a patient who developed anxiety and dysphoric mood and insomnia while using kratom, with these symptoms persisting after withdrawal. He did not respond to a variety of antidepressant combinations and tramadol for various months, and responded after 1 month of clomipramine. Well-being persisted after discontinuing tramadol.
Introduction
The interest of the medical world in Mitragyna speciosa Korthals (MsK) dates back to the1950s (1–6). MsK (kratom) was first described by the Dutch colonial botanist Pieter Korthals in 1839 and is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea, where it has been used in traditional medicine and religious (7) contexts since at least the 19th Century, as well as a voluptuary substance use (a surrogate to opium) well before Korthals' description (8, 9). In these countries, leaves of MsK are first dried and then chewed or consumed as smoke in long pipes, extract, or powder, or brewed into a tea (10). Mixtures with other substances are also made, thus increasing dangerousness of consumption. Some of them are confectioned into pills (11). Concern over its use was not raised until recently, when it became largely available in Western countries and its toxic potential realized. A first Malaysian report found kratom consumers to develop addiction and psychiatric symptoms (12), while its psychoactive properties were detailed in the late 1980s (13).
MsK alkaloids were quantitatively determined in its leaves after separation by thin-layer chromatography, with ultraviolet spectrophotometry (14), with colorimetry (15), densitometry (16); indoles and oxindoles were identified in the first place (17). Since then, more than 25 significant alkaloids were identified (11). The corynanthe-type indole mitragynine contributes 66% to MsK alkaloids, paynantheine 9%, 7-hydroxymitragynine 2%, and speciociliatine 1%; other alkaloids contribute <1% each (11). However, their contribution varies across locations (18) and products sold across the world might not always contain MsK at all (19). The first whose structure was determined in 1958 was mitraphylline (20), with many other alkaloids following suit (18). The MsK alkaloids may differ in their brain accessibility and crossing of the blood-brain barrier; for example, mitragynine penetrates in the brain significantly more than 7-hydroxymitragynine, at least in the rat (21). However, the latter is held to be responsible for almost all kratom effects on opioid receptors, and despite low content, it is produced by cytochrome P450 (CYP3A4 isoenzyme) conversion from mitragynine (22).
Other biochemically and neurochemically interesting compounds include rhynchophylline derivatives (23, 24), which down-regulate NMDA-mediated responses in animals (25–27), and a yohimbine and mitragynine analog, ajmalicine or raubasine (28), which differently from mitragynine (29), inhibits α2-adrenoceptors, although less than α1-adrenoceptors (30–32). Of note, kratom alkaloids closely interact with α2 adrenoceptors, and mitragynine and 7-hydroxymitragynine bind them (33). Furthermore, mitragynine inhibits the activity of 5-HT2A receptors, although indirectly so (29, 34, 35), as it shows a Ki > 10 μM for the 5-HT2A receptor (36). It is possible that the interplay between these receptor effects and between MsK alkaloids underpin the different effects of kratom at low vs. high doses.
Although kratom was reportedly used to substitute for opiate addiction and cure it (37), the demonstration of their binding by MsK had to await the discovery of opioid receptors (38, 39). Mitragynine and other kratom alkaloids were shown to be possibly allosteric (40) agonists to opioid receptors (41–44), to possess analgesic properties thanks to their binding to brain μ- and δ-opioid receptors, and to induce ileal and vas deferens distention through the same receptors at peripheral sites (43, 45). These properties were long harnessed by traditional healers in the countries where kratom grows. In South-East Asia kratom is used to alleviate muscle aches, and sometimes to heal wounds and cure worm infections, while some users support they assume it to increase resistance to fatigue and to stimulate sexuality (46). Indeed, mitragynine and kratom alkaloids are likely to be associated with “dependence” signs and symptoms which are less severe than those usually associated to opiates and they may be used to alleviate classical opiate withdrawal (47, 48). This is not surprising, since they act as agonists on opioid mu receptors.
Legislations concerning kratom varies across countries. In Europe it is illegal in Denmark, Finland, Ireland, Latvia, Lithuania, Poland, Romania, and Sweden (49), while in the UK it has been included in the Psychoactive Substances Bill 2015 (50), hence it is illegal since March 2016, being regulated through the Psychoactive Substances Act 2016 (51). In Italy, it became illegal in 2016. In Canada and Australia, kratom is illegal, while in New Zealand it is a regulated substance. In the United States it is forbidden in some States and not in other (49). Many US state legislations are likely to change their attitude toward kratom in the near future. Similarly, Thailand, one of kratom's major producers, which prohibits since 1943 the cultivation of new plants and mandates the abatement of the existing ones, while restricting possession and use and establishing sanctions for quantities superior or inferior to 10 Kg, is on the verge of changing its legislation. In Malaysia, Bhutan and Myanmar kratom is illegal, and in Indonesia it will be banned by 2022 (52). Discrepancies among the various legislations internationally, as well as the increase in the use of internet and globalization have resulted in an increased use of kratom for voluptuary purposes (53) indicating the need for international coordination of scientists and legislators (54). That kratom could induce an opioid-like withdrawal syndrome, therefore it can be included among addictive substances, is shown by the fact that it may be present in neonates exposed to the substance due to their mothers' heavy use during pregnancy (55–61). In fact, the World Anti-Doping Agency placed mitragynine on its Monitoring List since 2014, and 1 year later, four cases of mitragynine use among strength sportsmen were detected (62). Kratom use has been also reported in fitness settings (63).
The effects of the use of kratom are variable and may depend on the cultural and genetic background of the user as well as on differences in product composition. Product conservation and transport factors may also be involved, as are co-administered sedative or multisubstance use. In a US-Thailand comparison, for example, symptoms were more severe and mortality higher in the US sample, with drowsiness, irritability-agitation and tachycardia being the most common in order of increasing frequency (64). Kratom may be used according to users' taste and adjusted according to the desired effects, with low doses producing stimulant and activating effects and high doses sedative and tranquilizing effects (65–67), although these dose-related effects were not confirmed in a recent study and was unrelated to the amount and duration of kratom use (68). Many people, especially in South-East Asia, get to use kratom after being addicted to opioids and in the attempt to quit; others are prompted to use kratom due to its anxiolytic and mood enhancing effects (69–71). It is expected that upon discontinuing, rebound mood and anxiety symptoms emerge. In regular users, withdrawal symptoms may occur which are more intense in long-time users or after stopping heavy use, and involve usually moderate anxiety and depression (72), as well as aching and disordered sleep (73). However, kratom withdrawal syndromes are usually mild and transient (72–74), similar to but milder than those of opiate withdrawal (74, 75), but may be complicated in some users (54).
We here report the case of an adult man who used kratom and developed withdrawal symptoms while trying to quit. He did well on clompipramine just 1 month after initiation and, 9 months later, is currently symptom-free.
Case Report
A 44-year-old man, married to a 44-year-old, currently pregnant woman, with a 5-year-old son, a graduate in economy and employed as a researcher at a University, sought help at a community psychiatric service for symptoms of kratom withdrawal and elevated anxiety.
The patient was collaborative at interview, appropriately dressed and well-oriented in time and space; he showed free-floating and somatic anxiety, with tachycardia, profuse sweating, psychomotor agitation, insomnia, dysphoric mood, and emotional lability. His thoughts were focused on anxious experiences and hopelessness. He reported being treated during the last few months with various benzodiazepines and selective serotonin reuptake inhibitors (SSRIs), first paroxetine 40 mg/Day and then sertraline 200 mg/day, to which he associated cognitive-behavioral therapy, with no clear benefit.
The patient had experienced two important major depressive episodes coinciding with stressful life events, which he overcame through the use of SSRIs and long-term psychotherapy. When he was young, he had engaged in polysubstance use, while in his adult life he first used cannabis and alcohol, but later turned to benzodiazepines, alcohol, and kratom, which he obtained through dark internet sites. The patient has been vague as to when and how he started consumption, and also very unclear regarding dosing. His internet-related kratom sources varied, so we are not in a position to determine the purity of the samples he received. During the last 10 months preceding the visit, he had scheduled daily kratom infusions, but had discontinued quite sharply during the last 2 months. The patient used to continue drinking the infusion until he reached the desired effect. Having realized in the last 2 months he was becoming severely dependent, he decided to quit kratom and to no longer seek it on the internet.
Urinary drug testing was positive for benzodiazepines. Blood chemistry showed no abnormal values. However, kratom could not be quantified due to the unavailability of routine laboratory tests. The electrogram (ECG) showed no abnormalities, with a QTc of 385 ms and a heart rate of 60 beats/min. We established treatment with pregabalin 25 mg b.i.d., gradually tapering off sertraline and substituting it with 150 mg/day bupropion, taken in the morning, and 300 mg controlled-release trazodone, administered in the evening. His next visit was scheduled after 2 weeks.
During the second visit, his clinical conditions were unchanged. The patient was restless, anxious, agitated, insomniac, dysphoric, with frequent cry spells and unstructured ideation of self-harm. He craved for benzodiazepines and alcohol and often abused them. Bupropion was increased to 300 mg/day and pregabalin, 75 mg b.i.d. was initiated.
During his third visit, after further 15 days, the above clinical picture persisted. The patient reported to be able to relax, but observed no symptom improvement. We agreed to add 50 mg/day tramadol in the evening. He noted since the first days of tramadol addition a mild reduction in craving and restlessness, with disappearance of self-harm ideas, while anxiety, which the patient reported as paralyzing, dysphoric mood, cry spells, and avolition remained unchanged. The patient asked for a medical certificate to abstain from work, since he considered teaching at the University a complex and stressful activity. We agreed to increase tramadol to 100 mg b.i.d., gradually introducing clomipramine to a target dose of 75 mg/day, while gradually discontinuing bupropion.
Three months after the first visit and about 1 month after introducing clomipramine, the clinical picture was on the way to resolution; the patient himself asked to discontinue tramadol. Free-floating and somatic anxiety had subsided and craving for all substances, including alcohol, benzodiazepines, and kratom, was significantly attenuated, while mood was stable and in the normal range (euthymic).
In the following months, given the clear clinical improvement and the remission of withdrawal symptoms, it was possible to gradually discontinue both pregabalin and trazodone.
Currently, the clinical picture is stable; the patient continues on clomipramine 75 mg/day and about 9 months after its introduction reports to have resumed normal life.
The patient signed free informed consent for the publication of his case and all treatments received.
Discussion
In this report we presented the case of an adult Italian man in his forties, who deliberately used kratom to soothe his anxiety symptoms. The patient was well-educated and upper socioeconomic class. He had started kratom after engaging in multisubstance use and psychotherapy, while completing steps toward reaching a high social status. He used the internet to obtain kratom, but had no available supplies when he came to our attention, so we could not analyse any kratom specimen he used. After trying several therapeutic strategies, including pharmacotherapy, he was unable to resolve his anxiety symptoms, either during kratom use or during abstinence, and was switched to low-dose clomipramine eventually discontinuing all other psychotherapeutic drugs; 1 month after initiating clomipramine, his symptoms had resolved and so were his anxiety symptoms that had originated psychiatric visits.
There have been several case reports of kratom use toxicity and withdrawal in literature, but clomipramine treatment had not been reported to date. Cases vary in severity and symptom presentation. One of the first described cases of mitragynine toxicity was of severe seizures and come occurring in a 64-year-old man, that resolved soon with symptomatic treatment, that is, intubation to preserve airway integrity (76). In another case, seizures occurred when a 43-year-old man tried to self-treat his opiate dependence with a kratom-modafinil combination (69); the case resolved with few kratom-related withdrawal symptoms. A further case presenting with seizures occurred in a 18-year old man and treated with antiepileptic drugs. Magnetic resonance imaging showed bilateral alterations in the striatum, cerebral peduncles, and subthalamic nuclei in this chronic kratom user, indicating possible permanent effects of kratom in brain structure (77). Finally, a 27-year-old nab with history of anxiety, attention-deficit/hyperactivity disorder, substance use disorders (benzodiazepines and opioids) developed seizures while using kratom and opioids and recovered with anti-anxiety agents (78). Another 36-year-old man was unresponsive to external stimuli and near comatose, did not respond to naloxone and was treated with respiratory support and symptomatic management (79). Another kratom overdose case occurred in a 38-year-old woman who resented with respiratory depression at the emergency department and resolved with naloxone (80). A 33-year-old male polysubstance user exhibited cardiovascular shock features and high procalcitonin levels promptly treated with vasopressors (81). An otherwise healthy 35-year-old man suffered a cardiac arrest after using kratom alone and was found with small brain infarcts, but recovered spontaneously (82). Finally, a 62-year-old woman who used kratom for the first time to soothe traumatic pain presented at the emergency room with intractable vomiting and nausea that responded to ondansetron, promethazine, and famotidine (83).
Cases of kratom-related deaths are usually linked to simultaneous assumption of kratom with other drugs, as in the above described case. Initial death reports regarded associations, but more recent cases show that people who only take kratom are at risk. One case of death of a 20-year-old man occurred with propylhexedrine and kratom; the latter was not determined to have caused the death, which has been associated to accidental propylhexedrine (84). Nine cases of death occurring in one year were described in Sweden in 2011 with the simultaneous intake of mitragynine and O-desmethyltramadol. Decedents' age ranged 22–35; seven were men and two were women (85). The authors concluded that mitragynine-related herbal mixes are not so safe as per internet propaganda. Another death case in which mitragynine was involved, but the death was attributed to quetiapine overdose, has been described in a 27-year-old man succumbing to hyperthermia associated with seizures. One case of a 17-year adolescent male who was trying to quit opioid use by self-medicating with kratom, points to kratom being occasionally toxic; the boy was found dead with pulmonary congestion and oedema, as well as urinary bladder distension, which are typical of opiate intoxication (86). The case was labeled as “probable kratom toxicity.” Another case of kratom intoxication-related death was found to be associated with high blood amounts of mitragynine and 7-hydroxymitragynine and unremarkable pathological finding at autopsy in a middle-aged man with psychiatric history and illicit drug use disorder (87). Another report of death related to kratom use was one of a 24-year man with opiate and alcohol use disorders, who was found dead with high peripheral alkaloid concentrations, pulmonary oedema and congestion, and urinary retention, compatible with opioid intoxication; the patient was using several psychiatric medications that were found at therapeutic blood levels (88). Further two cases of young men could not be attributed to the documented kratom use, despite high mitragynine levels in femoral blood (89). One of the patients had attempted suicide just after taking kratom with prescription drugs, while the other took a mix of drugs. Another fatality was due to 3-methoxyphencyclidine, and mitragynine was just one of many other substances the 58-year-old man had taken (90). An emergency case presenting with cardiorespiratory arrest could not be rescued despite the use of intralipid, that nevertheless improved somehow the conditions of a 26-year-old man, but proved ineffective in avoiding exitus, attributed to cardiorespiratory failure and hypoxic brain damage (91). A Canadian 56-year-old woman with chronic obstructive pulmonary disease, after skipping her medication and consuming kratom purchased from Indonesia, died due to respiratory failure (92). Her mitragynine levels in the femoral vein were found to be substantial but sublethal (under the reporting laboratory's threshold of fatality, which was 0.21 mg/L). Another case of multiple drug use ensuing in death has been related to mitragynine due to the very high doses found in inferior cava blood of a 33-year-old man (93). In general, fatality case studies suffer from heterogeneity in kratom alkaloid detection methods and sites.
Cases of chronic kratom used followed by withdrawal symptoms have been reported to resolve with gabapentin in a 26-year-old woman and gabapentin and clonidine in a 27-year-old man (94). A case similar to ours has been described in a 44-year-old man with a history of alcohol use and anxiety; gradually tapered-off dihydrocodeine and lofexidine were followed by rapid withdrawal symptom resolution (95). In our case, the psychiatric symptoms of our patient were more prominent and stubborn, and briefly trialed clonidine in the past had sorted no effect. Hence the need for something more specific for anxiety disorders. Cases of kratom withdrawal in a 47-year-old woman (96) and in a 24-year-old man with an autism spectrum disorder (97) have been treated with clonidine and hydroxyzine, similarly to ordinary opiate withdrawal syndromes. The latter case and four other cases of kratom withdrawal were treated successfully with buprenorphine-naloxone maintenance (98–100). A further withdrawal from combined kratom-tilidine addiction has been successfully treated with retarded morphine (101). Finally, a recent paper reported an unusual presentation of obsessive-compulsive disorder-like syndrome during kratom withdrawal that responded to lorazepam (102). We did not use treatments aimed at treating patient's kratom withdrawal, since the syndrome was mild despite being obstinate, but rather focused on the anxiety disorder, which usually responds to antidepressants. By treating our patient's background psychological symptoms, we were successful in reducing withdrawal symptomatology.
Kratom use has been often linked to liver toxicity. Kratom has been associated with biliary cholangitis and cholestasis in several cases (67, 103–110) and with one case of hepatomegaly (111), but also with acute hepatitis (112). Mitragynine inhibits hepatic and intestinal cytochrome P450 3A activities (113) and hepatic microsomal CYP2D6 (114), thus increasing blood levels of other concomitantly administered drugs that are metabolized by these isoenzymes, that is, most psychiatric drugs. This may expose to further hepatotoxicity (115, 116). Our patient did not develop liver abnormalities during his kratom use period, despite the fact he was concurrently using alcohol. We did not perform kratom quantification analyses in our patient throughout the treatment period. This was because the patient refused to provide organic specimens or leaves for forensic analyses. There are reliable methods for detecting mitragynine and its derivatives in the urine (117) and in plant and extracts (118) for forensic purposes, but these are not currently routine practice. There is need for standardizing methods of kratom alkaloid detection in reported users.
A limitation of the current review is that the supposed benefits-to-risk ratio of kratom use cannot be currently addressed adequately. There is insufficient epidemiological documentation as to the extent of kratom use worldwide and in specific countries (119), so to estimate how many people use it and how many develop unwanted effects. Besides this, risks may increase, as many kratom users have concurrent other substance use (120), and this is difficult to disentangle. The most recent estimates in indicate kratom use in the adult US population is 0.8% for the past year and 1.3% lifetime (120). The debate on epidemiological issues is strong and ongoing, and points to the evergreen “more studies are needed” (121, 122). The advocates of kratom use to ease opioid dependence and harness its effects on strength and endurance while involved in work activities do not publish in scientific literature, but put forward their uncontrolled views and opinions in sites of their own property. Hence, it is an impervious task to try to respond to the question whether kratom use is relatively safe, but it appears it is not (123). Currently, there is not sufficient evidence to recommend changes in kratom regulation, nor to recommend the use of clomipramine in cases of kratom withdrawal.
Our patient showed while withdrawing from kratom mitigated signs and symptoms typical of opiate withdrawal, which were mixed with other psychiatric symptoms presumably linked to his background psychopathology. Knowing that the withdrawal is generally time-limited and mild, we chose to use an anxiety-specific agent, clomipramine, with preference for serotonin transporter over noradrenaline transporter inhibition, which is a tricyclic antidepressant used in anxiety disorders and obsessive-compulsive disorder and has shown good evidence in these disorders. We used it at 75 mg/day, which is on the lower range of clinical effectiveness for these disorders. Mitragynine counters serotonin 5-HT2A receptors (29) and clomipramine down-regulates the same receptors after chronic treatment (124, 125); furthermore, it has pain supressing effects even at low doses through spinal mechanisms (126). Hence, it is possible that some mitragynine withdrawal symptoms were alleviated concomitantly with clomipramine's anxiety relieving effects. However, this is not the most likely mechanism whereby clomipramine reduced our patient's symptomatology. In fact, clomipramine may obviate for the opiate-like mitragynine withdrawal syndrome through interference with opioid receptors, which it was shown to bind (127); chronic, but not subacute clomipramine administration, induced a mu receptor down-regulation in the rat (128). In this case, clomipramine could reduce the quantity of opioid receptors in the need for occupation, as it occurs in opiate withdrawal. However, the response of human opioid receptors to chronic clomipramine appears to be weak (129). We are unsure about how improvement was obtained, but the timeline appears to match the usual onset of clomipramine antidepressant effects.
Concluding Remarks
Summarizing the above evidence, we may conclude that kratom may induce addiction, acute toxicity which may be sometimes lethal and, upon discontinuation, it induces a withdrawal syndrome, which may vary in intensity. In many instances that appeared in literature, kratom was regularly used by patients with psychiatric history and/or substance use disorders. Legislations should take very seriously peer-reviewed published evidence and regulate the substance. In parallel, we need to enforce kratom detection methods in consent-providing users for forensic purposes. International drug policies should be coordinated and inform the public about kratom and other novel addictive drugs.
Data Availability Statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.
Ethics Statement
The patient signed free informed consent for the publication of his case and all treatments received.
Author Contributions
AV, SP, and SD saw the patient and wrote the first draft. FS, FN, and JC supervised the case and the writing of the manuscript. GK wrote the last draft and performed literature searches. All authors saw and approved the final version of the manuscript.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgments
We thank Librarians of the Library of the Sapienza University of Rome, Faculty of Medicine and Psychology Mimma Ariano, Ales Casciaro, Teresa Prioreschi, and Susanna Rospo for rendering precious bibliographical material accessible.
References
1. Raymond-Hamet A. Les alcaloïdes du Mitragyna speciosa Korthals [The alkaloids of Mitragyna speciosa Korthals–French]. Ann Pharm Fr. (1950) 8:482–90.
2. Ongley PA. Les alcaloïdes des Mitragyna [The alkaloids of Mitragyna]. Ann Pharm Fr. (1953) 11:594–602.
3. Shellard EJ, Lees MD. The Mitragyna species of Asia. V The anatomy of the leaves of Mitragyna speciosa. Korth Planta Med. (1965) 13:280–90. doi: 10.1055/s-0028-1100122
4. Beckett AH, Shellard EJ, Phillipson JD, Lee CM. Alkaloids from Mitragyna speciosa (Korth.). J Pharm Pharmacol. (1965) 17:753–735. doi: 10.1111/j.2042-7158.1965.tb07599.x
5. Beckett AH, Shellard EJ, Phillipson JD, Lee CM. The Mitragyna species of Asia. VII Indole alkaloids from the leaves of Mitragyna speciosa Korth. Planta Med. (1966) 14:277–88. doi: 10.1055/s-0028-1100055
6. Beckett AH, Shellard EJ, Phillipson JD, Lee CM. The Mitragyna species of Asia. VI. Oxindole alkaloids from the leaves of Mitragyna speciosa Korth. Planta Med. (1966) 14:266–76. doi: 10.1055/s-0028-1100054
7. Singh D, Narayanan S, Vicknasingam B. Traditional and non-traditional uses of Mitragynine (Kratom): a survey of the literature. Brain Res Bull. (2016) 126(Pt 1):41–6. doi: 10.1016/j.brainresbull.2016.05.004
9. Burkill IH. A Dictionary of the Economic Products of the Malay Peninsula, Vol. II. London: Crown Agents for the Colonies (1935). p. 1480–3.
11. Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R, et al. From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction. Neurosci Biobehav Rev. (2013) 37:138–51. doi: 10.1016/j.neubiorev.2012.11.012
13. Jansen KL, Prast CJ. Psychoactive properties of mitragynine (kratom). J Psychoactive Drugs. (1988) 20:455–7. doi: 10.1080/02791072.1988.10472519
14. Shellard EJ, Alam MZ. The quantitative determination of some mitragyna oxindole alkaloids after separation by thin-layer chromatography. I Ultraviolet spectrophotometry. J Chromatogr. (1968) 32:472–88. doi: 10.1016/s0021-9673(01)80520-3
15. Shellard EJ, Alam MZ. The quantitative determination of some mitragyna oxindole alkaloids after separation by thin-layer chromatography. II Colorimetry, using the Vitali-Morin reaction. J Chromatogr. (1968) 32:489–501. doi: 10.1016/s0021-9673(01)80521-5
16. Shellard EJ, Alam MZ. The quantitative determination of some mitragyna oxindole alkaloids after separation by thin layer chromatography. I. Ultraviolet spectrophotometry. J Chromatogr. (1968) 33:347–69. doi: 10.1016/s0021-9673(00)98661-8
17. Beckett AH, Dwuma-Badu D, Haddock RE. Some new mitragyna-type indoles and oxindoles the influence of stereochemistry on mass spectra. Tetrahedron. (1969) 25:5961–9. doi: 10.1016/s0040-4020(01)83103-3
18. Shellard EJ. The alkaloids of Mitragyna with special reference to those of Mitragyna speciosa, Korth. Bull Narc. (1974) 26:41–55.
19. Ogata J, Kawamura M, Hakamatsuka T, Kikura-Hanajiri R. 改良 PCR-RFLP 法による Kratom 品の [Discrimination of kratom products by an improved PCR-RFLP method–Japanese]. Yakugaku Zasshi. (2020) 140:1501–8. doi: 10.1248/yakushi.20-00170
21. Yusof SR, Mohd Uzid M, Teh EH, Hanapi NA, Mohideen M, Mohamad Arshad AS, et al. Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: the missing link in pharmacodynamic studies. Addict Biol. (2019) 24:935–45. doi: 10.1111/adb.12661
22. Kruegel AC, Uprety R, Grinnell SG, Langreck C, Pekarskaya EA, Le Rouzic V, et al. 7-Hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects. ACS Cent Sci. (2019) 5:992–1001. doi: 10.1021/acscentsci.9b00141
23. Sinou V, Fiot J, Taudon N, Mosnier J, Martelloni M, Bun SS, et al. High-performance liquid chromatographic method for the quantification of Mitragyna inermis alkaloids in order to perform pharmacokinetic studies. J Sep Sci. (2010) 33:1863–9. doi: 10.1002/jssc.201000008
24. Flores-Bocanegra L, Raja HA, Graf TN, Augustinović M, Wallace ED, Hematian S, et al. The chemistry of kratom [Mitragyna speciosa]: Updated characterization data and methods to elucidate indole and oxindole alkaloids. J Nat Prod. (2020) 83:2165–77. doi: 10.1021/acs.jnatprod.0c00257
25. Zhou JY, Mo ZX, Zhou SW. Rhynchophylline down-regulates NR2B expression in cortex and hippocampal CA1 area of amphetamine-induced conditioned place preference rat. Arch Pharm Res. (2010) 33:557–65. doi: 10.1007/s12272-010-0410-3
26. Shao H, Yang Y, Mi Z, Zhu GX, Qi AP, Ji WG, et al. Anticonvulsant effect of Rhynchophylline involved in the inhibition of persistent sodium current and NMDA receptor current in the pilocarpine rat model of temporal lobe epilepsy. Neuroscience. (2016) 337:355–69. doi: 10.1016/j.neuroscience.2016.09.029
27. Yang Y, Ji WG, Zhu ZR, Wu YL, Zhang ZY, Qu SC. Rhynchophylline suppresses soluble Aβ1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors. Neuropharmacology. (2018) 135:100–12. doi: 10.1016/j.neuropharm.2018.03.007
28. León F, Habib E, Adkins JE, Furr EB, McCurdy CR, Cutler SJ. Phytochemical characterization of the leaves of Mitragyna speciosa grown in U.S.A. Nat Prod Commun. (2009) 4:907–10.
29. Matsumoto K, Mizowaki M, Takayama H, Sakai S, Aimi N, Watanabe H. Suppressive effect of mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head-twitch response in mice. Pharmacol Biochem Behav. (1997) 57:319–23. doi: 10.1016/s0091-3057(96)00314-0
30. Demichel P, Gomond P, Roquebert J. alpha-Adrenoceptor blocking properties of raubasine in pithed rats. Br J Pharmacol. (1982) 77:449–54. doi: 10.1111/j.1476-5381.1982.tb09317.x
31. Roquebert J, Demichel P. Inhibition of the alpha 1 and alpha 2-adrenoceptor-mediated pressor response in pithed rats by raubasine, tetrahydroalstonine and akuammigine. Eur J Pharmacol. (1984) 106:203–5. doi: 10.1016/0014-2999(84)90698-8
32. Roquebert J. Selectivity of raubasine stereoisomers for alpha 1- and alpha 2-adrenoceptors in the rat. Arch Int Pharmacodyn Ther. (1986) 282:252–61
33. Obeng S, Kamble SH, Reeves ME, Restrepo LF, Patel A, Behnke M, et al. Investigation of the adrenergic and opioid binding affinities, metabolic stability, plasma protein binding properties, and functional effects of selected indole-based kratom alkaloids. J Med Chem. (2020) 63:433–9. doi: 10.1021/acs.jmedchem.9b01465
34. Chang-Chien GC, Odonkor CA, Amorapanth P. Is kratom the new 'legal high' on the block?: the case of an emerging opioid receptor agonist with substance abuse potential. Pain Physician. (2017) 20:E195–E198.
35. Johnson LE, Balyan L, Magdalany A, Saeed F, Salinas R, Wallace S, et al. The potential for kratom as an antidepressant and antipsychotic. Yale J Biol Med. (2020) 93:283–9.
36. Váradi A, Marrone GF, Palmer TC, Narayan A, Szabó MR, Le Rouzic V, et al. Mitragynine/Corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2. J Med Chem. (2016) 59:8381–97. doi: 10.1021/acs.jmedchem.6b00748
38. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science. (1973) 179:1011–4. doi: 10.1126/science.179.4077.1011
39. Terenius L. Stereospecific interaction between narcotic analgesics and a synaptic plasm a membrane fraction of rat cerebral cortex. Acta Pharmacol Toxicol. (1973) 32:317–20. doi: 10.1111/j.1600-0773.1973.tb01477.x
40. Zhou Y, Ramsey S, Provasi D, El Daibani A, Appourchaux K, Chakraborty S, et al. Predicted mode of binding to and allosteric modulation of the μ-opioid receptor by kratom's alkaloids with reported antinociception in vivo. Biochemistry. (2020). doi: 10.1021/acs.biochem.0c00658. [Epub ahead of print].
41. Matsumoto K, Mizowaki M, Suchitra T, Takayama H, Sakai S, Aimi N, et al. Antinociceptive action of mitragynine in mice: evidence for the involvement of supraspinal opioid receptors. Life Sci. (1996) 59:1149–55. doi: 10.1016/0024-3205(96)00432-8
42. Matsumoto K, Mizowaki M, Suchitra T, Murakami Y, Takayama H, Sakai S, et al. Central antinociceptive effects of mitragynine in mice: contribution of descending noradrenergic and serotonergic systems. Eur J Pharmacol. (1996) 317:75–81. doi: 10.1016/s0014-2999(96)00714-5
43. Yamamoto LT, Horie S, Takayama H, Aimi N, Sakai S, Yano S, et al. Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa. Gen Pharmacol. (1999) 33:73–81. doi: 10.1016/s0306-3623(98)00265-1
44. Takayama H, Ishikawa H, Kurihara M, Kitajima M, Aimi N, Ponglux D, et al. Studies on the synthesis and opioid agonistic activities of mitragynine-related indole alkaloids: discovery of opioid agonists structurally different from other opioid ligands. J Med Chem. (2002) 45:1949–56. doi: 10.1021/jm010576e
45. Thongpradichote S, Matsumoto K, Tohda M, Takayama H, Aimi N, Sakai S, et al. Identification of opioid receptor subtypes in antinociceptive actions of supraspinally-administered mitragynine in mice. Life Sci. (1998) 62:1371–8. doi: 10.1016/s0024-3205(98)00075-7
46. Warner ML, Kaufman NC, Grundmann O. The pharmacology and toxicology of kratom: from traditional herb to drug of abuse. Int J Legal Med. (2016) 130:127–38. doi: 10.1007/s00414-015-1279-y
47. Wilson LL, Harris HM, Eans SO, Brice-Tutt AC, Cirino TJ, Stacy HM, et al. Lyophilized kratom tea as a therapeutic option for opioid dependence. Drug Alcohol Depend. (2020) 216:108310. doi: 10.1016/j.drugalcdep.2020.108310
48. Wilson LL, Chakraborty S, Eans SO, Cirino TJ, Stacy HM, Simons CA, et al. Kratom alkaloids, natural and semi-synthetic, show less physical dependence and ameliorate opioid withdrawal. Cell Mol Neurobiol. (2021). doi: 10.1007/s10571-020-01034-7. [Epub ahead of print].
49. Veltri C, Grundmann O. Current perspectives on the impact of Kratom use. Subst Abuse Rehabil. (2019) 10:23–31. doi: 10.2147/SAR.S164261
50. Barber S. The Psychoactive Substances Bill 2015. Briefing Paper Number CBP 7334. London: House of Commons Library (2015).
51. Review of the Psychoactive Substances Act 2016 Presented to Parliament pursuant to Section 58 of the Psychoactive Substances Act 2016 November 2018. London: APS Group on behalf of the Controller of Her Majesty's Stationery Office (2018).
52. Kratom Herald. Indonesian Kratom Ban Has Been Moved Up From 2024 To 2022, And This Would Cut Off The Entire Supply Of Kratom In The United States, But There Is Some Hope. (2021). Available online at: https://kratomherald.com/indonesian-kratom-ban-has-been-moved-up-from-2024-to-2022-and-this-would-cut-off-the-entire-supply-of-kratom-in-the-united-states-but-there-is-some-hope/ (accessed on February 24, 2021).
53. Prozialeck WC, Avery BA, Boyer EW, Grundmann O, Henningfield JE, Kruegel AC, et al. Kratom policy: the challenge of balancing therapeutic potential with public safety. Int J Drug Policy. (2019) 70:70–7. doi: 10.1016/j.drugpo.2019.05.003
54. Swogger MT, Walsh Z. Kratom use and mental health: a systematic review. Drug Alcohol Depend. (2018) 183:134–40. doi: 10.1016/j.drugalcdep.2017.10.012
55. Eldridge WB, Foster C, Wyble L. Neonatal abstinence syndrome due to maternal kratom use. Pediatrics. (2018) 142:e20181839. doi: 10.1542/peds.2018-1839
56. Mackay L, Abrahams R. Novel case of maternal and neonatal kratom dependence and withdrawal. Can Fam Physician. (2018) 64:121–2.
57. Chomchai S, Phuditshinnapatra J, Mekavuthikul P, Chomchai C. Effects of unconventional recreational drug use in pregnancy. Semin Fetal Neonatal Med. (2019) 24:142–8. doi: 10.1016/j.siny.2019.01.010
58. Davidson L, Rawat M, Stojanovski S, Chandrasekharan P. Natural drugs, not so natural effects: Neonatal abstinence syndrome secondary to 'kratom'. J Neonatal Perinatal Med. (2019) 12:109–12. doi: 10.3233/NPM-1863
59. Murthy P, Clark D. An unusual cause for neonatal abstinence syndrome. Paediatr Child Health. (2019) 24:12–4. doi: 10.1093/pch/pxy084
60. White CM. Pharmacologic and clinical assessment of kratom: An update. Am J Health Syst Pharm. (2019) 76:1915–25. doi: 10.1093/ajhp/zxz221
61. Bin Abdullah MFIL. Kratom dependence and treatment options: a comprehensive review of the literature. Curr Drug Targets. (2020) 21:1566–79. doi: 10.2174/1389450121666200719011653
62. Guddat S, Görgens C, Steinhart V, Schänzer W, Thevis M. Mitragynine (Kratom) - monitoring in sports drug testing. Drug Test Anal. (2016) 8:1114–8. doi: 10.1002/dta.1970
63. Nacca N, Schult RF, Li L, Spink DC, Ginsberg G, Navarette K, et al. Kratom adulterated with phenylethylamine and associated intracerebral hemorrhage: Linking toxicologists and public health officials to identify dangerous adulterants. J Med Toxicol. (2020) 16:71–4. doi: 10.1007/s13181-019-00741-y
64. Davidson C, Cao D, King T, Weiss ST, Wongvisavakorn S, Ratprasert N, et al. A comparative analysis of kratom exposure cases in Thailand and the United States from 2010-2017. Am J Drug Alcohol Abuse. (2020) 24:1–10. doi: 10.1080/00952990.2020.1836185
65. Babu KM, McCurdy CR, Boyer EW. Opioid receptors and legal highs: Salvia divinorum and Kratom. Clin Toxicol. (2008) 46:146–52. doi: 10.1080/15563650701241795
66. Burillo-Putze G, López Briz E, Climent Díaz B, Munné Mas P, Nogue Xarau S, Pinillos MA, et al. Drogas emergentes (III): plantas y hongos alucinógenos [Emergent drugs (III): hallucinogenic plants and mushrooms–Spanish]. An Sist Sanit Navar. (2013) 36:505–18. doi: 10.4321/s1137-66272013000300015
67. Gandhi D, Ahuja K, Quade A, Batts KP, Patel L. Kratom induced severe cholestatic liver injury histologically mimicking primary biliary cholangitis: A case report. World J Hepatol. (2020) 12:863–9. doi: 10.4254/wjh.v12.i10.863
68. Singh D, Narayanan S, Grundmann O, Dzulkapli EB, Vicknasingam B. Effects of kratom (Mitragyna speciosa Korth.) use in regular users. Subst Use Misuse. (2019) 54:2284–9. doi: 10.1080/10826084.2019.1645178
69. Boyer EW, Babu KM, Adkins JE, McCurdy CR, Halpern JH. Self-treatment of opioid withdrawal using kratom (Mitragynia speciosa Korth). Addiction. (2008) 103:1048–50. doi: 10.1111/j.1360-0443.2008.02209.x
70. Smith KE, Lawson T. Prevalence and motivations for kratom use in a sample of substance users enrolled in a residential treatment program. Drug Alcohol Depend. (2017) 180:340–8. doi: 10.1016/j.drugalcdep.2017.08.034
71. Ismail I, Wahab S, Sidi H, Das S, Lin LJ, Razali R. Kratom and future treatment for the opioid addiction and chronic pain: Periculo beneficium? Curr Drug Targets. (2019) 20:166–72. doi: 10.2174/1389450118666170425154120
72. Singh D, Narayanan S, Müller CP, Swogger MT, Rahim AA, Leong Bin Abdullah MFI, et al. Severity of kratom (Mitragyna speciosa Korth.) psychological withdrawal symptoms. J Psychoactive Drugs. (2018) 50:445–0. doi: 10.1080/02791072.2018.1511879
73. Singh D, Narayanan S, Vicknasingam BK, Prozialeck WC, Ramanathan S, Zainal H, et al. Severity of pain and sleep problems during Kratom (Mitragyna speciosa Korth.) cessation among regular kratom users. J Psychoactive Drugs. (2018) 50:266–74. doi: 10.1080/02791072.2018.1443234
74. Halpenny GM. Mitragyna speciosa: Balancing potential medical benefits and abuse. ACS Med Chem Lett. (2017) 8:897–9. doi: 10.1021/acsmedchemlett.7b00298
75. Saingam D, Assanangkornchai S, Geater AF, Lerkiatbundit S. Factor analytical investigation of Krathom (Mitragyna speciosa Korth.) withdrawal syndrome in Thailand. J Psychoactive Drugs. (2016) 48:76–85. doi: 10.1080/02791072.2016.1156791
76. Nelsen JL, Lapoint J, Hodgman MJ, Aldous KM. Seizure and coma following Kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol. (2010) 6:424–6. doi: 10.1007/s13181-010-0079-5
77. Tatum WO, Hasan TF, Coonan EE, Smelick CP. Recurrent seizures from chronic kratom use, an atypical herbal opioid. Epilepsy Behav Case Rep. (2018) 10:18–20. doi: 10.1016/j.ebcr.2018.04.002
78. Afzal H, Esang M, Rahman S. A case of kratom-induced seizures. Cureus. (2020) 12:e6588. doi: 10.7759/cureus.6588
79. Palasamudram Shekar S, Rojas EE, D'Angelo CC, Gillenwater SR, Martinez Galvis NP. Legally lethal kratom: a herbal supplement with overdose potential. J Psychoactive Drugs. (2019) 51:28–30. doi: 10.1080/02791072.2018.1562591
80. Overbeek DL, Abraham J, Munzer BW. Kratom (Mitragynine) ingestion requiring naloxone reversal. Clin Pract Cases Emerg Med. (2019) 3:24–6. doi: 10.5811/cpcem.2018.11.40588
81. Zuberi M, Guru PK, Bansal V, Diaz-Gomez J, Grieninger B, Alejos D. Undifferentiated shock and extreme elevation of procalcitonin related to kratom use. Indian J Crit Care Med. (2019) 23:239–41. doi: 10.5005/jp-journals-10071-23170
82. Abdullah HMA, Haq I, Lamfers R. Cardiac arrest in a young healthy male patient secondary to kratom ingestion: is this 'legal high' substance more dangerous than initially thought? BMJ Case Rep. (2019) 12:e229778. doi: 10.1136/bcr-2019-229778
83. Singh V, Mulla N, Wilson JL, Umansky A, Lee J, Stead T, et al. Intractable nausea and vomiting in naïve ingestion of kratom for analgesia. Int J Emerg Med. (2020) 13:42. doi: 10.1186/s12245-020-00301-0
84. Holler JM, Vorce SP, McDonough-Bender PC, Magluilo JJr, Solomon CJ, Levine B. A drug toxicity death involving propylhexedrine and mitragynine. J Anal Toxicol. (2011) 35:54–9. doi: 10.1093/anatox/35.1.54
85. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. J Anal Toxicol. (2011) 35:242–7. doi: 10.1093/anatox/35.4.242
86. Neerman MF, Frost RE, Deking J. A drug fatality involving Kratom. J Forensic Sci. (2013) 58(Suppl 1):S278–S279. doi: 10.1111/1556-4029.12009
87. Karinen R, Fosen JT, Rogde S, Vindenes V. An accidental poisoning with mitragynine. Forensic Sci Int. (2014) 245:e29–32. doi: 10.1016/j.forsciint.2014.10.025
88. McIntyre IM, Trochta A, Stolberg S, Campman SC. Mitragynine 'Kratom' related fatality: a case report with postmortem concentrations. J Anal Toxicol. (2015) 39:152–5. doi: 10.1093/jat/bku137
89. Domingo O, Roider G, Stöver A, Graw M, Musshoff F, Sachs H, et al. Mitragynine concentrations in two fatalities. Forensic Sci Int. (2017) 271:e1–e7. doi: 10.1016/j.forsciint.2016.12.020
90. Mitchell-Mata C, Thomas B, Peterson B, Couper F. Two fatal intoxications involving 3-methoxyphencyclidine. J Anal Toxicol. (2017) 41:503–7. doi: 10.1093/jat/bkx048
91. Aggarwal G, Robertson E, McKinlay J, Walter E. Death from Kratom toxicity and the possible role of intralipid. J Intensive Care Soc. (2018) 19:61–3. doi: 10.1177/1751143717712652
92. Wang C, Walker AE. Fatal mitragynine-associated toxicity in Canada: A case report and review of the literature. Acad Forensic Pathol. (2018) 8:340–6. doi: 10.1177/1925362118782076
93. Matson M, Schenk N. Fatality of 33-year-old man involving kratom toxicity. J Forensic Sci. (2019) 64:1933–5. doi: 10.1111/1556-4029.14082
94. Stanciu CN, Gnanasegaram SA, Ahmed S, Penders T. Kratom withdrawal: A systematic review with case series. J Psychoactive Drugs. (2019) 51:12–8. doi: 10.1080/02791072.2018.1562133
95. McWhirter L, Morris S. A case report of inpatient detoxification after kratom (Mitragyna speciosa) dependence. Eur Addict Res. (2010) 16:229–31. doi: 10.1159/000320288
96. Galbis-Reig D. A case report of kratom addiction and withdrawal. WMJ. (2016) 115:49–52. quiz 53.
97. Diep J, Chin DT, Gupta S, Syed F, Xiong M, Cheng J. Kratom, an emerging drug of abuse: a case report of overdose and management of withdrawal. A A Pract. (2018) 10:192–4. doi: 10.1213/XAA.0000000000000658
98. Buresh M. Treatment of kratom dependence with buprenorphine-naloxone maintenance. J Addict Med. (2018) 12:481–3. doi: 10.1097/ADM.0000000000000428
99. Schmuhl KK, Gardner SM, Cottrill CB, Bonny AE. Home induction and outpatient treatment of kratom use disorder with buprenorphine-naloxone: A case report in a young adult. Subst Abus. (2020) 41:311–4. doi: 10.1080/08897077.2019.1671945
100. Bowe A, Kerr PL. A complex case of kratom dependence, depression, and chronic pain in opioid use disorder: effects of buprenorphine in clinical management. J Psychoactive Drugs. (2020) 17:1–6. doi: 10.1080/02791072.2020.1773586
101. Müller E, Hillemacher T, Müller CP. Kratom instrumentalization for severe pain self-treatment resulting in addiction - A case report of acute and chronic subjective effects. Heliyon. (2020) 6:e04507. doi: 10.1016/j.heliyon.2020.e04507
102. Sablaban IM, Gautam M. The diagnosis of severe obsessions in the setting of kratom withdrawal and treatment with lorazepam: case report. J Addict Dis. (2020) 12:1–2. doi: 10.1080/10550887.2020.1813357
103. Kapp FG, Maurer HH, Auwärter V, Winkelmann M, Hermanns-Clausen M. Intrahepatic cholestasis following abuse of powdered kratom (Mitragyna speciosa). J Med Toxicol. (2011) 7:227–31. doi: 10.1007/s13181-011-0155-5
104. Dorman C, Wong M, Khan A. Cholestatic hepatitis from prolonged kratom use: a case report. Hepatology. (2015) 61:1086–7. doi: 10.1002/hep.27612
105. Drago JZ, Lane B, Kochav J, Chabner B. The harm in kratom. Oncologist. (2017) 22:1010–1. doi: 10.1634/theoncologist.2017-0279
106. Riverso M, Chang M, Soldevila-Pico C, Lai J, Liu X. Histologic characterization of kratom use-associated liver injury. Gastroenterology Res. (2018) 11:79–82. doi: 10.14740/gr990e
107. Osborne CS, Overstreet AN, Rockey DC, Schreiner AD. Drug-induced liver injury caused by kratom use as an alternative pain treatment amid an ongoing opioid epidemic. J Investig Med High Impact Case Rep. (2019) 7:2324709619826167. doi: 10.1177/2324709619826167
108. Fernandes CT, Iqbal U, Tighe SP, Ahmed A. Kratom-induced cholestatic liver injury and its conservative management. J Investig Med High Impact Case Rep. (2019) 7:2324709619836138. doi: 10.1177/2324709619836138
109. Aldyab M, Ells PF, Bui R, Chapman TD, Lee H. Kratom-induced cholestatic liver injury mimicking anti-mitochondrial antibody-negative primary biliary cholangitis: a case report and review of literature. Gastroenterology Res. (2019) 12:211–5. doi: 10.14740/gr1204
110. Antony A, Lee TP. Herb-induced liver injury with cholestasis and renal injury secondary to short-term use of kratom (Mitragyna speciosa). Am J Ther. (2019) 26:e546–e547. doi: 10.1097/MJT.0000000000000802
111. Griffiths CL, Gandhi N, Olin JL. Possible kratom-induced hepatomegaly: a case report. J Am Pharm Assoc (2003). (2018) 58:561–3. doi: 10.1016/j.japh.2018.05.006
112. Mousa MS, Sephien A, Gutierrez J, O'Leary C. N-acetylcysteine for acute hepatitis induced by kratom herbal tea. Am J Ther. (2018) 25:e550–e551. doi: 10.1097/MJT.0000000000000631
113. Tanna RS, Tian DD, Cech NB, Oberlies NH, Rettie AE, Thummel KE, et al. Refined prediction of pharmacokinetic kratom-drug interactions: time-dependent inhibition considerations. J Pharmacol Exp Ther. (2020) 376:64–73. doi: 10.1124/jpet.120.000270
114. Kamble SH, Sharma A, King TI, Berthold EC, León F, Meyer PKL, et al. Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids. Toxicol Lett. (2020) 319:148–54. doi: 10.1016/j.toxlet.2019.11.005
115. Hughes RL. Fatal combination of mitragynine and quetiapine - a case report with discussion of a potential herb-drug interaction. Forensic Sci Med Pathol. (2019) 15:110–3. doi: 10.1007/s12024-018-0049-9
116. Schimmel J, Dart RC. Kratom (Mitragyna Speciosa) liver injury: a comprehensive review. Drugs. (2020) 80:263–83. doi: 10.1007/s40265-019-01242-6
117. Philipp AA, Meyer MR, Wissenbach DK, Weber AA, Zoerntlein SW, Zweipfenning PG, et al. Monitoring of kratom or Krypton intake in urine using GC-MS in clinical and forensic toxicology. Anal Bioanal Chem. (2011) 400:127–35. doi: 10.1007/s00216-010-4464-3
118. Parthasarathy S, Ramanathan S, Murugaiyah V, Hamdan MR, Said MI, Lai CS, et al. A simple HPLC-DAD method for the detection and quantification of psychotropic mitragynine in Mitragyna speciosa (ketum) and its products for the application in forensic investigation. Forensic Sci Int. (2013) 226:183–7. doi: 10.1016/j.forsciint.2013.01.014
119. Henningfield JE, Grundmann O, Babin JK, Fant RV, Wang DW, Cone EJ. Risk of death associated with kratom use compared to opioids. Prev Med. (2019) 128:105851. doi: 10.1016/j.ypmed.2019.105851
120. Schimmel J, Amioka E, Rockhill K, Haynes CM, Black JC, Dart RC, et al. Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study. Addiction. (2021) 116:176–81. doi: 10.1111/add.15082
121. Grundmann O, Babin JK, Henningfield JE, Garcia-Romeu A, Kruegel AC, Prozialeck WC, et al. Kratom use in the United States: a diverse and complex profile. Addiction. (2021) 116:202–3. doi: 10.1111/add.15173
122. Schimmel J, Amioka E, Rockhill K, Haynes CM, Black JC, Dart RC, et al. Kratom use in the United States: Response to Grundmann et al. Addiction. (2021) 116:203–4. doi: 10.1111/add.15170
123. Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS. Kratom use and toxicities in the United States. Pharmacotherapy. (2019) 39:775–7. doi: 10.1002/phar.2280
124. Todd KG, McManus DJ, Baker GB. Chronic administration of the antidepressants phenelzine, desipramine, clomipramine, or maprotiline decreases binding to 5-hydroxytryptamine2A receptors without affecting benzodiazepine binding sites in rat brain. Cell Mol Neurobiol. (1995) 15:361–70. doi: 10.1007/BF02089946
125. Attar-Lévy D, Martinot J-L, Blin J, Dao-Castellana M-H, Crouzel C, Mazoyer B, et al. The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine. Biol Psychiatry. (1999) 45:180–6. doi: 10.1016/s0006-3223(98)00007-9
126. Kostadinov ID, Delev DP, Kostadinova II. Antinociceptive effect of clomipramine through interaction with serotonin 5-HT2 and 5-HT3 receptor subtypes. Folia Med (Plovdiv). (2012) 54:69–77. doi: 10.2478/v10153-012-0008-2
127. Carydakis C, Bourhim N, Giraud P, Cantau P, Oliver C, Castanas E. Les antidépresseurs tricycliques interagissent directement avec les sites de liaison opiacés dans la médullosurrénale bovine [Direct interaction of tricyclic antidepressants with opiate binding sites in the bovine adrenal medulla–French]. C R Acad Sci III. (1986) 302:419–22.
128. Benkelfat C, Aulakh CS, Bykov V, Rice KC, De Costa BR, Rothman RB. Apparent down-regulation of rat brain mu- and kappa-opioid binding sites labelled with [3H]cycloFOXY following chronic administration of the potent 5-hydroxytryptamine reuptake blocker, clomipramine. J Pharm Pharmacol. (1989) 41:865–7. doi: 10.1111/j.2042-7158.1989.tb06390.x
Keywords: kratom, mitragynine, substance use disorder, clomipramine, withdrawal syndrome
Citation: Vento AE, de Persis S, De Filippis S, Schifano F, Napoletano F, Corkery JM and Kotzalidis GD (2021) Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant. Front. Psychiatry 12:640218. doi: 10.3389/fpsyt.2021.640218
Received: 10 December 2020; Accepted: 05 March 2021;
Published: 31 March 2021.
Edited by:
Liana Fattore, National Research Council (CNR), ItalyReviewed by:
Oliver Grundmann, University of Florida, United StatesWalter Prozialeck, Midwestern University, United States
Susruta Majumdar, St. Louis College of Pharmacy, United States
Copyright © 2021 Vento, de Persis, De Filippis, Schifano, Napoletano, Corkery and Kotzalidis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Georgios D. Kotzalidis, giorgio.kotzalidis@uniroma1.it