What Does Kratom Do To Your Blood Pressure?

What are the cardiovascular effects of kratom?

Conclusion: Previously reported adverse cardiovascular events from Kratom use include tachycardia, hypertension, chest pain, conduction defects, QTc prolongation as well as cardiac arrest.

Does kratom cause liver damage?

Kratom is popular for its psychotropic and opioid-like activity. In addition to its addictive potential, kratom has been shown to cause acute liver injury and, in a rare case, acute liver failure resulting in the need for liver transplantation. Kratom has become increasingly available in western countries.

Can kratom cause irregular heartbeat?

Discussion – Our literature review aimed to provide a comprehensive and timely description of kratom use’s adverse cardiovascular effects and cardiotoxicity risk. Based on our findings, we summarize a few salient features of the adverse cardiovascular effects and cardiotoxicity related to kratom use.

1. First, the most common acute adverse cardiovascular effects of kratom consumption were tachycardia and hypertension.
2. Second, in the context of kratom’s effects on cardiac rhythm, a few in vitro studies reported that mitragynine—the most abundant psychoactive alkaloid in the kratom leaf—could induce prolonged QTc intervals and precipitate the risk of torsades de pointes in a dose-dependent manner.

A few case reports also speculatively suggested that kratom consumption may have induced ventricular arrhythmia, particularly ventricular tachycardia and fibrillation, resulting in cardiopulmonary arrest. However, the findings of a recent study demonstrated that regular kratom consumption (the ingestion of a brewed kratom decoction) appeared to increase QTc intervals but did not induce a prolonged QTc interval or torsades de pointes ( Leong Abdullah et al., 2021 ).

1. Similarly, data from the national poison data system and autopsy reports of mortality cases indicated that conduction defects and cardiac arrhythmia were, indeed, rare.
2. Third, autopsy and coroner reports of deaths related to kratom use recorded a few cardiac pathologies related to myocardial ischemia, such as coronary atherosclerosis, focal band necrosis in the myocardium, and hypertensive cardiovascular disease.

However, a study of ECG findings by Leong Abdullah et al. (2021) proved that myocardial ischemia (T-wave inversion) did not occur differently among kratom users versus the control group. Fourth, concerning the risk of heart failure related to kratom use, autopsy and coroner reports of fatalities noted a few related cardiac pathologies, including left ventricular hypertrophy, cardiomegaly, and cardiomyopathy.

Again, however, no significant differences were observed in the occurrence of left ventricular hypertrophy between kratom users and a control group ( Leong Abdullah et al., 2021 ). Moreover, case reports did not indicate any features of heart failure related to kratom use. Fifth, the risk of cardiotoxicity may increase with the co-administration of kratom alongside other substances.

The mechanism underlying this finding may result from mitragynine’s role as a hepatic cytochrome P450 2D6 (CYP2D6) inhibitor that suppresses the metabolism of co-administered substances and increases their cardiotoxicity risk ( Kong et al., 2011 ; Hanapi et al., 2013 ).

1. Polymorphism of the CYP2D6 enzyme isoform categorized kratom users into a few sub-populations, such as ultra-rapid, extensive, intermediate, and poor metabolizers.
2. Interestingly, co-administered substances that are also competitive CYP2D6 inhibitors of mitragynine could functionally convert kratom users who are extensive metabolizers to the poor metabolizers category via phenocopying ( Bernard et al., 2006 ).

Finally, no animal studies have been conducted to investigate kratom’s effects on cardiovascular function. Animal studies are vital for assessment of toxicity related to a particular drug or compound. Animal studies allow the estimation of the lethal dose (LD 50 ) related to cardiotoxicity of kratom or its pharmacoactive alkaloids, such as mitragynine or 7-HMG.

However, importantly, these findings should be interpreted with caution due to several limitations in these studies. First, human studies that have investigated the effects of kratom consumption on cardiac functioning and cardiotoxicity have been lacking—except for a cross-sectional study of ECG findings that was limited by its small sample size and lack of serum mitragynine concentration assessments among kratom users ( Leong Abdullah et al., 2021 ).

Furthermore, the findings of in vitro studies on cardiotoxicity should not be exclusively extrapolated to represent cardiotoxicity risk in humans. Second, despite a few case reports suggesting cardiotoxicity related to kratom use, the patients described in these case reports had either co-administered kratom with other substances ( Aggarwal et al., 2018 ; Sheikh et al., 2021 ) or had a long, established history of polysubstance use that may have led them to co-administer kratom with other illicit substances ( Abdullah et al., 2019 ; Eljack et al., 2020 ).

Unfortunately, these case reports did not assess patients’ serum mitragynine levels. Third, although a few studies investigating national poisoning data, coroner reports, and autopsy reports suspected cardiotoxicity linked to multiple kratom-induced outcomes, a significant number of these cases had involved polysubstance use.

Moreover, whether the described pathologies were caused by kratom use per se or had been partially compounded by underlying medical disorders is unclear. Another vital concern among kratom researchers pertains to the validity of published data since cases have been self-reported, without verification by a poison center, and these data’s hierarchy of evidence was not sufficiently reliable because most of these data had been obtained from case reports and descriptive studies ( Corkery et al., 2019 ; Post et al., 2019 ; Davidson et al., 2021 ).

Despite these limitations, the data we examined in this literature review have allowed us to offer a few recommendations for future research. Despite the lack of related studies using a rigorous methodology, our findings suggest that chronic, regular kratom consumption may affect the cardiac rhythm and be associated with a risk of myocardial ischemia.

Given the gap in the related research and kratom’s still unknown safety profile, more rigorous human studies with sufficiently large samples of respondents are urgently needed. Moreover, these studies should examine serum cardiac markers, echocardiograms, Holter monitoring, serum mitragynine levels, and serum 7-hydroxymitragynine levels in order to fully understand the potential cardiotoxicity risk of kratom use.

Animal studies should, perhaps, also be conducted to determine the mechanisms underlying kratom use’s effects on cardiovascular function. Additionally, since in vitro studies have suggested that the upregulation of the hERG1a-Hsp90 complexes may be due to a mitragynine-induced hERG1a channel misfolding ( Tay et al., 2019 ), a human study investigating whether kratom consumption activates the UPR and ERAD system would be interesting, potentially indicating kratom-induced endoplasmic reticulum stress.

Finally, future case reports can be more informative than previous reports by including an assessment of serum mitragynine levels and, in the case of polysubstance use, the serum levels of other co-administered substances. Thus, we cannot offer a definitive conclusion about kratom’s cardiotoxicity due to the lack of data and methodological limitations reported in existing studies.

1. Nonetheless, our review offers two notable contributions to the literature.
2. First, kratom’s most common adverse cardiovascular effects include tachycardia and hypertension.
3. And second, kratom use may affect the cardiac rhythm in a dose-dependent manner.
4. Therefore, a kratom overdose or the concurrent use of kratom with other illicit substances or medications that affect the cardiac rhythm (e.g., antiarrhythmics, antipsychotics, calcium channel blockers, beta-blockers, and antidepressants) may lead to cardiac arrhythmia.

Moreover, the psychoactive alkaloids in kratom’s chemical profile remain poorly understood. Therefore, the question of whether kratom use can cause a cardiotoxicity risk merits further investigation.

Does kratom cause memory loss?

Brain swelling – Large amounts of kratom have also been associated with brain swelling and encephalopathy. Permanent brain damage can occur as a result of the swelling, which can cause paralysis, poor functioning, and memory loss.

Does kratom decrease serotonin?

Abstract – Introduction: Kratom, an unregulated herbal supplement, has emerged as self-treatment for anxiety/depression. Kratom exhibits inhibition at multiple cytochrome P450 isozymes involved in metabolism of prescription medications, including serotonergic agents.

1. We report a case of possible serotonin syndrome induced by kratom use in combination with prescription psychotropic medications.
2. Case: A 63-year-old male presented with diaphoresis, flushing, aphasia, confusion, dysarthria, right facial droop, and oral temperature of 39.6 o C (103.2 o F), lactate 2.7 mmol/L, and creatine phosphokinase of 1507 IU/L.

Initial differential diagnoses included acute ischemic stroke and bacterial meningitis. Despite partial treatment with alteplase and broad-spectrum antibiotics, symptoms persisted, and subsequent physical exam noted hyperreflexia, clonus, tremors, and temperature of 41.1 o C (106 o F).

Home medications included a chronic regimen for anxiety/depression with bupropion, buspirone, desvenlafaxine, trazodone, and ziprasidone, in addition to kratom. Clinical suspicion for serotonin syndrome led to initiation of cyproheptadine, lorazepam, and cooling blankets. Aphasia, facial droop, and confusion improved after administration of cyproheptadine.

Bupropion was restarted during hospitalization; remaining medications restarted at the discretion of the primary care provider. Discussion: Risk of serotonin syndrome with multiple serotonergic agents is well-known. Kratom is metabolized by cytochrome P40 isozymes 3A4, 2C9, and 2D6, and exhibits inhibition at those enzymes, in addition to 1A2.

Pharmacokinetic interactions of kratom with prescription serotonergic agents metabolized through these isozymes has the potential to increase systemic exposure of serotonin, potentially leading to serotonin syndrome. Conclusion: Because substances contained in kratom can inhibit metabolism of prescription serotonergic medications, clinicians must be aware of potential development of serotonin syndrome.

Keywords: kratom; mitragynine; serotonin syndrome.

Does kratom act on dopamine?

Kratom has been shown to bind to dopamine D2 receptors (Boyer et al., 2008) while also binding at low affinity to D1 receptors (Stolt et al., 2014). Repeated administration of MG has been shown to decrease D2 and increase DAT sites in the mesencephalon, which houses the VTA, but not in the NAc (Yusoff et al., 2014).

What drug is most toxic to liver?

Acetaminophen. Taking acetaminophen in excess is the leading cause of drug-induced liver injury.

Does kratom lower testosterone?

Assessment of gonadotropins and testosterone hormone levels in regular Mitragyna speciosa (Korth.) users, 15 July 2018, Pages 30-36 Kratom ( Mitragyna speciosa Korth.) Havil. (family Rubiaceae) is an indigenous medicinal plant of Southeast Asia (Singh et al., 2016).

• Mitragynine as the dominant alkaloid of M.speciosa is reported to have opioid-like activity (Kruegel and Grundmann, 2017).
• Ratom leaves can be freshly chewed or ingested as an herbal solution.
• Ratom has dose-dependent stimulant and sedative effects.
• Historically, despite it being regulated in Malaysia, kratom is still widely used in traditional context in Malaysia and Thailand as a folk remedy, stimulant drug for enhancing work performances and substitute for illicit opiates (Suwanlert, 1975, Vicknasingam et al., 2010, Singh et al., 2016).

Kratom has received significant attention recently in the West, when incidents related to the adverse effects of kratom use were highlighted by regulatory agencies like the U.S Drug Enforcement Administration (DEA), and the U.S Centers for Disease Control and Prevention (CDC) (Anwar et al., 2016).

In the West, kratom extracts are being used as supplements in self-managing chronic pain, opiate dependence and psychological problems (Grundmann, 2017). Sexual and reproductive function is an important aspect of quality of life which is often disrupted by acute and chronic opioid use (Bawor et al., 2015).

Regular opioid use induces androgen deficiency and hypogonadism with prevalence of 21–86% (Reddy et al., 2010, Mendelson et al., 1984, Woody et al., 1988, Bawor et al., 2015), and is more common in men than in women (Fraser et al., 2009). Through action on the opioid receptors in the hypothalamus (Vuong et al., 2010), opioids suppress the hypothalamic-pituitary-gonadal axis (Katz and Mazer, 2009), and disrupt the secretion of gonadotropin releasing hormone (GnRH), luteinising hormone (LH) and follicle stimulating hormone (FSH) (Reddy et al., 2010, Rajagopal et al., 2003, Schug et al., 1992, Haddox et al., 1997, Smith and Elliott, 2012).

Free testosterone concentration is also suppressed and leads to reproductive health problems and decline in sexual libido and function (Azizi et al., 1973, Daniell, 2002). Morphine use, for example, induces a long-lasting decrease in testosterone (Aloisi et al., 2005), and hypogonadism may persist for months or years, even after cessation of opioid treatment (Birthi et al., 2015).

Opioids affect the testes and can decrease sperm production, testicular interstitial fluid and intratesticular testosterone (Ragni et al., 1988). Besides sexual dysfunction, disruptions to testosterone concentrations caused by opioids also affect mood, stress reactivity and elevate aggression (Smith and Elliott, 2012, Borjesson et al., 2011, Kosten and Ambrosio, 2002).

Failure to treat hypogonadism in opioid users can lead to erectile dysfunction, impotence, loss of muscle mass in men, infertility, osteopenia, osteoporosis, depression, emotional disturbance, fatigue, impaired glucose tolerance, dyslipidemia and reduced quality of life (Colameco and Coren, 2009, Yeap et al., 2009, Kravitaki and Wass, 2010, Vestergaard et al., 2006, Hedley, 2004).

Katz and Mazer (2009) caution that chronic opioid use can also disrupt endocrine function that may ultimately be lethal. On the contrary, kratom leaves are consumed in Southeast Asia as an aphrodisiac (Suwanlert, 1975; Vicknasingam et al., 2010; Ahmad and Aziz, 2012).

In Thailand, male users chew fresh kratom leaves to prolong sexual intercourse (Suwanlert, 1975). Vicknasingam et al. (2010) and Ahmad and Aziz (2012) found kratom tea/juice consumption can help users experience heightened sexual desire and better sexual performance. Conversely, Saingam et al. (2012) observed that kratom users normally experience increase in sexual desire in the first 10 years of kratom use.

In fact, most users in that study attributed sexual ability to other factors like general health, age and use of other substances like tobacco. These self-report based descriptive studies suggest that testosterone and sexual function, as well as drive are not diminished by regular kratom use.

Unfortunately, there is no scientific evidence to support the non-testosterone impairing effects of kratom use. Recently, Singh et al. (2018) found regular kratom tea/juice consumption over prolonged periods does not cause significant impairments in the hematological and biochemical parameters of kratom users.

Since Daud et al. (2011) reported that kratom could alter sperm morphology and reduce sperm motility in mice, the aim of this study was to investigate whether chronic kratom tea/juice consumption could impair gonadotrophins and testosterone levels in regular kratom users and risk of hypogonadism similar to chronic opioid use (Bawor et al., 2015).

The study was conducted between October 2016 and December 2016. A total of 19 regular kratom users were recruited through snowball sampling for this cross-sectional study. All the respondents were recruited from the state of Penang, Malaysia where kratom use is reported to be widespread in the community.

The inclusion criteria were; 1) above 18 years of age, and 2) self-reported as a regular kratom user with kratom use history exceeding 2 years. We recruited subjects with long-term kratom use The socio-demographic characteristics and kratom use history are summarized in Table 1.

1. We assessed 19 male kratom users, with 17 of Malay ethnicity (90%, n = 17/19).
2. Mean age was 30.0 years (SD=5.6), and mean age of first kratom use was 22.5 years (SD=6.0).
3. More than half of the respondents were older than 28 years (63%, n = 12/19), and single (58%, n = 11/19).
4. Approximately 90% had completed 11 years of education (n = 17/19) and were employed (n = 17/19).

Mean duration of kratom use was 82.7 To the best of our knowledge, this study is the first to determine if regular kratom tea/juice consumption is associated with testosterone suppression in male kratom users. Kratom has opiate like-effects, while its prolonged use is reported to cause dependence and unpleasant side-effects if taken in higher doses while lower doses of freshly chewed leaves actually cause an acute stimulant effect (Singh et al., 2014, Singh et al., 2016).

Testosterone production is regulated by the In summary, findings showed that regular kratom tea/juice consumption does not affect circulating testosterone, FSH, or LH levels in healthy male adults. We would like to thank all the study subjects who have participated in this study. We would also like to thank Dr.

Sitharthan Naidu (Clinic Tanah Melayu) for his kind assistance in handling all the blood-test procedures, Mr. Azlan Rahim, Mr. Mohd Hafifi Jamri, and Mr. Mohd Eshal for coordinating the field work, and Mrs. Nur Sabrina Mohd Yusof and Nelson Jeng-Yeou Chear for conducting the laboratory analysis.

This work was supported by Higher Institution’s Centre of Excellence (HICoE) grant ( Singh, Murugaiyah and Mansor, designed the study, analysed the study data and wrote the manuscript;,,, Hamid, Balasingam, Chan, Ho and Grundmann revised the manuscript;,, michan_007 @hotmail.com,,, Chear performed the experiments;,

We declared there is no conflict of interest.

K. Ahmad et al. A.M. Aloisi et al. F. Azizi et al. M. Bawor et al. G. Borjesson et al. H.W. Daniell O. Grundmann Y. Ikeda et al. T. Kosten et al. A. Rajagopal et al.

D. Singh et al. D. Singh et al. D. Singh et al. B. Vicknasingam et al. M. Ahow et al. M. Anwar et al. P. Birthi et al. S. Colameco et al. Daud, M.S.M., Mossadeq, W.M.S., Kadir, A.A., Hussein, F.N., 2011. Effect of Short-Term Ingestion of the Methanolic. L. Fraser et al.

Mitragyna speciosa, referred to as “kratom”, is increasingly used in the United States for self-treating pain, psychiatric, and substance use disorder symptoms. It is used by some to attenuate opioid withdrawal and as a longer-term drug substitute. Most self-report data have come from online surveys, small in-person surveys, and case reports. These may not be representative of the broader kratom-using population. Analyze user-generated social media posts to determine if independent, descriptive accounts are generally consistent with prior U.S. kratom survey findings and gain a more nuanced understanding of kratom use patterns. Reddit posts mentioning kratom from 42 subreddits between June 2019–July 2020 were coded by two independent raters. Relevant posts (number of comments, upvotes, and downvotes) from 1274 posts comprised the final sample (n = 280). Of the 1521 codes applied, 1273 (83.69%) were concordant. Desirable kratom effects were described among a majority, but so too were adverse effects. Reports of kratom as acute self-treatment for opioid withdrawal were more prominent compared to longer-term opioid substitution. Quantitative analysis found higher kratom doses associated (p <,001) with greater odds of reported kratom addiction (OR = 3.56) or withdrawal (OR = 5.88), with slightly lower odds of desirable effects (OR = 0.53, p =,014). Despite perceived therapeutic benefits, kratom was characterized by some in terms of addiction that, in some cases, appeared dose-dependent. Polydrug use was also prominently discussed. Results validated many prior survey findings while illustrating complexities of kratom use that are not being fully captured and require continued investigation. Kratom leaves from Mitragyna speciosa (Korth.) trees are believed to have medicinal value, and have a long-history of folk medicine use for self-treatment of a broad range of indications. In Southeast Asia, traditional uses of kratom include as an aphrodisiac and a sexual performance enhancer. The study evaluated sexual functioning in a cohort of long-term male kratom users in the state of Penang, Malaysia. A field face-to-face survey, including the Malay version of the Brief Male Sexual Function Inventory (BMSFI) called Mal-BMSFI was conducted between January and December of 2017. The mean (SD) age of the cohort (N = 92) was 37.0 (11.2) years, and the mean (SD) duration of kratom use was 9.14 (5.5) years. All participants reported consuming kratom decoction, with an average amount of 1200 ml daily. Seventy-two participants (78%) reported using kratom to enhance sexual performance, and 71 of them (71/72, 99%) reported experiencing improved sexual performance. Of those who reported not using kratom to enhance sexual performance, 7/20 (35%) also experienced improved sexual performance after kratom use. The reported enhancements of sexual performance included: more energy during sex (75/92), delayed ejaculation (71/92), help to maintain erection (70/92), longer climax (51/92), increased sexual desire (44/92), and reduced sex organ sensitivity (43/92). The mean (SD) Mal-BMSFI score was 33.9 (7.1) and 78/92 (85%) reported overall high satisfaction with their sex life in the past 30 days. In conclusion long-term daily, male users of kratom decoction in Malaysia reported improved sexual functioning attributed to their kratom consumption. A case of a patient with a history of depression, who was concomitantly using Kratom has been described. Kratom ( Mitragyna speciosa ) is a psychoactive plant indigenous to certain regions of southeast Asia where it has been traditionally used for its stimulatory and analgesic effects. The active compounds in Kratom are mitragynine and 7-hydroxymitragynine. Kratom's use for self-management of chronic pain and as supportive therapy for managing opioid withdrawal is increasing. This case highlights the observation that Kratom use is also prevalent amongst patients with other mental health and/or substance abuse conditions. The discussion explores the current understanding on pharmacology and toxicology of mitragynine and 7-hydroxymitragynine, and analytical methods used for kratom analysis in a toxicology laboratory. Mitragyna speciosa (Korth.) is a traditional medicinal plant widely used in Southeast Asia for its opioid-like effects. Although kratom produces analgesia through binding of mitragynine and other alkaloids at the mu-opioid receptor (MOR), the association of long-term kratom use with adverse opioid-like effects remains unknown. Aim of the study: To determine the self-reported prevalence and severity of opioid-related adverse effects after kratom initiation in a cohort of illicit opioid users. A total of 163 illicit opioid users with current kratom use history were recruited through convenience sampling from the northern states of Peninsular Malaysia. Face-to-face interviews were conducted using a semi-structured questionnaire. Respondents were all males, majority Malays (94%, n = 154/163), with a mean age of 37.10 years (SD = 10.9). Most were single (65%, n = 106/163), had 11 years of education (52%, n = 85/163) and employed (88%, n = 144/163). Half reported using kratom for over >6 years (50%, n = 81/163), and 41% consumed >3 glasses of kratom daily (n = 67/163). Results from Chi-square analysis showed kratom initiation was associated with decreased prevalence of respiratory depression, constipation, physical pain, insomnia, depression, loss of appetite, craving, decreased sexual performance, weight loss and fatigue. Our findings indicate that kratom initiation (approximately 214.29 mg of mitragynine) was associated with significant decreases in the prevalence and severity of opioid adverse effects. The leaves of Mitragyna speciosa (Korth.) or kratom have been traditionally used in Malaysia and Thailand mainly to enhance work productivity, as a folk remedy for treating common ailments, and as a mood enhancer. This present study sought to investigate kratom use motives among regular kratom users in Malaysia. A total of 116 regular kratom users were recruited for this cross-sectional survey. The Drinking Motives Questionnaire (DMQ) was administered to measure kratom use motives. Our results indicate that heavy (>3 glasses daily, each glass contains 48.24–50.4 mg of mitragynine ) kratom use was associated with coping (t 87.09 =3.544, p  < 0.001), and enhancement (t 114 =2.180, p  = 003). Single subjects had higher mean scores on the coping domain, relative to married subject (t 113.89 =3.029, p  < 0.003), while those earning more than RM1500 per month had higher mean scores on the enhancement domain, compare to those earning less than RM1500 per month (t 107 =2.151, p  < 0.034). Higher scores on the co p ing domain was significantly associated with higher (>3 glasses daily) kratom consumption ( p  < 0.0045). Coping was associated with high (>3 glasses daily) kratom consumption among regular kratom users in traditional, rural settings.

Mitragyna speciosa and its extracts are called kratom (dried leaves, extract). They contain several alkaloids with an affinity for different opioid receptors. They are used in traditional medicine for the treatment of different diseases, as a substitute by opiate addicts, and to mitigate opioid withdrawal symptoms. Apart from their medical properties, they are used to enhance physical endurance and as a means of overcoming stress. The aim of this study was to determine the mechanisms underlying the effects of kratom on restraint-stress-induced analgesia which occurs during or following exposure to a stressful or fearful stimulus. To gain further insights into the action of kratom on stress, we conducted experiments using restraint stress as a test system and stress-induced analgesia as a test parameter. Using transgenic mu opioid-receptor (MOR) deficient mice, we studied the involvement of this receptor type. We used nor-binaltorphimine (BNT), an antagonist at kappa opioid receptors (KOR), to study functions of this type of receptor. Membrane potential assay was also employed to measure the intrinsic activity of kratom in comparison to U50,488, a highly selective kappa agonist. Treatment with kratom diminished stress-induced analgesia in wildtype and MOR knockout animals. Pretreatment of MOR deficient mice with BNT resulted in similar effects. In comparison to U50,488, kratom exhibited negligible intrinsic activity at KOR alone. The results suggest that the use of kratom as a pharmacological tool to mitigate withdrawal symptoms is related to its action on KOR. Mitragynine, an indole alkaloid from the plant Mitragyna speciosa (Kratom), has been reported to modify hippocampal synaptic transmission. However, the role of glutamatergic neurotransmission modulating synaptic plasticity in mitragynine-induced synaptic changes is still unknown. Here, we determined the role of AMPA- and NMDA glutamate receptors in mitragynine-induced synaptic plasticity in the hippocampus. Male Sprague Dawley rats received either vehicle or mitragynine (10 mg/kg), with or without the AMPA receptor antagonist, NBQX (3 mg/kg), or the NMDA receptor antagonist, MK-801 (0.2 mg/kg). Field excitatory postsynaptic potentials (fEPSP) during baseline, paired-pulse facilitation (PPF) and long-term potentiation (LTP) were recorded in-vivo in the hippocampal CA1 area of anaesthetised rats. Basal synaptic transmission and LTP were significantly impaired after mitragynine, NBQX, and MK-801 alone, without an effect on PPF. Combined effects suggest a weak functional AMPA- as well as NMDA receptor antagonist action of mitragynine. Mitragyna speciosa (kratom), a Southeast Asian plant belonging to the Mitragyna genus, has a long history of traditional uses. There are several therapeutic properties attributed to kratom such as energy booster, pain reliever, mood enhancer, remedy for various ailments, and management of opiate addiction. In recent years, kratom leaves and derivatized botanical products (e.g., extracts, solutions) are being sold as dietary supplements and marketed worldwide via the internet for the management of pain, anxiety, and depression. Indole and oxindole alkaloids are the major chemical constituents that are most likely implicated in the pharmacological effects of kratom products. In Western countries, other than in Southeast Asia, several issues have been alarming, such as adulteration, substitution, and spiking the plant material with neuropharmacological and illicit substances. This chapter provides a summary of the ethnobotany and alkaloid chemistry of kratom including plant biosynthesis and chemical synthesis of alkaloid molecules. Recent developments in the alkaloid detection methods for kratom profiling and authentication of kratom products are also discussed in this chapter. Additionally, this chapter discusses a compilation of the available information from the literature related to the CNS exposure and interaction of major kratom alkaloids. Kratom ( Mitragyna speciosa ) is a native medicinal plant of Southeast Asia widely reported to be used to reduce opioid dependence and mitigate withdrawal symptoms. There is also evidence to suggest that opioid poly-drug users were using kratom to abstain from opioids. To determine the patterns and reasons for kratom use among current and former opioid poly-drug users in Malaysia. A total of 204 opioid poly-drug users (142 current users vs.62 former users) with current kratom use history were enrolled into this cross-sectional study. A validated UPLC-MS/MS method was used to evaluate the alkaloid content of a kratom street sample. Results from Chi-square analysis showed that there were no significant differences in demographic characteristics between current and former opioid poly-drug users except with respect to marital status. Current users had higher odds of being single (OR: 2.2: 95%CI: 1.21–4.11; p < 0.009). Similarly, there were no significant differences in the duration (OR: 1.1: 0.62–2.03; p < 0.708), daily quantity (OR: 1.5: 0.85–2.82; p < 0.154) or frequency of kratom use between current and former opioid poly-drug users (OR: 1.1: 0.62–2.06; p < 0.680). While both current and former opioid users reported using kratom to ameliorate opioid withdrawal, current users had significantly higher likelihood of using kratom for that purpose (OR: 5.4: 95%CI: 2.81–10.18; p < 0.0001). In contrast, former opioid users were more likely to be using kratom for its euphoric (mood elevating) effects (OR: 1.9: 95%CI: 1.04–3.50; p < 0.035). Results from the UPLC-MS/MS analysis indicated the major alkaloids present in the representative kratom street sample (of approximately 300 mL of brewed kratom) were mitragynine, followed by paynantheine, speciociliatine and speciogynine, as well as low levels of 7-hydroxymitragynine. Both current and former opioid poly-drug users regularly used kratom (three glasses or about 900 mL daily or the equivalent of 170.19 mg of mitragynine ) to overcome opioid poly-drug use problems. : Kratom is a botanical product used as an opium substitute with abuse potential. : Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort. : Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients. : Kratom can cause severe liver injury with jaundice.

: Assessment of gonadotropins and testosterone hormone levels in regular Mitragyna speciosa (Korth.) users

Does kratom affect serotonin and dopamine?

3 Interactions of Kratom Alkaloids With Central Nervous System Receptors – The effects of kratom alkaloids on central nervous system (CNS) receptors have been extensively studied in vitro and in vivo assays. In vitro radioligand binding studies revealed that kratom alkaloids interact with opioid μ, δ, κ subtypes, and non-opioid receptors including alpha-1A, alpha-2A, 5-HT1A, 5-HT2A, D1, and D2 ( Takayama et al., 2002 ; Boyer et al., 2008 ; Kruegel et al., 2016 ; Ellis et al., 2020 ; Obeng et al., 2020 ; Chear et al., 2021 ; Obeng et al., 2021 ).

In vivo studies demonstrated that kratom alkaloids exert central analgesic, anti-anxiety, anti-drug addiction, and antipsychotic effects primarily through activation of central opioidergic, adrenergic, serotoninergic, and dopaminergic neurotransmission systems ( Matsumoto et al., 1996a ; Matsumoto et al., 1996b ; Matsumoto et al., 1997 ; Takayama et al., 2002 ; Hazim et al., 2014 ; Vijeepallam et al., 2016 ; Foss et al., 2020 ; Obeng et al., 2020 ; Chear et al., 2021 ; Obeng et al., 2021 ).

To better understand the CNS pharmacological targets of kratom alkaloids, this section is structured as follows: opioid receptors and non-opioid receptors (adrenergic, serotonin, and dopamine receptors).

Does kratom effect cortisol?

Abstract – Abstract ID 52920 Poster Board 424 Kratom is a tropical evergreen tree indigenous to Southeast Asia whose leaves and decoctions have long been used in traditional folk medicine for the relief of pain and enhancement of vitality. In recent years kratom use has increased in the United States, where an estimated 10-15 million people use the herb for the self-management of pain and opioid withdrawal.

Ratom leaves contain over 40 active alkaloids. Previous studies in our laboratory demonstrated that mitragynine was the only kratom alkaloid that enhanced cortisol secretion in a human adrenocortical cell line. To further investigate the molecular mechanism by which mitragynine enhances cortisol secretion, we examined the effect of mitragynine on the expression of the steroidogenic enzymes and cofactors involved in cortisol production.

HAC15 cells were exposed to vehicle or mitragynine (10 μM). After 72 h, mRNA expression of the following steroidogenic enzymes, cofactors, and receptors was examined: CYP11A1, HSD3B2, CYP21A2, CYP11B1, StAR, FDXR, FDX1, and MC2R. While mRNA expression was upregulated for all of these steroidogenic factors, CYP11B1 was induced to the greatest extent (fold change: vehicle, 1.0±0.2; 10 μM mitragynine, 18.4±1.5; n=6).

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics

Does kratom increase depression?

Kratom is a plant that practitioners of Eastern medicine use to treat various ailments, including depression. While some research suggests that kratom may help relieve some of the symptoms of depression, scientists are not yet sure that it is effective.

It also carries some severe risks that a person should be aware of before using it. Kratom is an herbal extract from an evergreen tree called Mitragyna speciosa, This tree grows in parts of Southeast Asia, including Malaysia and Thailand. The leaves of this tree contain the active ingredient in kratom, which is called mitragynine.

Read on to find out more about kratom’s effectiveness and safety in treating depression, Mitragynine is an alkaloid that works on the opioid receptors. Although it is not technically an opioid, it does have opioid-like effects because of its chemical structure.

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Scientists have not conducted much research on kratom and its effects on mental health, However, a 2017 study on kratom use showed that people who used kratom to self-treat mental health conditions, such as depression and anxiety, reported a perceived reduction in symptoms.

A 2018 review on kratom use and mental health confirmed these findings, showing that some people found that kratom enhanced their mood and reduced anxiety symptoms. The authors noted that kratom has potential as an opioid substitute for people with opioid use disorder. Scientists believe that certain compounds in kratom leaves interact with opioid receptors in the brain.

Depending on how much kratom a person takes, this interaction may result in the following effects:

sedationpleasurelower perception of pain

Mitragynine, one of the active compounds in kratom, also works with other systems in the brain to cause a stimulant effect. At low doses, kratom may act as a mild stimulant, giving users more energy, whereas at moderate doses, it may bring on feelings of euphoria.

However, when a person takes very high doses of kratom, it may have a sedating effect. Although the results of some studies suggest that kratom may have a positive effect on depression and other mood disorders, many scientists believe that the risk of harmful side effects outweighs any possible benefits of taking kratom.

Harmful side effects of kratom may include:

nausea and vomiting dry mouth tongue numbness constipation an uncontrollable urge to urinate

In addition to those harmful effects, kratom may have cognitive side effects, including:

aggression and ragehallucinationsdelusionsrisk of dependency

In large doses, kratom can cause:

difficulty breathingseizuresbrain swellingliver damage and death

The FDA warn consumers not to use kratom because its properties might put them at risk of addiction, If a person becomes addicted to kratom, they may experience unpleasant withdrawal symptoms when they stop taking it. These symptoms can include:

muscle and bone painnauseauncontrollable shaking fatigue mood swingsconfusiondelusionshallucinations

In some people, kratom withdrawal can increase feelings of depression and anxiety, making it difficult for a person to feel any pleasure at all. As the FDA do not regulate kratom, it comes with other risks. Kratom is not subject to regulation, so its products may contain other harmful substances, such as heavy metals, or bacteria, such as Salmonella,

Additionally, a person buying kratom will never know its exact purity and potency. Share on Pinterest Many healthcare professionals recommend exercise as a self-care technique for depression. A person seeking treatment for depression or another mood disorder has many treatment options aside from kratom.

Depression treatments include:

prescription medications, including selective serotonin reuptake inhibitors such as sertraline (Zoloft) cognitive behavioral therapy (CBT)

There are also many self-care techniques that a person can use to relieve the symptoms of depression without risking the harmful side effects of kratom. These self-care methods include:

exercisingspending time outdoors each dayjournalingmeditatinggoing to a support groupeating wellgetting enough sleepmanaging stress

A person living with depression should work with their doctor to create a treatment plan that is effective for them. Kratom comes from the leaves of a tree that grows in Southeast Asia. People often use kratom to self-treat depression and anxiety, but the risks may outweigh any potential benefits.

Does kratom help with mental health?

Kratom also enhances mood and relieves anxiety among many users. For many, kratom’s negative mental health effects – primarily withdrawal symptoms – appear to be mild relative to those of opioids.

What are the long-term cognitive effects of kratom?

(2015) found that 17% of long-term kratom users experienced difficulties in concentration and in recall of past events, while Assanangkornchai et al. (2007) noted that poor thinking ability and impaired memory were among the negative effects associated with long-term kratom use.

How common is seizures with kratom?

Summary – Since 2008, kratom use is rising in prevalence in the United States aided by lack of regulation. Neurologists need to be aware of its association with seizure and other neurologic side effects. Kratom is an herbal supplement derived from the Mitragyna speciosa tree, which is indigenous to Southeast Asia, Malaysia, and the Philippines.

For centuries, kratom has been used recreationally throughout Southeast Asia to enhance productivity and mood. In the mid-twentieth century, it was also used to mitigate opioid withdrawal.1 It is primarily consumed as tea or by chewing whole leaves. In the United States, its primary use has been recreational for euphoric effects and for self-treating the symptoms of opioid withdrawal, 2 as at high doses, kratom has opioid-like effects.3 Kratom is currently legal and available for retail purchase in the United States.

The US Drug Enforcement Administration (DEA) has now listed kratom as a “drug of concern,” as it has been involved in over 150 overdose-related deaths as of 2017.3 Kratom is of interest to the neurologist, given the variety of neurologic adverse effects. There have been reports of agitation, drowsiness, confusion, seizure, tremor, vertigo, hallucinations, coma, ataxia, headache, syncope, slurred speech, and muscle weakness following kratom use.4 There has even been a report of kratom use associated with spontaneous intracranial hemorrhage.5 However, seizures are common and have been reported after single-substance exposure with an incidence of 6.1% 2 to 9.6% 4 in the United States.

In Thailand, seizures have been seen in as high as 17.5% of cases.6 As of 2019, there have been 4 case reports characterizing seizures following kratom use. Of these 4 cases, none had underlying epilepsy or a full neurologic workup. We hypothesize that kratom use is associated with seizure in patients with epilepsy.

We present 3 cases of seizure in patients following kratom use, 2 with preexisting epilepsy and 1 with subsequently diagnosed epilepsy. We believe that US health care providers may not be aware of the neurologic effects of kratom. We will discuss the pharmacology of kratom, its clinical effects, and review the current understanding of the clinical relevance and regulation of kratom use in the United States.

What street drug increases serotonin?

The Difficulty of Studying Serotonin Receptors – Serotonin and the serotonergic system of receptors are widespread in the brain. There are at least 14 different serotonin receptors, which are differentially expressed throughout the central nervous system and elsewhere in the body.

Because many of these receptors have only recently been discovered, selective drugs for studying their function are often unavailable. This makes them hard to study, and not all of them have been well characterized. “There’s a lot left to be learned,” says Parsons. Experimental approaches that broadly activate or block the 14 different receptors can only take scientists so far, because these different receptors are distributed unevenly throughout the brain and affect various neural circuits differentially.

Serotonin-1B receptors, for instance, affect one subset of neural circuits, whereas serotonin-6 receptors affect a completely different subset. Things become complicated quickly since some circuits under the control of a particular receptor contribute to the positive or euphoric effects of drugs, while circuits under the control of another receptor inhibit drug-induced euphoria, or even produce aversion.

There are also regional differences in the serotinergic response to a drug. Cocaine and alcohol both increase the levels of serotonin in the brain, but cocaine does it broadly and potently across many parts of the brain by blocking the reuptake of serotonin. Alcohol, on the other hand, produces much more subtle changes in serotonin in a more regionally selective manner.

And some receptors may interact selectively with some drugs and not others. If you block serotonin-6 receptors, for instance, you greatly increase the reinforcing effects of amphetamines but not cocaine, even though both drugs are in the same class of psychostimulant compounds that increase dopamine.

Further complicating the picture are the differences in how individual serotonin receptors respond to long-term drug use. Even if you consider a single receptor subtype, like the serotonin-1B receptor, there may be different responses in different parts of the brain. For example, during abstinence from extended cocaine use serotonin1B receptors in the nucleus accumbens area of the brain are upregulated, while these receptors are simultaneously downregulated in the ventral tegmental area.

So, different drugs can cause regionally different serotonergic responses, and the subsequent activation of different serotonin receptor subtypes can either enhance or inhibit the pleasurable effects of that drug. What’s more, the balance between these facilitory and inhibitory mechanisms can be altered by long-term drug use.

What does serotonin syndrome feel like?

Serotonin syndrome is a serious drug reaction. It is caused by medications that build up high levels of serotonin in the body. Serotonin is a chemical that the body produces naturally. It’s needed for the nerve cells and brain to function. But too much serotonin causes signs and symptoms that can range from mild (shivering and diarrhea) to severe (muscle rigidity, fever and seizures).

• Severe serotonin syndrome can cause death if not treated.
• Serotonin syndrome can occur when you increase the dose of certain medications or start taking a new drug.
• It’s most often caused by combining medications that contain serotonin, such as a migraine medication and an antidepressant.
• Some illicit drugs and dietary supplements are associated with serotonin syndrome.

Milder forms of serotonin syndrome may go away within a day or two of stopping the medications that cause symptoms and, sometimes, after taking drugs that block serotonin. Serotonin syndrome symptoms usually occur within several hours of taking a new drug or increasing the dose of a drug you’re already taking.

Agitation or restlessness Insomnia Confusion Rapid heart rate and high blood pressure Dilated pupils Loss of muscle coordination or twitching muscles High blood pressure Muscle rigidity Heavy sweating Diarrhea Headache Shivering Goose bumps

Severe serotonin syndrome can be life-threatening. Signs include:

High fever Tremor Seizures Irregular heartbeat Unconsciousness

If you suspect you might have serotonin syndrome after starting a new drug or increasing the dose of a drug you’re already taking, call your health care provider right away or go to the emergency room. If you have severe or rapidly worsening symptoms, seek emergency treatment immediately.

• Excessive accumulation of serotonin in the body creates the symptoms of serotonin syndrome.
• Typically, nerve cells in the brain and spinal cord produce serotonin that helps regulate attention, behavior and body temperature.
• Other nerve cells in the body, primarily in the intestines, also produce serotonin.

Serotonin plays a role in regulating the digestive process, blood flow and breathing. Although it’s possible that taking just one drug that increases serotonin levels can cause serotonin syndrome in some people, this condition occurs most often when people combine certain medications.

For example, serotonin syndrome may occur if you take an antidepressant with a migraine medication. It may also occur if you take an antidepressant with an opioid pain medication. Another cause of serotonin syndrome is intentional overdose of antidepressant medications. A number of over-the-counter and prescription drugs may be associated with serotonin syndrome, especially antidepressants.

Illicit drugs and dietary supplements also may be associated with the condition. The drugs and supplements that could potentially cause serotonin syndrome include:

Selective serotonin reuptake inhibitors (SSRIs), antidepressants such as citalopram (Celexa), fluoxetine (Prozac), fluvoxamine (Luvox), escitalopram (Lexapro), paroxetine (Paxil, Pexeva, Brisdelle) and sertraline (Zoloft) Serotonin and norepinephrine reuptake inhibitors (SNRIs), antidepressants such as desvenlafaxine (Pristiq), levomilnacipran (Fetzima), milnacipran (Savella), duloxetine (Cymbalta, Drizalma Sprinkle) and venlafaxine (Effexor XR) Bupropion (Zyban, Wellbutrin SR, Wellbutrin XL), an antidepressant and tobacco-addiction medication Tricyclic antidepressants, such as amitriptyline and nortriptyline (Pamelor) Monoamine oxidase inhibitors (MAOIs), antidepressants such as isocarboxazid (Marplan) and phenelzine (Nardil) Anti-migraine medications, such as carbamazepine (Tegretol, Carbatrol, others), valproic acid and triptans, which include almotriptan, naratriptan (Amerge) and sumatriptan (Imitrex, Tosymra, others) Pain medications, such as opioid pain medications including codeine, fentanyl (Duragesic, Abstral, others), hydrocodone (Hysingla ER), meperidine (Demerol), oxycodone (Oxycontin, Roxicodone, others) and tramadol (Ultram, ConZip) Lithium (Lithobid), a mood stabilizer Illicit drugs, including LSD, ecstasy, cocaine and amphetamines Herbal supplements, including St. John’s wort, ginseng and nutmeg Over-the-counter cough and cold medications containing dextromethorphan (Delsym) Anti-nausea medications such as granisetron (Sancuso, Sustol), metoclopramide (Reglan), droperidol (Inapsine) and ondansetron (Zofran) Linezolid (Zyvox), an antibiotic Ritonavir (Norvir), an anti-retroviral medication used to treat human immunodeficiency virus (HIV)

Some people are more likely to be affected by the drugs and supplements that cause serotonin syndrome than are others, but the condition can occur in anyone. You’re at increased risk of serotonin syndrome if:

You recently started taking or increased the dose of a medication known to increase serotonin levels You take more than one drug known to increase serotonin levels You take herbal supplements known to increase serotonin levels You use an illicit drug known to increase serotonin levels

Serotonin syndrome generally doesn’t cause any problems once serotonin levels are back to their original levels. If left untreated, severe serotonin syndrome can lead to unconsciousness and death. Taking more than one serotonin-related medication or increasing your dose of a serotonin-related medication increases your risk of serotonin syndrome.

1. Now what medications you take and share a complete list of your medications with your doctor or pharmacist.
2. Be sure to talk to your doctor if you or a family member has experienced symptoms after taking a medication.
3. Also talk to your doctor about possible risks.
4. Don’t stop taking any medications on your own.

If your doctor prescribes a new medication, make sure he or she knows about all the other medications you’re taking, especially if you receive prescriptions from more than one doctor. If you and your doctor decide the benefits of combining certain serotonin-level-affecting drugs outweigh the risks, be alert to the possibility of serotonin syndrome.

What blocks serotonin?

Assess the drug. – Because serotonin toxicity is a drug-induced condition, an accurate drug history is necessary for diagnosis, especially when a patient has recently used an MAOI or another serotonin-elevating drug. Serotonin toxicity most often happens when 2 or more serotonin-elevating drugs are used together, especially if they increase serotonin in different ways.1, 2, 12, 13 An MAOI with an SSRI, an SNRI, or another MAOI is the riskiest combination, but other combinations can also result in toxicity. Serotonin physiology: Serotonin is formed in the presynaptic terminal from tryptophan. Once packaged into vesicles, it is released into the synaptic cleft where it can bind to serotonin receptors on the postsynaptic neuron to exert its action. Serotonin is transported through a transporter to the presynaptic terminal where it is broken down by monoamine oxidase.15 The 3 classes of drugs that increase serotonin in synapses are highlighted in red.5HT—5-hydroxytryptamine.

Monoamine oxidase inhibitors: Monoamine oxidase inhibitors slow the breakdown of serotonin by blocking monoamine oxidase.15 This class of drugs is most concerning, specifically MAOIs that bind irreversibly and non-selectively to both types of monoamine oxidase (MAO-A and MAO-B); MAO-A inhibitors are more likely to cause toxicity because MAO-A plays a larger role in the breakdown of serotonin.1, 15 Combination of 2 MAOIs or an MAOI and another serotonergic drug carries the greatest risk of serotonin toxicity.

Although not common anymore, the most recognizable MAOIs are those used to treat depression, such as phenelzine, isocarboxazid, tranylcypromine, and moclobemide. Other agents less frequently recognized as MAOIs include the antibiotics isoniazid (irreversible, non-selective) and linezolid (reversible, non-selective).3, 16 Serotonin reuptake inhibitors: Serotonin reuptake inhibitors prevent the transport of serotonin from the synapse back into the presynaptic terminal to be degraded, keeping it at the site of action.15 Drugs that prevent the reuptake of serotonin include SNRIs, SSRIs, tramadol, certain tricyclic antidepressants (TCAs), certain opioids, dextromethorphan, the antihistamines chlorpheniramine and brompheniramine, and herbals such as St John’s wort.7, 13 After MAOIs, SNRIs and SSRIs are the most concerning serotonergic drugs, as their main mechanism is to increase serotonin.1, 2 The SNRI venlafaxine causes toxicity more often than SSRIs do, possibly because it has another serotonergic mechanism other than a reuptake inhibitor.3 Certain synthetic opioids such as tramadol, methadone, meperidine, fentanyl, and dextromethorphan are weak serotonin reuptake inhibitors and can cause toxicity, but opioids with a structure similar to morphine are not reuptake inhibitors, meaning that morphine, codeine, oxycodone, and buprenorphine do not cause toxicity.7 Because of the risk of dextromethorphan and the antihistamines chlorpheniramine and brompheniramine, remind patients who take serotonin drugs to talk to a physician or pharmacist before taking a cough and cold medication.

Tricyclic antidepressants are also serotonin reuptake inhibitors, with clomipramine and imipramine being the most potent and likely the only TCAs to be involved in serotonin toxicity; other TCAs such as amitriptyline are weaker inhibitors and are thus unlikely to cause toxicity.3, 7 Serotonin releasers: Serotonin releasers cause more serotonin to be released from the presynaptic terminal into the synapse.

Serotonin releasers include amphetamine, but not methylphenidate, and the illicit drug ecstasy (3,4-methylenedioxymethamphetamine).3, 7, 12 l -Tryptophan: A drug that does not fit into any of these 3 categories is l -tryptophan, which can be used for various mood disorders.3 l -Tryptophan can increase serotonin levels because serotonin is made from tryptophan; however, the risk is low.

What is the antagonist of kratom?

Pharmacology – Kratom preparations contain several phytochemicals in varying ratios rendering their proper pharmacological evaluation difficult. Human clinical studies are scarce. In general, the effects of kratom in humans are dose-dependent: small doses produce ‘cocaine-like’ stimulation while larger dosages cause ‘morphine-like’ sedative-narcotic effects.

After taking a few grams of dried leaves, the invigorating effects and euphoria are felt within 10 minutes and last for one to one and a half hours. Kratom users report increased work capacity, alertness, sociability and sometimes heightened sexual desire. The pupils are usually normal or very slightly contracted; blushing may be noted.

In one of the few human clinical experiments, a 50 mg oral dose of mitragynine produced motor excitement, followed by giddiness, loss of motor coordination (positive Romberg’s test ), and tremors of the extremities and face. For regular kratom users, loss of weight, tiredness, constipation, and hyperpigmentation of the cheek may be notable side effects.

• The pharmacological mechanism responsible for stimulant activity is unclear.
• Ratom taken in large, sedating doses corresponding to 10–25 g of dried leaves may initially produce sweating, dizziness, nausea and dysphoria but these effects are shortly superseded with calmness, euphoria and a dreamlike state that last for up to six hours.

Contracted pupils ( miosis ) are noted. Mitragynine and 7-hydroxymitragynine, the two alkaloids mainly responsible for the effects of kratom, are selective and full agonists of the μ-subtype opioid receptor (MOR), The receptor agonist effect of kratom alkaloids is antagonised by the opioid receptor antagonist naloxone,

1. In addition, 5-HT 2a and postsynaptic α 2 -adrenergic receptors, as well as neuronal Ca 2+ channels are also involved in the unique pharmacological and behavioural activity of mitragynine.
2. In animal studies, the antinociceptive and cough-suppressant effects of mitragynine were comparable to those of codeine.

In mice, 7-hydroxymitragynine was several times more potent analgesic than morphine even upon oral administration. Kratom is slightly toxic to animals. Mice chronically treated with 7-hydroxymitragynine developed tolerance, cross-tolerance to morphine and withdrawal signs that could be precipitated by naloxone administration.

• Regular kratom use may produce dependence.
• The withdrawal symptoms in humans are relatively mild and typically diminish within a week.
• Craving, weakness and lethargy, anxiety, restlessness, rhinorrhea, myalgia, nausea, sweating, muscle pain, jerky movements of the limbs, tremor as well as sleep disturbances and hallucination may occur.

Treatment, if needed, may include dihydrocodeine-lofexidine combination, non-steroidal antiinflammatory agents, antidepressants and/or anxiolytics. The metabolism of mitragynine in humans occurs via hydrolysis of the side-chain ester, O -demethylation of the methoxy groups, oxidative and/or reductive transformations, and the formation of glucuronide and sulfate conjugates.

In a man who fatally overdosed propylhexedrine and kratom, the postmortem mitragynine concentrations ranged from 0.01 mg/kg to 1.20 mg/l. The consumption of kratom concomitantly with other drugs can provoke serious side effects. In fact, adverse drug interactions involving kratom tea taken with carisoprodol, modafinil, propylhexedrine or Datura stramonium have been reported.

A fatal case in the United States involved a blend of kratom, fentanyl, diphenhydramine, caffeine and morphine sold as a herbal drug. top of page

What drugs increase dopamine levels?

Medications – Ropinirole and pramipexole can help neural receptors use dopamine more effectively, Levodopa is the precursor to dopamine, which means it is something the body needs to produce dopamine. Doctors may prescribe these drugs to treat Parkinson’s disease or disorders that cause unwanted movement, such as restless legs syndrome,

Decreased dopamine activity may play a role in several conditions, including ADHD, addiction, and obesity. The loss of dopamine-producing cells also causes Parkinson’s disease. Scientists are still learning how this impacts people and how to address it. Medications are available that increase dopamine for people with specific conditions.

A person should speak with a doctor if they are concerned about their dopamine levels or have questions about how they can improve them.

What is the metabolism of kratom?

Elimination – In general, kratom alkaloids demonstrated a long elimination half-life upon administration of kratom tea to healthy adult participants ( Tanna et al., 2022 ). Following the trend observed for absorption and distribution, the terminal half-lives for the indole alkaloids with the 3 S configuration (24–45 hours) were longer than analogs with the 3 R configuration (∼12–18 hours). In addition, the fraction of the dose excreted unchanged in the urine (f e ) was higher for the 3 R compared with the 3 S configured alkaloids. However, for all alkaloids, f e was <0.2%, indicating that urinary excretion is a minor route of systemic elimination. Consistent with that interpretation, renal clearance (CL R ) for all alkaloids was much lower than effective renal plasma flow (<0.5 vs.36 l/h). Kratom alkaloids, including mitragynine, primarily undergo oxidative metabolism, which can subsequently be either glucuronidated or sulfated based on the species ( Philipp et al., 2009 ; Basiliere et al., 2018 ) ( Fig.2 ). These alkaloids were extensively metabolized in an NADPH-dependent manner in both enteric (human intestinal microsomes) and hepatic (human liver microsomes) tissue fractions ( Tanna et al., 2022 ). The extent of metabolism of kratom alkaloids is stereoselective (i.e., the indole alkaloids with the 3 S configuration are more rapidly metabolized than those with the 3 R configuration). Cytochrome P450 (P450) 3A4 is the major enzyme that metabolizes mitragynine to 7-hydroxymitragynine ( Kamble et al., 2019 ; Kruegel et al., 2019 ).7-Hydroxymitragynine was further reported to be metabolized by an unknown human plasma enzyme to a 31-fold more potent activator of the μ -opioid receptor, mitragynine pseudoindoxyl ( Kamble et al., 2020a ). CYP2C9, CYP2C19, and CYP2D6 have minor roles in the metabolism of mitragynine ( Kamble et al., 2019 ). Mitragynine acid formation from mitragynine was catalyzed by human carboxylesterase (hCES) 1c (K m = 87 μ M; V max = 0.7 nmol/min per mg) but not by hCES2 ( Meyer et al., 2015 ). However, based on the low intrinsic clearance, the clinical relevance of the hCES1c pathway is unlikely. Fig.2. Proposed metabolic scheme for mitragynine based on reported in vitro and in vivo evaluations. Boxes suggest the tentative site of metabolism.

What are the cardiovascular effects of cannabinoids?

Cardiovascular effects – One of the few things scientists know for sure about marijuana and cardiovascular health is that people with established heart disease who are under stress develop chest pain more quickly if they have been smoking marijuana than they would have otherwise.

This is because of complex effects cannabinoids have on the cardiovascular system, including raising resting heart rate, dilating blood vessels, and making the heart pump harder. Research suggests that the risk of heart attack is several times higher in the hour after smoking marijuana than it would be normally.

While this does not pose a significant threat to people who have minimal cardiovascular risk, it should be a red flag for anyone with a history of heart disease. Although the evidence is weaker, there are also links to a higher risk of atrial fibrillation or ischemic stroke immediately following marijuana use.

How do cannabinoids affect the cardiovascular system?

Heart Health Marijuana can make the heart beat faster and can make blood pressure higher immediately after use.1,2 It could also lead to increased risk of stroke, heart disease, and other vascular diseases.3-7 Most of the scientific studies linking marijuana to heart attacks and strokes are based on reports from people who smoked marijuana (as opposed to other methods of using it).

• Smoked marijuana delivers tetrahydrocannabinol (THC) and other cannabinoids to the body.
• Marijuana smoke also delivers many of the same substances researchers have found in tobacco smoke—these substances are harmful to the lungs and cardiovascular system.8,9 It is hard to separate the effects of marijuana chemicals on the cardiovascular system from those caused by the irritants and other chemicals that are present in the smoke.

More research is needed to understand the full impact of marijuana use on the cardiovascular system to determine if marijuana use leads to higher risk of death.

Sidney S. Cardiovascular consequences of marijuana use. The Journal of Clinical Pharmacology,2002;42(S1):64S-70S. Subramaniam VN, Menezes AR, DeSchutter A, Lavie CJ. The cardiovascular effects of marijuana: are the potential adverse effects worth the high? Missouri Medicine,2019;116(2):146. Wolff V, Armspach J-P, Lauer V, et al. Cannabis-related stroke: myth or reality? Stroke,2013;44(2):558-563. Wolff V, Zinchenko I, Quenardelle V, Rouyer O, Geny B. Characteristics and Prognosis of Ischemic Stroke in Young Cannabis Users Compared with Non-Cannabis Users. J Am Coll Cardiol.2015;66(18): 2052-2053. Franz CA, Frishman WH. Marijuana use and cardiovascular disease. Cardiology in Review,2016;24(4):158-162. Rumalla K, Reddy AY, Mittal MK. Association of recreational marijuana use with aneurysmal subarachnoid hemorrhage. Journal of Stroke and Cerebrovascular Diseases,2016;25(2):452-460. Rumalla K, Reddy AY, Mittal MK. Recreational marijuana use and acute ischemic stroke: a population-based analysis of hospitalized patients in the United States. Journal of the Neurological Sciences,2016;364:191-196. Moir D, Rickert WS, Levasseur G, et al. A comparison of mainstream and sidestream marijuana and tobacco cigarette smoke produced under two machine smoking conditions. Chemical Research in Toxicology,2008;21(2):494-502. US Department of Health and Human Services. The Health Consequences of Smoking—50 Years of Progress. A Report of the Surgeon General. Atlanta, GA.2014.

: Heart Health

Does kratom affect ECG?

The prevalence of ECG abnormalities in kratom users (28%) did not differ from that of control subjects (32%). Kratom use was not associated with ECG abnormalities, except for significantly higher odds of sinus tachycardia (OR = 8.61, 95% CI = 1.06–70.17, p = 0.035) among kratom users compared with control subjects.

Does kratom cause high cortisol?

Abstract – Abstract ID 52920 Poster Board 424 Kratom is a tropical evergreen tree indigenous to Southeast Asia whose leaves and decoctions have long been used in traditional folk medicine for the relief of pain and enhancement of vitality. In recent years kratom use has increased in the United States, where an estimated 10-15 million people use the herb for the self-management of pain and opioid withdrawal.

Kratom leaves contain over 40 active alkaloids. Previous studies in our laboratory demonstrated that mitragynine was the only kratom alkaloid that enhanced cortisol secretion in a human adrenocortical cell line. To further investigate the molecular mechanism by which mitragynine enhances cortisol secretion, we examined the effect of mitragynine on the expression of the steroidogenic enzymes and cofactors involved in cortisol production.

HAC15 cells were exposed to vehicle or mitragynine (10 μM). After 72 h, mRNA expression of the following steroidogenic enzymes, cofactors, and receptors was examined: CYP11A1, HSD3B2, CYP21A2, CYP11B1, StAR, FDXR, FDX1, and MC2R. While mRNA expression was upregulated for all of these steroidogenic factors, CYP11B1 was induced to the greatest extent (fold change: vehicle, 1.0±0.2; 10 μM mitragynine, 18.4±1.5; n=6).

Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics