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Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users

Singh D, Müller CP, Vicknasingam BK

Drug Alcohol Depend, 2014 Jun 1;139:132-7.
PMID: 24698080 DOI: 10.1016/j.drugalcdep.2014.03.017

BACKGROUND: Kratom (Mitragyna speciosa) preparations have been traditionally used in Southeast Asia for its medicinal properties. Lately, Kratom use has spread to Europe and the US, where abuse potential and health hazards increasingly emerge. This study is the first to measure systematically Kratom dependence, withdrawal symptoms, and drug craving in regular Kratom users in Malaysia.
METHODS: A cross-sectional survey of 293 regular Kratom users was conducted in the community across three northern peninsular states of Malaysia. The Leeds Dependence Questionnaire, Marijuana Withdrawal Checklist, and Marijuana Craving Questionnaire-Short Form were used to measure Kratom dependence, withdrawal and craving.
RESULTS: More than half of the regular users (>6 month of use) developed severe Kratom dependence problems, while 45% showed a moderate Kratom dependence. Physical withdrawal symptoms commonly experienced include muscle spasms and pain, sleeping difficulty, watery eyes/nose, hot flashes, fever, decreased appetite, and diarrhoea. Psychological withdrawal symptoms commonly reported were restlessness, tension, anger, sadness, and nervousness. The average amount of the psychoactive compound, mitragynine, in a single dose of a Kratom drink was 79mg, suggesting an average daily intake of 276.5mg. Regular users who consumed ≥3 glasses Kratom per day, had higher odds of developing severe Kratom dependence, withdrawal symptoms, and inability to control Kratom craving.
CONCLUSIONS: The findings from this study show that regular Kratom use is associated with drug dependency, development of withdrawal symptoms, and craving. These symptoms become more severe with prolonged use and suggest a stronger control of the drug.

Matched MeSH terms: Substance Withdrawal Syndrome/psychology
Long-Term Cognitive Effects of Kratom (Mitragyna speciosa Korth.) Use

Singh D, Narayanan S, Müller CP, Vicknasingam B, Yücel M, Ho ETW, et al.

J Psychoactive Drugs, 2018 12 15;51(1):19-27.
PMID: 30556488 DOI: 10.1080/02791072.2018.1555345

Kratom or Mitragyna speciosa (Korth.) is a medicinal plant of Southeast Asia. As a result of its opioid-like effects, it remains unknown whether consumption of kratom tea is associated with impaired cognitive function. We assessed the cognitive function of 70 regular kratom users and 25 control participants using the Cambridge Neuropsychological Test Automated Battery. Participants performed six neuropsychological tasks that assessed motor, learning and memory, attention and executive function. Relative to control participants, higher consumption (>3 glasses daily or mitragynine doses between 72.5 mg and 74.9 mg) of kratom tea was selectively associated with impaired performance on the Paired Associates Learning task, reflecting deficits in visual episodic memory and new learning. Overall, the performance of kratom users compared to control participants, and the performance of high (>3 glasses per day) as well as low (≤3 glasses per day) kratom using groups, were comparable on all neuropsychological domains. Higher intake of kratom juice (>3 glasses daily) did not appear to impair motor, memory, attention or executive function of regular kratom users.

Matched MeSH terms: Substance Withdrawal Syndrome/psychology
Assessing physiological dependence and withdrawal potential of mitragynine using schedule-controlled behaviour in rats

Harun N, Johari IS, Mansor SM, Shoaib M

Psychopharmacology (Berl), 2020 Mar;237(3):855-867.
PMID: 31832720 DOI: 10.1007/s00213-019-05418-6

RATIONALE: Kratom is proposed to exhibit therapeutic potential as an opium substitute, but little is known about its dependence-producing profile, particularly of its main psychoactive compound, mitragynine (MG).
OBJECTIVES: This study examined the dependence-producing effects of MG using operant-scheduled behaviour in rats and investigated the potential therapeutic effect of MG by comparing effects to buprenorphine in morphine-dependent rats using the same schedule-controlled behavioural task.
METHODS: The effects of acutely administered MG and morphine were determined in rats trained to respond under fixed-ratio (FR) 10 schedule of food reinforcement. Next, the rats were administered MG and morphine twice daily for 14 consecutive days to determine if physiological dependence would develop by examining cessation of drug treatment and following antagonist-precipitated withdrawal. The study then examined the effects of MG substitution to suppress naloxone-precipitated morphine withdrawal effects on scheduled responding.
RESULTS: Acute doses of MG did not produce dose-related decreases on FR schedules of responding compared to morphine. Unlike morphine, MG-treated rats showed no suppression of response rates following cessation of MG treatment. However, withdrawal effects were evident for MG after precipitation by either naloxone or SR141716A (rimonabant), similar to morphine-treated rats. MG in higher doses (10 and 30 mg/kg) attenuated the naloxone-precipitated morphine withdrawal effects while smaller doses of buprenorphine (0.3 and 1.0 mg/kg) were necessary to alleviate these effects.
CONCLUSION: The findings suggest that MG does not induce physiological dependence but can alleviate the physical symptoms associated with morphine withdrawal which represent the desired characteristics of novel pharmacotherapeutic interventions for managing opioid use disorder (OUD).

Matched MeSH terms: Substance Withdrawal Syndrome/psychology*
Severity of Kratom (Mitragyna speciosa Korth.) Psychological Withdrawal Symptoms

Singh D, Narayanan S, Müller CP, Swogger MT, Rahim AA, Leong Bin Abdullah MFI, et al.

J Psychoactive Drugs, 2018 08 28;50(5):445-450.
PMID: 30152738 DOI: 10.1080/02791072.2018.1511879

Kratom leaves (Mitragyna speciosa Korth.) are traditionally used in Southeast Asia for their medicinal value. Self-report studies suggest that cessation from chronic kratom tea consumption (freshly brewed kratom tea) was associated with unpleasant psychological symptoms. This study sought to assess the severity of anxiety and depression during kratom cessation. Regular kratom users (N = 150) were recruited from the northern state of Penang (Malaysia) for this retrospective study. The Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scales were used to assess the severity of the symptoms of anxiety and depression. Most respondents (70%) experienced symptoms of mild anxiety, while 81% experienced symptoms of mild depression during kratom cessation. Those who consumed higher quantities of kratom tea daily (≥4 glasses) had higher odds of reporting longer duration of kratom use history (OR = 4.8, 95% CI 2.3 -10.1, p

Matched MeSH terms: Substance Withdrawal Syndrome/psychology*
Fulltext Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish

Khor BS, Jamil MF, Adenan MI, Shu-Chien AC

PLoS One, 2011;6(12):e28340.
PMID: 22205946 DOI: 10.1371/journal.pone.0028340

A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.

Matched MeSH terms: Substance Withdrawal Syndrome/psychology
Alpha-asarone attenuates depression-like behavior in nicotine-withdrawn mice: Evidence for the modulation of hippocampal pCREB levels during nicotine-withdrawal

Chellian R, Pandy V, Mohamed Z

Eur J Pharmacol, 2018 Jan 05;818:10-16.
PMID: 29042206 DOI: 10.1016/j.ejphar.2017.10.025

In the present study, the effect α-asarone on nicotine withdrawal-induced depression-like behavior in mice was investigated. In this study, mice were exposed to drinking water or nicotine solution (10-200µg/ml) as a source of drinking for forty days. During this period, daily fluid consumption, food intake and body weight were recorded. The serum cotinine level was estimated before nicotine withdrawal. Naïve mice or nicotine-withdrawn mice were treated with α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) for eight consecutive days and the forced swim test (FST) or locomotor activity test was conducted. In addition, the effect of α-asarone or bupropion on the hippocampal pCREB, CREB and BDNF levels during nicotine-withdrawal were measured. Results indicated that α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment did not significantly alter the immobility time in the FST or spontaneous locomotor activity in naïve mice. However, the immobility time of nicotine-withdrawn mice was significantly attenuated with α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment in the FST. Besides, α-asarone (5, 10 and 20mg/kg, i.p.) or bupropion (10mg/kg, i.p.) pretreatment significantly attenuated the hippocampal pCREB levels in nicotine-withdrawn mice. Overall, the present results indicate that α-asarone treatment attenuated the depression-like behavior through the modulation of hippocampal pCREB levels during nicotine-withdrawal in mice.

Matched MeSH terms: Substance Withdrawal Syndrome/psychology*