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Chemical structure of methylone
Source publication
We report a case of ethcathinone and methylone poisoning with severe clinical toxicity. This is to our knowledge the first case reported in the medical toxicology literature.
A 22-year-old woman was brought to the emergency department following several episodes of tonicoclonic seizures, a few hours after ingesting "legal ecstasy". The patient neede...
Context in source publication
Context 1
... recently, this drug has been identified as a new designer drug, more specifically in European markets. Methylone is marketed on the internet as a high-purity plant food, which can give false confidence to teenagers and young adults attracted to stimulants similar to ecstasy (Figs. 1, 2, 3) [3]. ...
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Introduction
Over the past decade, there has been a sharp increase in the number of newly identified synthetic drugs. These new drugs are often derivatives of previously abused substances but have unpredictable toxicity. One of these drugs is gacyclidine, a derivative of phencyclidine (PCP). Gacyclidine has been studied as a neuroprotective agent...
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Citations
... Like other synthetic cathinones, recreational users often consume small doses after the initial large dose to induce prolonged effects; this pattern of use increases the risk of intoxication or overdose (Liakoni et al., 2017;Gomila et al., 2022) and, in the worst case scenario, death (Boulanger-Gobeil et al., 2012;Cawrse et al., 2012;Pearson et al., 2012;Warrick et al., 2012;Carbone et al., 2013;McIntyre et al., 2013;Barrios et al., 2016;Shimomura et al., 2016;deRoux and Dunn, 2017). Common adverse effects associated with intoxication include anxiety, agitation, palpitations, sweating, tremors, seizures, hyperthermia, and vomiting (Karila et al., 2016;Liakoni et al., 2017). ...
Methylone is one of the most common synthetic cathinones popularized as a substitute for 3,4-methylenedioxymethamphetamine (MDMA, midomafetamine) owing to its similar effects among users. Both psychostimulants exhibit similar chemistry (i.e., methylone is a β-keto analog of MDMA) and mechanisms of action. Currently, the pharmacology of methylone remains scarcely explored in humans. Herein, we aimed to evaluate the acute pharmacological effects of methylone and its abuse potential in humans when compared with that of MDMA following oral administration under controlled conditions. Seventeen participants of both sexes (14 males, 3 females) with a previous history of psychostimulant use completed a randomized, double-blind, placebo-controlled, crossover clinical trial. Participants received a single oral dose of 200 mg of methylone, 100 mg of MDMA, and a placebo. The variables included physiological effects (blood pressure, heart rate, oral temperature, pupil diameter), subjective effects using visual analog scales (VAS), the short form of the Addiction Research Center Inventory (ARCI), the Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire (VESSPA-SSE), and the Sensitivity to Drug Reinforcement Questionnaire (SDRQ), and psychomotor performance (Maddox wing, psychomotor vigilance task). We observed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects, such as stimulation, euphoria, wellbeing, enhanced empathy, and altered perception. Methylone exhibited an effect profile similar to MDMA, with a faster overall onset and earlier disappearance of subjective effects. These results suggest that abuse potential of methylone is comparable to that of MDMA in humans. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05488171; Identifier: NCT05488171.
... Hyponatremia is a rare presentation in synthetic cathinone poisoning. 35,36 It may be caused by excessive sweating with electrolyte loss and increased free water consumption during cathinone use (presumably the main reason for hyponatremia in our case). Additionally, some synthetic cathinones possess an MDMA-like effect, which can result in hyponatremia by inducing secretion of antidiuretic hormone mediated via serotonin. ...
Background
Synthetic cathinone abuse is a global health issue. Synthetic cathinones emerged in Taiwan in 2009, and their prevalence rapidly rose. They are usually made into “instant coffee packets,” and these so-called “toxic coffee packets” may also contain psychoactive drugs other than synthetic cathinones. Due to the diversity of the ingredients, clinical presentations can be complex.
Methods
Retrospective analysis of emergency department (ED) patients who reported ingesting toxic coffee packets at three Chang-Gung Memorial Hospitals located in northern Taiwan between January, 2015 and December, 2019.
Results
Sixty patients were included. Their mean age was 28.85 ± 9.24 years and 47(78.33%) were male. The most common presentations were palpitation, agitation, hallucination, and altered consciousness. Tachycardia and hypertension were common, while hyperthermia was observed in only three patients. Three patients (5%) developed rhabdomyolysis, and one underwent transient hemodialysis. Most patients were discharged from the ED, but 15(25%) were admitted, of whom nine (15%) were admitted to the intensive care unit (ICU), and one eventually died. Confirmation tests (mass-spectrometry-based analysis) were available in 10 patients; all reported positive for at least one type of synthetic cathinone. Polysubstance exposure was common. In multivariate logistic regression analyses, Glasgow coma scale ≤13 and the presence of seizure were associated with ICU admission.
Conclusion
Patients who report ingesting toxic coffee packets are very likely to have been exposed to synthetic cathinones. Polysubstance exposure is common following ingestion. Cardiovascular and neurological symptoms are the main presentations, and severe complications such as rhabdomyolysis and life-threatening dysrhythmia can occur.
... According to user reports, methylone also displays a similar but milder range of effects compared to MDMA that encompasses stimulation, calm euphoria, a sense of wellbeing and happiness, alertness, reduced fatigue, heightened empathy, and entactogenic effects (sense of oneness) [25,26]. Among the published cases of intoxication involving methylone [27][28][29][30][31][32], a patient that visited the emergency department after using 1.0-1.5 g of methylone presented vomiting, palpitations, agitation, sweating, paresthesia, muscle twitching, tremors, and vertigo [33]. Other adverse effects associated with methylone intoxication are hyperthermia, anxiety, seizures, psychosis, hallucinations, and suicidal ideation [6]. ...
... Participants had a mean age of 30 ± 5 years (range[23][24][25][26][27][28][29][30][31][32][33][34][35][36][37], weighed 64.88 ± 9.20 kg (range 54.0-78.0), and had a mean body mass index (BMI) of 22.24 ± 3.50 kg/m 2 (range 16.48-26.03). ...
Considered the β-keto analogue of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-Methylenedioxymethcathinone (methylone) is a synthetic cathinone. Over the years, methylone has been used as a substitute for conventional psychostimulants, such as MDMA. To date, little is known about the human pharmacology of methylone; the only available information has been provided by surveys or published intoxication reports. In the present observational–naturalistic study, we evaluate the acute subjective and physiological effects of methylone after oral self-administration in comparison to MDMA in healthy poly-drug users. Fourteen participants (10 males, 4 females) selected their single oral doses of methylone from 100 to 300 mg (n = 8, mean dose 187.5 mg) or MDMA from 75 to 100 mg (n = 6, mean dose 87.5 mg) based on their experience. Study variables were assessed at 0, 1, 2, and 4 h (h) and included vital signs (non-invasive blood pressure, heart rate, cutaneous temperature) and subjective effects using visual analogue scales (VAS), the 49-item Addiction Research Centre Inventory (ARCI) short form, and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) questionnaire. Additionally, oral fluid concentrations of methylone and MDMA were determined. Acute pharmacological effects produced by methylone followed the prototypical psychostimulant and empathogenic profile associated with MDMA, although they were less intense. Methylone concentrations in oral fluid can be considered a useful biomarker to detect acute exposure in oral fluid. Oral fluid concentrations of MDMA and methylone peaked at 2 h and concentrations of MDMA were in the range of those previously described in controlled studies. Our results demonstrate that the potential abuse liability of methylone is similar to that of MDMA in recreational subjects.
... In vitro, 4-FA predominantly interacts with NET and DAT, which supports this hypothesis (Luethi et al., 2019a). Similarly, synthetic cathinones have been associated with headache, tremor, seizures, cerebral edema, and stroke (Beck et al., 2015Boulanger-Gobeil et al., 2012;Forrester, 2012;Franzén et al., 2018;James et al., 2011;Ross et al., 2012;Wood et al., 2010). The majority of the abovementioned symptoms occurred in cases of poly-drug use, including combinations of different synthetic cathinones. ...
... As for 4-FA, these effects can mainly be explained by the potent activation of catecholaminergic systems by cathinones. Furthermore, seizures and hyponatremia caused by intoxication with cathinones have been linked to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (Boulanger-Gobeil et al., 2012). Benzofuran and indole NPS have sporadically been linked to neurological adverse effects as well, which is not unexpected given the potent interactions of these substances with monoaminergic systems. ...
... However, potential additional NPS that have remained undetected and the fentanyl treatment during her hospitalization may possibly have augmented or rather caused the serotonin toxicity (Liu et al., 1996;Mugele et al., 2012;Rickli et al., 2018). Importantly, serotonin toxicity can consequently lead to a variety of non-neurological clinical sequelae, such as SIADH (Boulanger-Gobeil et al., 2012). SIADH is a well-known adverse drug reaction of SSRIs, SNRIs (Liu et al., 1996;Oliver et al., 2020), and MDMA (Hartung et al., 2002;Liu et al., 1996;Rosenson et al., 2007;Simmler et al., 2011). ...
New psychoactive stimulants and psychedelics continue to play an important role on the illicit new psychoactive substance (NPS) market. Designer stimulants and psychedelics both affect monoaminergic systems, although by different mechanisms. Stimulant NPS primarily interact with monoamine transporters, either as inhibitors or as substrates. Psychedelic NPS most potently interact with serotonergic receptors and mediate their mind-altering effects mainly through agonism at serotonin 5-hydroxytryptamine-2A (5-HT2A) receptors. Rarely, designer stimulants and psychedelics are associated with potentially severe adverse effects. However, due to the high number of emerging NPS, it is not possible to investigate the toxicity of each individual substance in detail. The brain is an organ particularly sensitive to substance-induced toxicity due to its high metabolic activity. In fact, stimulant and psychedelic NPS have been linked to neurological and cognitive impairments. Furthermore, studies using in vitro cell models or rodents indicate a variety of mechanisms that could potentially lead to neurotoxic damage in NPS users. Cytotoxicity, mitochondrial dysfunction, and oxidative stress may potentially contribute to neurotoxicity of stimulant NPS in addition to altered neurochemistry. Serotonin 5-HT2A receptor-mediated toxicity, oxidative stress, and activation of mitochondrial apoptosis pathways could contribute to neurotoxicity of some psychedelic NPS. However, it remains unclear how well the current preclinical data of NPS-induced neurotoxicity translate to humans.
... Indeed, one study found that one in four of female MDMA users sampled at a rave party had mild (subclinical) hyponatraemia as compared to only 3% of males, suggesting that particular caution should be exercised by female MDMA users [98]. In addition to MDMA, related compounds methylone and ethcathinone (marketed as 'legal ecstasy') have also been associated with severe hyponatraemia [14]. Hyponatraemia has rarely been reported in association with cocaine use; however three of the four cases involved cocaine adulterated with levamisole (the fourth case was not tested for levamisole), and it is possible that this (rather than the cocaine) may have been the cause of hyponatraemia [37,52]. ...
The kidneys receive approximately 25% of cardiac output and are highly exposed to the influence of drugs of addiction. While many drugs have long been known to cause kidney injury or other metabolic derangements, such as electrolyte and acid-base disorders, the mechanism and the longer-term implications of many drug-induced kidney diseases often remain poorly understood. However, both drug-induced kidney injury and pre-existing kidney disease are frequently encountered in primary care, acute medicine and critical care and when treating people with a history of drug use or addiction. Here, we define the classification and presentation of renal disease before describing the wide spectrum of renal disease associated with drugs of addiction. Both direct nephrotoxicity and indirect injury stemming from injecting drug use, such as the renal complications of blood-borne viruses, are reviewed. In addition, the interaction between drug use and chronic kidney disease and renal replacement therapy is briefly considered. Finally, we describe the spectrum of electrolyte and acid-base derangements associated with drug use.
... Son estimulantes similares a las anfetaminas y se comportan como inhibidores de la captación de serotonina. Se cree que el mecanismo implicado en la hiponatremia se debe a las características similares con el MDMA, que puede inducir un SIADH mediado por el sistema serotoninérgico [9]. ...
Las enfermedades pueden generar un desequilibrio de electrolitos como parte de su fisiopatología, al igual que los medicamentos usados crónicamente y algunas sustancias tóxicas disponibles en nuestro medio. A pesar de todos los datos estadísticos existentes, la incidencia global de los trastornos electrolíticos secundarios a fármacos o sustancias tóxicas permanece desconocida, y, posiblemente, subregistrada; por lo tanto, el objetivo de esta revisión es analizar los trastornos electrolíticos que causan algunos medicamentos y sustancias tóxicas, y describir el mecanismo a través del cual se producen las alteraciones, en particular, del sodio, potasio, magnesio, calcio y fósforo, con el fin de alertar a los profesionales de la salud en el momento de enfrentarse a este tipo de condiciones en su práctica clínica. El conocimiento de los efectos adversos relacionados con medicamentos y tóxicos es importante para prevenir, identificar y gestionar de forma eficaz, complicaciones que son potencialmente peligrosas. Esta revisión pretende ser un referente de apoyo para los profesionales de la salud en estas situaciones.
... The use of synthetic cathinones has been associated with mainly sympathomimetic toxicity, which may manifest as agitation, tachycardia, hypertension and less frequently as lower levels of consciousness, hallucinations, hyponatremia, chest pain, palpitations, and nausea (Bäckberg et al. 2015c;Beck et al. 2015Beck et al. , 2016Borek and Holstege 2012;Boulanger-Gobeil et al. 2012;Franzén et al. 2018;James et al. 2011;Ross et al. 2011Ross et al. , 2012Umebachi et al. 2016;Wood et al. 2010). Rarely, severe adverse effects (e.g., seizures, significant peripheral organ damage, and rhabdomyolysis) have been reported (Bäckberg et al. 2015c;Beck et al. 2015Beck et al. , 2016Borek and Holstege 2012;Boulanger-Gobeil et al. 2012;Franzén et al. 2018;Fröhlich et al. 2011;Penders et al. 2012;Ross et al. 2011Ross et al. , 2012. ...
... The use of synthetic cathinones has been associated with mainly sympathomimetic toxicity, which may manifest as agitation, tachycardia, hypertension and less frequently as lower levels of consciousness, hallucinations, hyponatremia, chest pain, palpitations, and nausea (Bäckberg et al. 2015c;Beck et al. 2015Beck et al. , 2016Borek and Holstege 2012;Boulanger-Gobeil et al. 2012;Franzén et al. 2018;James et al. 2011;Ross et al. 2011Ross et al. , 2012Umebachi et al. 2016;Wood et al. 2010). Rarely, severe adverse effects (e.g., seizures, significant peripheral organ damage, and rhabdomyolysis) have been reported (Bäckberg et al. 2015c;Beck et al. 2015Beck et al. , 2016Borek and Holstege 2012;Boulanger-Gobeil et al. 2012;Franzén et al. 2018;Fröhlich et al. 2011;Penders et al. 2012;Ross et al. 2011Ross et al. , 2012. In vitro studies in neuronal, skeletal muscle, and hepatic cells indicated various cytotoxic mechanisms of synthetic cathinones, including mitochondrial dysfunction, glutathione depletion, oxidative stress, and apoptosis pathway activation, which are aggravated under hyperthermic conditions (Dias da Silva et al. 2019;Luethi et al. 2017Luethi et al. , 2019bValente et al. 2016aValente et al. , b, 2017aZhou et al. 2019). ...
Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at μ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-d-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.
... Hyponatremia is another possible complication associated with the use of SCat (Romolo et al. 2016). It is a well-known feature among MDMA users, but it is also occasionally associated with mephedrone and methylone intoxications (Boulanger-Gobeil et al. 2012;Karila et al. 2016). It is thought to result from an increase of 5-HT-mediated antidiuretic hormone secretion, with consequent decrease of sodium concentration in the blood (Boulanger-Gobeil et al. 2012;Valente et al. 2014). ...
... It is a well-known feature among MDMA users, but it is also occasionally associated with mephedrone and methylone intoxications (Boulanger-Gobeil et al. 2012;Karila et al. 2016). It is thought to result from an increase of 5-HT-mediated antidiuretic hormone secretion, with consequent decrease of sodium concentration in the blood (Boulanger-Gobeil et al. 2012;Valente et al. 2014). ...
Synthetic cathinones (SCat) are amphetamine-like psychostimulants that emerged onto drug markets as “legal” alternatives to illicit drugs such as ecstasy, cocaine, and amphetamines. Usually they are sold as “bath salts,”“plant food,” or “research chemicals,” and rapidly gained popularity amongst drugs users due to their potency, low cost, and availability. In addition, internet drug sales have been replacing the old way of supplying drugs of abuse, contributing to their rapid spread. Despite the legislative efforts to control SCat, new derivatives continue to emerge on the recreational drugs market and their abuse still represents a serious public health issue. To date, about 150 SCat have been identified on the clandestine drugs market, which are one of the largest groups of new psychoactive substances (NPS) monitored by the United Nations Office on Drugs and Crime and the European Monitoring Center for Drugs and Drug Addiction. Similar to the classical stimulants, SCat affect the levels of catecholamines in the central nervous system, which results in their psychological, behavioral and toxic effects. Generally, the effects of SCat greatly differ from drug to drug and relatively little information is available about their pharmacology. The present work provides a review on the development of SCat as substances of abuse, current patterns of abuse and their legal status, chemical classification, known mechanisms of action, and their toxicological effects.
... Hyponatremia is another possible complication associated with the use of SCat (Romolo et al. 2016). It is a well-known feature among MDMA users, but it is also occasionally associated with mephedrone and methylone intoxications (Boulanger-Gobeil et al. 2012;Karila et al. 2016). It is thought to result from an increase of 5-HT-mediated antidiuretic hormone secretion, with consequent decrease of sodium concentration in the blood (Boulanger-Gobeil et al. 2012;Valente et al. 2014). ...
... It is a well-known feature among MDMA users, but it is also occasionally associated with mephedrone and methylone intoxications (Boulanger-Gobeil et al. 2012;Karila et al. 2016). It is thought to result from an increase of 5-HT-mediated antidiuretic hormone secretion, with consequent decrease of sodium concentration in the blood (Boulanger-Gobeil et al. 2012;Valente et al. 2014). ...
Synthetic cathinones (SCat) are amphetamine-like psychostimulants that emerged onto drug markets as “legal” alternatives to illicit drugs such as ecstasy, cocaine, and amphetamines. Usually they are sold as “bath salts,” “plant food,” or “research chemicals,” and rapidly gained popularity amongst drugs users due to their potency, low cost, and availability. In addition, internet drug sales have been replacing the old way of supplying drugs of abuse, contributing to their rapid spread. Despite the legislative efforts to control SCat, new derivatives continue to emerge on the recreational drugs market and their abuse still represents a serious public health issue. To date, about 150 SCat have been identified on the clandestine drugs market, which are one of the largest groups of new psychoactive substances (NPS) monitored by the United Nations Office on Drugs and Crime and the European Monitoring Center for Drugs and Drug Addiction. Similar to the classical stimulants, SCat affect the levels of catecholamines in the central nervous system, which results in their psychological, behavioral and toxic effects. Generally, the effects of SCat greatly differ from drug to drug and relatively little information is available about their pharmacology. The present work provides a review on the development of SCat as substances of abuse, current patterns of abuse and their legal status, chemical classification, known mechanisms of action, and their toxicological effects.
... The majority of cathinon-exposed patients is tachycardic with increased systolic and diastolic blood pressure. Cases of cathinone-induced hyponatremia have been reported, questioning the possibility of over hydration in the setting of drug-induced secretion of vasopressin like with MDMA [54]. In a large series of 236 patients exposed to "bath salts" and "legal highs", bought under 37 separate "brand" names in the US and identified as MDPV by gas chromatography/mass spectrometry when performed, the following clinical consequences were described: agitation (82%), combative behaviour (57%), tachycardia (56%), hallucinations (40%), paranoia (36%), confusion (35%), chest pain (17%), myoclonus (19%), hypertension (17%), mydriasis (13%), CPK elevations (9%), hypokalaemia (4%), and blurred vision (3%) [52]. ...
New psychoactive substances (NPS) have completely modified the drug scene and the current landscape of addiction. Synthetic substances, such as substituted or synthetic cathinones, also known as « legal highs », are often produced and used to mimic the effects of controlled drugs such as cocaine, methylenedioxymethamphetamine (MDMA, ecstasy), and methamphetamine. The overwhelming majority of synthetic cathinones are produced in China and South East Asian countries. The Internet has emerged as the new marketplace for NPS, playing a major role in providing information on acquisition, synthesis, extraction, identification, and substance use. All these compounds are intentionally mislabelled and sold on-line under slang terms such as bath salts, plant food, plant feeders and research chemicals. They are sometimes labelled « not for human use » or « not tested for hazards or toxicity ». The rapid spread of NPS forces member countries of the European Union to adapt their response to the potential new dangers that may cause. To date, not only health actors but also the general public need to be clearly informed and aware of dangers resulting from NPS spread and use. Here, we review the major clinical effects of synthetic cathinones to highlight their impact on public health. A literature search was conducted from 2009 to 2014 based on PubMed, Google Scholar, Erowid, and governmental websites, using the following keywords alone or in combination: “new psychoactive substances”, “synthetic cathinones”, “substituted cathinones”, “mephedrone”, “methylone”, “MDPV”, “4-MEC”, “addiction”, and “substance use disorder”.
