Journal of Clinical Medicine Review Abuse Potential of Cathinones in Humans: A Systematic Review Lourdes Poyatos 1,2,† , Adrián Torres 2,† , Esther Papaseit 1,2, *,† , Clara Pérez-Mañá 1,2,† , Olga Hladun 1,2 , Melani Núñez-Montero 1,2 , Georgina de la Rosa 1,2 , Marta Torrens 3,4 , Daniel Fuster 5,6 , Robert Muga 5,6 and Magí Farré 1,2, *,† 1 Department of Clinical Pharmacology, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), 08916 Badalona, Spain; lpoyatos@igtp.cat (L.P.); cperezm.mn.ics@gencat.cat (C.P.-M.); ohladun.germanstrias@gencat.cat (O.H.); mnunezmon.germanstrias@gencat.cat (M.N.-M.); grosalo.germanstrias@gencat.cat (G.d.l.R.) 2 Department of Pharmacology, Therapeutics and Toxicology, Universitat Autònoma de Barcelona (UAB), 08913 Cerdanyola del Vallés, Spain; adrian.torresv@e-campus.uab.cat 3 Institut de Neuropsiquiatria i Adiccions (INAD), Parc de Salut Mar, 08003 Barcelona, Spain; mtorrens@parcdesalutmar.cat 4 Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona (UAB), 08913 Cerdanyola del Vallés, Spain 5 Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias i Pujol (HUGTiP-IGTP), 08916 Badalona, Spain; dfuster.germanstrias@gencat.cat (D.F.); rmuga.germanstrias@gencat.cat (R.M.) 6 Department of Medicine, Universitat Autònoma de Barcelona (UAB), 08913 Cerdanyola del Vallés, Spain * Correspondence: epapaseit.germanstrias@gencat.cat (E.P.); mfarre.germanstrias@gencat.cat (M.F.) † These authors contributed equally to this study.  Abstract: Introduction and objective: Assessing the abuse potential of new substances with central  nervous system activity is essential for preventing possible risks of misuse and addiction. The Citation: Poyatos, L.; Torres, A.; same methodology is recommended for the evaluation of the abuse potential of recreational drugs. Papaseit, E.; Pérez-Mañá, C.; Hladun, This systematic review aims to assess the pharmacological effects related to the abuse potential O.; Núñez-Montero, M.; de la Rosa, and pharmacokinetics of cathinones, which are evaluated in both experimental and prospective G.; Torrens, M.; Fuster, D.; Muga, R.; et al. Abuse Potential of Cathinones observational studies in humans. Materials and Methods: A systematic search of the published literature in Humans: A Systematic Review. J. was conducted to retrieve studies that had administered cathinone, mephedrone, methylone, and Clin. Med. 2022, 11, 1004. https:// diethylpropion to evaluate their acute pharmacological effects related to abuse potential. Results: doi.org/10.3390/jcm11041004 The search yielded 583 results, 18 of which were included to assess the abuse potential of cathinone (n = 5), mephedrone (n = 7), methylone (n = 1), and diethylpropion (n = 5). All four substances induce Academic Editors: Antonio J. Carcas-Sansuán stimulant and euphorigenic effects that resemble those of amphetamines and MDMA, and their and Alberto M. Borobia Pérez different intensities may be associated with varying levels of abuse potential. Conclusions: Cathinone, mephedrone, methylone, and diethylpropion induce a range of desirable and reinforcing effects Received: 24 January 2022 that may, to some extent, result in abuse potential. Further investigation is needed to minimize and Accepted: 13 February 2022 prevent their impact on society and public health. Published: 15 February 2022 Publisher’s Note: MDPI stays neutral Keywords: cathinone; mephedrone (4-methylmethcathinone); methylone (3,4-methylenedioxymethca with regard to jurisdictional claims in thinone); diethylpropion; abuse potential; new psychoactive substance; pharmacological effects; published maps and institutional affil- pharmacokinetics iations. 1. Introduction Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. Evaluating the abuse potential of new substances, particularly that of those that are This article is an open access article able to affect the central nervous system, is necessary to determine future prescription distributed under the terms and conditions and the possible risk of misuse and addiction. In fact, the Prescriber Information conditions of the Creative Commons (PI for US-FDA) and the Summary of Product Characteristics (SPC in Europe-EMA) include Attribution (CC BY) license (https:// a specific section on this topic. creativecommons.org/licenses/by/ Research assessing abuse potential is performed in accordance with the methodology 4.0/). recommended by the Food and Drug Administration (FDA) in its industry guidelines J. Clin. Med. 2022, 11, 1004. https://doi.org/10.3390/jcm11041004 https://www.mdpi.com/journal/jcm J. Clin. Med. 2022, 11, 1004 2 of 19 entitled “Assessment of abuse potential of drugs”, published in 2017 [1]. Such studies in humans are considered Phase I clinical trials and include healthy recreational and regular substance users. In a similar manner to other Phase I trials, volunteers gain no therapeutic benefit from their participation. These studies are therefore typically carried out in spe- cialized units of human/clinical pharmacology. The methodology that is implemented for abuse potential assessment has been well established. It includes clinical trials that compare the subjective effects (such as evaluation of euphoria, liking, and well-being) that are induced by a known substance (positive control) compared to the new substance being evaluated and a placebo. Most abusable substances are generally introduced into the illegal market without specific studies and/or information. As a result, the methodology that has been described for medicines is used to evaluate the relative abuse potential of the new psychoactive substances compared to well-known drugs in order to recognize their abuse liability/potential. Abuse or addiction to a substance/medicine is an adverse drug reaction which, accord- ing to European and North American legislation, is defined as “A response to a medicinal product which is noxious and unintended” [2]. In a similar manner to other adverse drug reactions, the misuse, abuse, and addiction of a substance can be prevented by previous information and prescription limitations. Thus, it reinforces the need for experimental studies of abuse potential in animals and humans. As previously mentioned, the majority of new psychoactive substances are introduced into the illegal market and are consumed by an ever-increasing number of individuals. In most cases, these compounds become illegal due their deleterious health effects, including emergency cases and lethality. As an example, the cathinone derivative mephedrone (4-methylmethcathinone) arrived on the market in 2008. It was made illegal in 2010 in Europe and in 2011 in the United States after being used by millions around the world; the only data on its effects, however, were obtained from surveys and intoxication cases series [3]. The first Phase I clinical trial evaluating mephedrone abuse potential and pharmacokinetics in humans was published in 2016, five years after it was outlawed. This study was essential for understanding its patterns of use and abuse potential compared to MDMA. The aim of this study is to evaluate the pharmacological effects related to the abuse po- tential and pharmacokinetic properties of cathinone and synthetic cathinones by reviewing their origins, chemistry, pharmacodynamics, and pharmacokinetics using a standardized systematic review procedure. 1.1. Cathinones from Plant to Synthetics Khat (Catha edulis Forsk., Celastraceae), also known as qat, is a flowering plant that is native to Ethiopia, although it has also been widely cultivated and consumed in parts of East Africa and the Arabian Peninsula [4–7]. The fresh khat leaves are usually chewed to form a bolus (quid) to obtain stimulant and euphoric effects. In these countries, khat chewing represents a deep-rooted tradition that is undertaken to avoid hunger and fatigue as well as to ease social interaction [4,8]. This habit is a typical activity that is performed during social khat sessions, in which each participant commonly chews about 100–200 g of leaves [9]. Khat can also be ingested by making a drink from dried leaves, or more rarely, by smoking dried ones [10]. Beyond its traditional use, khat chewing has become popular among university students seeking to enhance their academic performance and to reduce fatigue [11,12]. The legal status of khat varies by region depending on its traditional use in some cultures, although it can be illegal under more general laws [6]. Khat use has spread to western countries. It can be found in major cities in the United States, Europe, and Australia, especially among immigrant communities that maintain this habit [6,13]. According to some authorities, the estimated number of individuals chewing fresh khat leaves on a regular basis ranges from 10 to 20 million, with almost half of whom doing so on a daily basis [5,6,14]. This finding indicates that it is possibly the most widely used psychoactive herb in the world [7]. In the previous decade, new psychoactive substances (NPS), also called legal highs, have become increasingly popular; according to United Nations Office on Drug and Crime (UNODC), the center of the global NPS market emerged in North America and Western and Central Europe, but it has moved to Asia, Africa, and Latin American in recent years [15]. These include non-illegal recreational alternatives that exploit the in- J. Clin. Med. 2022, 11, 1004 adequacies of existing controlled substance legislation [16,17]. According to the European 3 of 19 Drug report, synthetic cannabinoids and synthetic cathinones are the most seized NPS. In 2019, they represented 60% of seizures, although the prevalence of use of each individual substance In the is a minority previous [18].new decade, Some data clarifying psychoactive the trends substances andalso (NPS), prevalence of use called legal highs,of synthetic cathinones are provided by wastewater monitoring programs. have become increasingly popular; according to United Nations Office on Drug and Crime For instance, methylone the (UNODC), andcenter mephedrone have NPS of the global beenmarket detected in variable emerged low America in North levels in andseveral ana- Western lyzedCentral and areas of Australia. Europe, but Mephedrone it has moved and methylone to Asia, Africa,consumption were found and Latin American to be in recent higher[15]. years during These weekends, a pattern recreational include non-illegal that is consistent with that alternatives the patterns exploit the forinadequacies other illicit drugs of suchcontrolled existing as cocainesubstance and MDMA (3,4-methylenedioxymethamphetamine) legislation [16,17]. According to the European[19]. Drug report, synthetic cannabinoids and synthetic cathinones are the most seized NPS. In 2019, they 1.2. Chemistry represented 60% of seizures, although the prevalence of use of each individual substance is a minority The main[18]. Some data psychoactive clarifying alkaloid the is in khat trends and prevalence of derivative the phenylpropylamine use of synthetic cathi- cathinones are provided by wastewater monitoring programs. For instance, none (S-(-)-⍺-aminopropiophenone) (Figure 1), which comprises khat together with the methylone and less mephedrone have been detected psychoactive in variable low levels diastereomers phenylpropanolamine in several analyzed areas cathineof Australia. Mephedrone and methylone consumption (S,S-(+)-nor-pseudoephedrine) and R,S-(-)-norephedrine [5,20]. were found to be higher during weekends, a pattern In recent years, athat is consistent number with the of substituted patternshave cathinones for other been illicit drugs onto introduced suchtheas cocaine drug blackand MDMA market, (3,4-methylenedioxymethamphetamine) with some of the most relevant being[19]. mephedrone, methylone, ethylone, euthylone, and methylenedioxypyrovalerone (MDPV). However, not all syn- 1.2. Chemistry thetic cathinones are classified as abuse substances based on their psychostimulant ef- fects The andmain abusepsychoactive alkaloid potential. For in khat instance, is the phenylpropylamine diethylpropion (or amfepramone)derivative was cathinone marketed (S-(-)-α-aminopropiophenone) (Figure 1), which comprises khat as an appetite suppressant for the short-term management of obesity (schedule together with the less IV con- psychoactive phenylpropanolamine diastereomers cathine (S,S-(+)-nor-pseudoephedrine) trolled substance) for years, and bupropion is prescribed as an atypical antidepressant and and R,S-(-)-norephedrine treatment for smoking [5,20]. cessation (uncontrolled substance) [21]. (a) (b) (c) (d) Figure 1. Figure 1. Molecular structuresofofcathinone Molecular structures cathinone(a), (a),mephedrone mephedrone(b),(b), methylone methylone (c),(c), andand diethylpropion diethylpropion (d). (d). In recent years, a number of substituted cathinones have been introduced onto the 1.3. Mechanism drug of Action black market, with some of the most relevant being mephedrone, methylone, ethylone, The effects euthylone, of cathinone and its derivatives and methylenedioxypyrovalerone are mediated (MDPV). through However, thesynthetic not all reversal or in- cathi- nones hibitionareofclassified monoamineas abuse substances reuptake based onCathinone transporters. their psychostimulant preferentiallyeffects acts and as aabuse cate- potential. cholamine For instance, inhibitor anddiethylpropion (or amfepramone) dopamine releaser was marketed that has a similar profile to as an appetite amphetamine suppressant for the short-term management of obesity (schedule IV controlled [22]. In contrast, mephedrone has demonstrated its action as a nonselective monoamine substance) for years, uptake and bupropion inhibitor is prescribed and releaser as an atypical that is comparable to antidepressant MDMA [22–25]. andCathinone treatmentand for smoking mephedrone cessation (uncontrolled activity on serotoninsubstance) (SERT) and[21]. dopamine (DAT) transporters, specifically in the nucleus accumbens [26–29], may contribute to their psychostimulant-like and re- 1.3. Mechanism inforcing of Action effects, which resemble those of their respective non-βketo analogues, am- The effects phetamine and MDMA of cathinone and its [23,30,31]. derivatives Methylone has are mediated through demonstrated the reversal lower neuronal or activity inhibition of monoamine reuptake transporters. Cathinone preferentially acts as a cate- cholamine inhibitor and dopamine releaser that has a similar profile to amphetamine [22]. In contrast, mephedrone has demonstrated its action as a nonselective monoamine uptake inhibitor and releaser that is comparable to MDMA [22–25]. Cathinone and mephedrone activity on serotonin (SERT) and dopamine (DAT) transporters, specifically in the nu- cleus accumbens [26–29], may contribute to their psychostimulant-like and reinforcing effects, which resemble those of their respective non-βketo analogues, amphetamine and MDMA [23,30,31]. Methylone has demonstrated lower neuronal activity inhibition po- tency compared to MDMA, which may be caused by the addition of a ketone group for ethylone [32]. According to their selectivity on monoamine transporters, mephedrone and methylone have DAT/SERT ratios between 0.1 and 10, which are higher ratios than those obtained for MDMA. High selectivity on DAT with >10 DAT/SERT ratios may suggest increased abuse potential, especially given that dopamine has been related to reinforcing effects [33,34]. Although diethylpropion also induces dopamine efflux and slows dopamine J. Clin. Med. 2022, 11, 1004 4 of 19 reuptake in the nucleus accumbens and striatum [35], its effects are less potent compared to cocaine, bupropion, and ethcathinone [36]. 1.4. Pharmacological Effects Khat produces a plethora of effects that can mainly be attributed to cathinone and, to a lesser extent, other components of the plant, such as cathine [5,37]. Principally, khat chewing produces stimulant-like effects that are characterized by feelings of mild eupho- ria, increased alertness, and enhanced intellectual efficiency. Mild dysphoria, irritability, anorexia, and insomnia commonly appear as after effects [5,6,38]. Regarding mephedrone, it is principally consumed via the oral and intranasal routes, with usual doses ranging from 15 to 300 mg and 5 to 125 mg, respectively [39]. Mephedrone induces a spectrum of sympathomimetic and psychostimulant effects that mainly include euphoria, increased energy, mood enhancement, empathy, sociability, and changes in perception [40–42]. Methylone, similar to mephedrone, can be administered via multiples routes, although the oral route is the most common. Recreational users have reported that moderate oral doses (100–200 mg) induce a typical profile of euphorigenic and stimulant effects [43]. Diethylpropion was approved for treatment of obesity by the FDA in 1959 and has been used to achieve modest weight loss [44]. This synthetic cathinone is classified as a Schedule IV controlled substance in the United States and Canada since it has an accepted medical use. Nevertheless, although it has reduced stimulant activity and presumably low abuse potential compared to amphetamines [45], addiction should not be discarded. To date, there are few studies concerning the human pharmacology and abuse potential of cathinone and its synthetic analogues. The main purpose of this systematic review is to therefore examine and compare the pharmacological effects related to the abuse potential and pharmacokinetic properties of cathinone and synthetic cathinones, such as mephedrone, methylone, and diethylpropion, as evaluated in experimental and prospective observational studies in humans. 2. Materials and Methods This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. It has been submitted in PROSPERO with the registration ID CRD42021271851. First, eligible articles were systematically looked for and identified to select potential studies by two of the authors (A.T. and L.P.). Study selection was performed jointly, and in the cases of a discrepancy, the final decision was reached by the consensus of either both authors or with the involvement of a third person (M.F.) after reading the study summary. Data were collected by the authors A.T. and L.P. and were subsequently reviewed by another (M.F.). The published literature search was conducted with the PubMed database and covered the period up to September 2021. The keywords that were employed included “khat”, “mephedrone”, “methylone”, “diethylpropion”, “cathinone”, “synthetic cathinone”, “abuse potential”, “abuse liability”, “experimental study”, “observational study”, “naturalistic study”, “clinical trial”, “randomized clinical trial”, “pharmacological effect”, “subjective effect”, and “physiological effect”. Only articles whose abstracts met our selected criteria were included. The established inclusion criteria were experimental/observational studies evaluating the pharmacological effects related to the abuse potential of cathinone or its synthetic derivatives mephedrone, methylone, and diethylpropion in humans. Studies were considered eligible irrespective of the route used for substance administration and regardless of whether there was a control condition. Second, studies were excluded when they focused on animal models, were retrospective, and provided results obtained from a survey in which participants were not required to use the substance in order to respond (to be eligible, effects had to be evaluated during/immediately after administration/self- administration). Additionally, studies were excluded if they only provided the pharma- J. Clin. Med. 2022, 11, 1004 5 of 19 cokinetics results without evaluating the pharmacological effects. Publications identified as a commentary, editorial, or review were also excluded. Bupropion has a low abuse potential compared to amphetamines and other cathi- nones. The results of epidemiological studies show a very low prevalence of bupropion abuse. Bupropion is not a controlled substance. For these reasons, its inclusion in this systematic review was not contemplated, and studies that focused on this substance alone were excluded. The following information was obtained from the selected articles: study design, sam- ple size, dose, and route of administration; pharmacokinetic parameters in plasma/blood or oral fluid (if measured), such as maximum concentration (Cmax), time to achieve maximum concentrations (Tmax), and area under the curve (AUC); pharmacological effects related to abuse potential; and assessment tools for measuring those effects. Additionally, when possible, the correlation between the administered dose and the Cmax of the substance in blood was calculated. 3. Results In total, 583 results were obtained from the literature search, and 18 publications were selected after meeting the inclusion criteria (Figure 2). Tables 1–4 summarize the information retrieved from the selected studies about the human pharmacology and abuse- related effects of cathinone, mephedrone, methylone, and diethylpropion, respectively. All of the included studies provided results about the pharmacological effects related to abuse, and some of them also included the findings regarding pharmacokinetics. In the case of publications by the same authors that contained duplicated information about the study design, sample size, and administered dose, their results about the pharmacokinetics and pharmacological effects were unified in the corresponding table. From the accessible full-text articles about experimental studies that were screened, four were excluded for only including the pharmacokinetic data regarding the pharmacological effects of cathinone [46], diethylpropion [47], and mephedrone [48,49] without providing results. Another six studies were excluded since they evaluated pharmacological effects that were not related to the abuse potential of cathinone [9,50] or diethylpropion [51–54]. In the majority of the studies assessing the abuse potential of cathinone, mephedrone, and methylone, the participants were healthy individuals with previous psychostimulant use. Overall, most studies included small sample sizes, and not all of them comprised both genders. 3.1. Cathinone In total, we retrieved five publications (four studies) concerning cathinone adminis- tration in humans (Table 1) [4,8,20,31,55]. According to this search, four studies analyzed the pharmacokinetic properties of cathinone, which is the component responsible for the psychoactive properties of khat. In three studies, participants chewed khat leaf preparations for 1 h in doses from 0.5 to1.0 mg of cathinone per kg of body weight, which corresponds to the most popular and traditional route of administration. The mean Cmax of cathinone in the blood after khat-chewing ranged from 58.9 ng/mL to 127 ng/mL when obtained from doses of 0.684 mg/kg and 0.8 mg/kg, respectively, with a Tmax from 1.2 to 2.31 h. In another study, cathinone was orally administered in the form of gelatin capsules. They contained 0.5 mg cathinone per kg of body weight and were compared to placebo capsules. According to the figure showing the time-course of cathinone concentrations in blood, the maximum value of the time-course was approximately 105 ng/mL, and the Tmax was at 1.2 h post-administration. J. Clin. Med. 2022, 11, 1004 6 of 19 Table 1. Summary of studies evaluating abuse-related effects related to cathinone administration in humans included in this systematic review. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: 10 subjects experienced euphoria and increased intellectual efficiency and alertness (ARCI MBG, A, and BG). These effects were progressively replaced by Subjective effects: mild dysphoria and sedation Two khat bundles of 200 g, ARCI, VAS (appetite, vigilance (ARCI LSD and PCAG). Experimental, non-controlled, 14 male volunteers, habitual Nencini et al., 1986 [8] considered the usual dose for Not reported. and euphoria/dysphoria). The other four subjects reported open-label. khat users. an experienced khat user. Physiological effects: minimal amphetamine-like effects Supine SBP, DBP and HR. although they also experienced dysphoric effects. CATH showed mild anorectic effects. Physiological effects: CATH increased SBP, DBP, and HR in all the subjects. Data deduced from a figure. Subjective effects: CATH: CATH induced psychostimulant Cmax: approx. 105 ng/mL Subjective effects: and euphorigenic effects, Experimental, placebo- Orally administered gelatin AUC0–9 : 307 ± 71 ng/mL·h * ARCI. reflected by an increase in scores controlled, double-blind, capsules of 0.5 mg CATH/kg Tmax: 1.2 ± 0.55 h * Brenneisen et al., 1990 [31] Six healthy male volunteers. Physiological effects: for ARCI stimulation/ euphoria randomized and body weight. T1/2: 4.81 ± 1.05 h * SBP, DBP, and HR and amphetamine-like effects. crossover study. Placebo Norephedrine: were monitored. Physiological effects: Cmax: approx. 75 ng/mL CATH produced an increase in AUC0–9 : 489 ± 228 ng/mL·h * blood pressure and HR. Tmax: 2 h Subjective effects: CATH: CATH increased scores in the Cmax: 127 ± 53 ng/mL 0.8 mg cathinone/kg body amphetamine–effect, AUC0–9 : 415 ± 207 ng/mL·h weight (54 to 71 g fresh khat stimulation–euphoria, and Tmax: 2.12 ± 0.5 h leaves) of a standardized Subjective effects: stimulation–motor ARCI scales. Cathine: Experimental, Six healthy males without preparation of khat leaves ARCI, VAS. Subjects reported feeling more Cmax: 89 ± 51 ng/mL Widler et al., 1994 [4] placebo-controlled, previous khat chewed for 1 h. Physiological effects: SBP, excited and energetic in VAS. AUC0–9 : 466 ± 299 ng/mL·h double blind. chewing experience. CATH: 1.02 ± 0.11 mg DBP, and HR were Physiological effects: Tmax: 3.05 ± 1.22 h Cathine: 0.86 ± 0.06 mg continuously monitored. CATH produced a significant Norephedrine: Norephedrine: 0.47 ± 0.05 mg mild and slow increase in SBP Cmax: 110 ± 51 ng/mL Placebo: alkaloid-free khat. and DBP that persisted for 4 h. Tmax: 3.33 ± 2.23 h The increase in HR was AUC0–9 : 633 ± 337 ng/mL·h not significant. J. Clin. Med. 2022, 11, 1004 7 of 19 Table 1. Cont. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Blood concentrations: CATH: Cmax: 58.9 ± 18.8 ng/mL AUC: 245 ± 49 ng·min/L Tmax: 2.31 ± 0.65 h t 12 α: 0.39 ± 0.07 h Subjective effects: Subjective effects: The mental state of the subjects t 21 β: 1.50 ± 0.81 h All participants reported the was assessed using a list of Cathine: personal feeling of being alert paired terms describing Cmax: 71.2 ± 13.9 ng/mL and “energetic”. opposite states of emotion 0.6 g of khat leaves per kg body AUC: 713 ± 131 ng·min/mL Physiological effects: (“Befindlichkeitsskala”). weight chewed for 1 h: Tmax: 2.62 ± 0.77 h Participants experienced an Four (two M, two F) healthy, Physiological effects: Experimental, non-controlled, CATH: 1.14 mg/g khat (0.684 mg t 12 α: 0.24 ± 0.17 increase in blood pressure that Toennes et al., 2002; 2003 [20,55] without previous khat SBP, DBP, HR, PD, and rotator open label. cathinone/kg body weight) t 12 β: 5.22 ± 3.36 might not be caused by the chewing experience nystagmus. Reaction to visual Cathine: 0.83 mg/g khat Norephedrine: pharmacological action of the and acoustic stimuli was tested Norephedrine: 0.44 mg/g khat Cmax: 72.1 ± 12.2 ng/mL alkaloids. HR, PD, and reaction using the Wiener AUC: 710 ± 173 ng·min/mL to light showed no changes. Determinations test, and the Tmax: 2.84 ± 0.42 h Rotatory nystagmus and an individual attention and Urine concentrations: impairment of mental concentration performance was CATH: condition were not observed. tested using Test d2. Cmax: 2.5 mg/L Cathine: Cmax: 20 mg/L Norephedrine: Cmax: 30 mg/L * Data published in [4]. Table 2. Summary of studies evaluating abuse-related effects related to mephedrone administration in human included in this systematic review. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: Subjective effects: VAS, BDI, O-LIFE, and MFUQ. MEPHE produced an increase in Physiological effects: stimulant effects, particularly Not reported. - “self-confidence”, “buzzing”, and 20 MEPHE users (14 M, 6 F) MEPHE users Cognitive assessments: “dizziness”. Observational-naturalistic Freeman et al., 2012 [56] and 20 controls drug free self-administered the drug as Not reported. Prose recall (rivermead Physiological effects: controlled, open label (11 M, 9 F) they normally would (dose and behavioral memory test), - route of administration). spatial N-back, phonological Cognitive assessments: fluency, semantic fluency, trail MEPHE impaired concentration making test, Wechsler adult and memory and also enhanced reading test. psychomotor speed. J. Clin. Med. 2022, 11, 1004 8 of 19 Table 2. Cont. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: Subjective effects: Cmax: 134.6 ± 63.5 ng/mL MEPHE induced stimulant-like VAS, VESSPA, ARCI, and Experimental AUC0–12 : 519.5 ± 287.0 ng/mL·h effects, euphoria, and 12 healthy males who were pharmacological class placebo- controlled 200 mg of oral MEPHE AUC0–24 : 556.2 ± 320.2 ng/mL·h well-being and induced mild recreational users of identification questionnaire. Papaseit et al., 2016 [57] double-blind, double 100 mg of oral MDMA AUC0–inf : 556.2 ± 320.2 ng/mL·h changes in perceptions amphetamines MDMA, Physiological effects: dummy, randomized, and Placebo Tmax: 1.25 (0.5–4) h comparable to those of MDMA. MEPHE, and cathinones. Non-invasive SBP, DBP, HR, crossover trial Ke: 0.33 ± 0.07 per h Physiological effects: and PD. Electrocardiogram was t1/2: 2.15 ± 0.4 h MEPHE increased SBP, DBP, continuously monitored. HR, and PD. Subjective effects: MEPHE induced stimulant-like effects (euphoria, well-being, MEPHE alone feelings of pleasure) and mild Cmax: 172.6 ± 82.9 ng/mL Subjective effects: changes in perceptions that AUC0–6 : 549.0 ± 315.0 ng/mL·h VAS, VESSPA, ARCI, and were more intense and 200 mg of oral MEPHE + 0.8 g/kg AUC0–24 : 778.4 ± 512.9 ng/mL·h pharmacological class prolonged in combination alcohol Tmax: 1.5 (0.5–2) h identification questionnaire. Experimental with alcohol. 11 healthy males, 200 mg of oral MEPHE + placebo Ke: 0.29 ± 0.09 per h Physiological effects: placebo-controlled, Physiological effects: De Sousa et al., 2016 [58]; recreational users of alcohol t1/2: 2.68 ± 0.92 h SBP, DBP, and HR were double-blind, randomized, MEPHE produced a significant Papaseit et al., 2020 [59] amphetamines, MDMA, Placebo MEPHE + 0.8 g/kg MEPHE with alcohol continuously monitored. Oral crossover phase I increase in BP, HR, and PD. MEPHE, or cathinones. alcohol Cmax: 175.7 ± 71.1 ng/mL temperature was measured, clinical trial. Cardiovascular effects were Placebo MEPHE + placebo AUC0–6 : 516.8 ± 264.6 ng/mL·h and DP and the Maddox wing increased in combination alcohol AUC0–24 : 709.8 ± 477.1 ng/mL·h were recorded. with alcohol. Tmax: 1.5 (0.75–2) h Neurocognitive assessment: Neurocognitive assessment: Ke: 0.35 ± 0.14 per h SMT, CTT, DAT. MEPHE improves psychomotor t1/2: 2.32 ± 1.01 h performance, impairs spatial memory, and does not affect divided attention performance. MEPHE 50 mg Cmax: 37.4 ± 16.4 ng/mL Subjective effects: AUC0–8 : 122.5 ± 59.7 ng/mL·h MEPHE induced subjective Tmax: 2 (1–2) h effects (VAS high, good effects, MEPHE 100 mg stimulated) that showed a Cmax: 51.7 ± 20.5 ng/mL Subjective effects: positive correlation with drug Experimental double-blind, 50 and 100 mg of oral MEPHE AUC0–8 : 169.4 ± 93.5 ng/mL·h VAS. concentrations in the plasma at placebo controlled, Nine healthy males, (n = 3) Tmax: 1 (1–2) h Olesti et al., 2017; 2019 [60,61] Physiological effects: each tested MEPHE dose. randomized, crossover, recreational users of NPS. 150 and 200 mg of oral MEPHE MEPHE 150 mg SBP, DBP, and HR were Physiological effects: phase I clinical trial. (n = 6) Cmax: 179.0 ± 29.3 ng/mL continuously monitored. MEPHE produced AUC0–8 : 588.2 ± 93.4 ng/mL·h cardiovascular effects that Tmax: 1 (1–2) h correlated positively with drug MEPHE 200 mg concentrations in the plasma at Cmax: 255.6 ± 70.0 ng/mL each tested MEPHE dose. AUC0–8 : 879.4 ± 194.1 ng/mL·h Tmax: 1 (1–2) h J. Clin. Med. 2022, 11, 1004 9 of 19 Table 2. Cont. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: Oral fluid concentrations MEPHE oral Oral MEPHE: self-administration in Self-administration of oral Cmax: 1571 ± 1367 ng/mL Subjective effects: comparison to intranasal MEPHE (n = 5, 100–200 mg; AUC0–4 : 3684 ± 3443 ng/mL·h VAS, VESSPA, ARCI. produced greater and larger Observational-naturalistic, 10 (4 F, 6 M) healthy subjects, mean 150 mg) Papaseit et al., 2021 [62] Tmax: 2 (1–2) h Physiological effects: effects on some subjective non-controlled, open label. recreational users. Self-administration of intranasal Intranasal MEPHE: Non-invasive SBP, DBP, HR, measures. MEPHE (n = 5, 50–100 mg, Cmax: 4950 ± 5545 ng/mL and cutaneous temperature. Physiological effects: mean 70 mg) AUC0–4 : 7919 ± 7717 ng/mL·h Both MEPHE Tmax: 1 (1–1) h self-administrations produced an increase in SBP, DBP, HR. Table 3. Summary of studies evaluating abuse-related effects related to methylone administration in human included in this systematic review. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD (Range)] Subjective effects: METHY induced similar Self-administration of oral Subjective effects: psychostimulant and METHY (n = 8, 100–300 mg; Oral fluid concentrations: VAS, VESSPA, ARCI. empathogenic effects to Observational- naturalistic 14 (4 F, 10 M) healthy mean 187.5 mg) Cmax: 15,514.00 ± 9748.86 ng/mL Poyatos et al., 2021 [63] Physiological effects: MDMA, but they were non-controlled, open label. subjects, recreational users. Self-administration of oral AUC0–4 : 40,623.79 ± 20,001.70 ng/mL·h Non-invasive SBP, DBP, HR, less intense. MDMA (n = 6, 75–100 mg, Tmax: 2 (2–2) h and cutaneous temperature. Physiological effects: mean 87.5 mg) METHY produced an increase in SBP and HR. Table 4. Summary of studies evaluating abuse-related effects related to diethylpropion included in this systematic review. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: Relative to placebo, both doses of Subjective effects: DEP gave results in the same 25, 50 mg of oral DEP Scales comprising 20 variables direction as pipradrol. Compared Double-blind study in 20 mg of oral pipradrol (e.g., happiness, alertness, to placebo, DEP obtained higher Jonsson et al., 1969 [64] 116 subjects of both genders. Not reported. natural environment. 100 mg of oral amobarbital relaxation, flight of thoughts), scores for “happy”, “alert”, and Placebo Physiological effects: “flight of thoughts” and lower - scores in “relaxed”. Physiological effects: - J. Clin. Med. 2022, 11, 1004 10 of 19 Table 4. Cont. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: DEP produced stimulant-like effects reflected in feelings of 50 mg of oral DEP Subjective effects: “happiness” similar to 10 mg of oral dexamphetamine Scales comprising ratings of dexamphetamine, “alertness”, Experimental, triple-blind Jonsson et al., 1969 [64] 30 young males. 50 mg oral phenmetrazine Not reported. pleasantness. and “pleasantness”. The effects of study in laboratory conditions. 250 mg caffeine Physiological effects: “pleasantness” came in between Placebo - phenmetrazine and dexamphetamine. Physiological effects: - Subjective effects: DEP produced effects that were Subjective effects: qualitatively similar to those of 150, 300, and 600 mg of Drug identifications and d-amphetamine subcutaneous DEP “liking scores” from the including euphoria. nine healthy federal prisoners 100, 200, and 400 mg of Experimental, comparative, subject’s and observer’s Orally DEP was 1/6 to 1/11 as with documented histories of oral DEP placebo controlled, single-dose opiate potent as d-amphetamine, while Jasinski et al., 1974 [65] narcotic abuse. All admitted 7.5, 15, and 30 mg of Not reported. double-blind, questionnaires and ARCI (BG, subcutaneously, DEP was 1/10 to prior abuse of subcutaneous d-amphetamine randomized, crossover. MBG, A). 1/20 as potent as d-amphetamine. amphetamine-like agents. 10, 20, and 40 mg of oral Physiological effects: Physiological effects: d-amphetamine SBP, DBP, HR, rectal DEP increased blood pressure Placebo condition temperature, and PD. and body temperature and decreased caloric intake and sleep. Subjective effects: Subjects participated in three to In comparisons between DEP and six different choice experiments d-amphetamine, d-amphetamine Subjective effects: self-administering oral was generally preferred. Drug preference, POMS, choice procedure. Johanson et al., 1978 [66] 10 (7 M, 3 F) healthy volunteers. capsules of: Not reported. However, as the dose of DEP placebo controlled. Physiological effects: 25, 50 mg of DEP increased, preference for - 5, 10 mg of d-amphetamine d-amphetamine decreased. Placebo Physiological effects: - Subjective effects: DEP, with a similar profile to Subjective effects: amphetamine, maintained drug Drug preference, Not reported. 75 mg of DEP Choice procedure. Bigelow et al., 1984 [67] Not reported. preference well above placebo placebo controlled. Overweight patients. Placebo Physiological effects: levels (approx. 75%). - Physiological effects: - J. Clin. Med. 2022, 11, 1004 11 of 19 Table 4. Cont. Pharmacokinetics Reference Type of Study Sample Size Dose Assessments Abuse-Related Effects [Mean ± SD, (Range)] Subjective effects: In terms of abuse potential, 200 mg of DEP was appraised as having a comparable street value Experimental, placebo 200 mg of oral DEP Subjective effects: 38 (32 M, 6 F) volunteers with a as 100 and 150 mg of LDX. controlled, double-blind, 50, 100, and 150 mg of oral LDX DRQS, ARCI, SVAQ. Jasinski et al., 2009 [68] history of stimulant abuse. Not reported. Physiological effects: randomized, six-period 40 mg of oral d-amphetamine Physiological effects: Only 36 completed the study. All treatments produced crossover study. Placebo SBP, DBP, HR. cardiovascular effects. Increases in SBP and DBP were significantly lower for 50 mg LDX and DEP than for d-amphetamine. Abbreviations: Cmax, maximum concentration after administration; Tmax, time needed to reach maximum concentrations; AUC, area under the curve; T1/2, elimination half-life; Ke, elimination rate constant; SD, standard deviations; F, female; M, male; CATH, cathinone; DEP, diethylpropion; LDX, lisdexamfetamine dimesylate; MEPHE, mephedrone; MDMA, 3,4-methylenedioxymethamphetamine; METHY, methylone; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; PD, pupillary diameter; ARCI, Addiction Research Center Inventory; PCAG, pentobarbital–chlorpromazine–alcohol group (sedation); MBG, morphine–benzedrine group (euphoria); BG, benzedrine group (intellectual efficiency); A, amphetamine group (increased energy); VAS, visual analogue scales; VESSPA, Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire; POMS, Profile of Mood States; DRQS, Liking Scale of the Drug Rating Questionnaire-Subject; SVAQ, Street Value Assessment Questionnaire; BDI, Beck depression inventory, O-LIFE, Oxford–Liverpool inventory of feelings and experiences, MFUQ, Mephedrone and future use questionnaire; SMT, Spatial Memory Test; CTT, Critical Tracking Test; DAT, Divided Attention Test. J. Clin.11, J. Clin. Med. 2022, Med. 10042022, 11, x FOR PEER REVIEW 12 of 19 6 of Identification of studies via databases and registers Identification Records identified from: Records removed after applying filters (n= 306) PubMed (n= 583) - Not human subjects (n= 296) - Review or editorial literature (n= 10) Records screened (titles and Records excluded after screening of titles and abstracts) (n= 277) abstracts (n= 223) - Did not addressed substances of interest (n= 126) - Did not addressed outcomes of interest (n= 97) Screening Records assessed for eligibility Full-text articles excluded (n= 28) (full-text articles) (n= 46) - Not prospective studies (n= 18) - Only pharmacokinetic data (n= 4) - Did not evaluated abuse related effects (n= 6) Included Records included in review (full-text articles) (n= 18) Figure 2. PRISMA flow chart for the study selection and data extraction. Figure 2. PRISMA flow chart for the study selection and data extraction. Regarding abuse-related effects, cathinone produced an increase in the participants’ From the accessible full-text articles about experimental studies that were screened blood pressure and heart rate, and the most common subjective effects were euphorigenic four were ones, increased excluded energy, for only and motor including the pharmacokinetic data regarding the pharma stimulation. cological effects of cathinone [46], diethylpropion [47], and mephedrone [48,49] withou providing results. Another six studies were excluded since they evaluated pharmaco 3.2. Mephedrone logical A total effects of seven that werecorresponding publications, not related totothe fiveabuse potential studies, of pharmacokinetic about the cathinone [9,50] or dieth ylpropion [51–54]. and acute effects of mephedrone in humans were retrieved (Table 2) [56–62]. Out of the six studies, fiveInevaluated the majority of the mephedrone studies assessing concentrations the or in the blood abuse potential oral fluid, whileofthecathinon mephedrone, and methylone, the participants were healthy individuals other only collected the pharmacological effects reported by the participants after using with previou psychostimulant use. Overall, most studies included small sample unknown doses. Specifically, four studies analyzed the time course of the mephedrone sizes, and not all o them comprised both genders. concentrations in the blood, whereas oral fluid was used as an alternative matrix in an observational study. In one study, mephedrone was also administrated in combination with alcohol (0.8 g/kg) to assess their interaction and impact on the subjective, cardiovascular, and hormone effects as well as the pharmacokinetics. Together with the evaluation of abuse-related effects, the mephedrone concentrations in blood and oral fluid were studied after oral administration in four studies (doses from 50 to 200 mg) and after intranasal administration in an observational one (doses from 50 to 100 mg, mean dose 70 mg). The Cmax following the oral administration of mephedrone seemed to be dose de- pendent. The lowest oral dose of 50 mg resulted in a Cmax of 37.4 ng/mL, whereas the highest Cmax value of 255.6 ng/mL corresponded to 200 mg. In general, the maximum concentrations of mephedrone reached between 1 and 1.5 h after oral administration. Studies that evaluated the pharmacological effects of mephedrone found its stimu- lant effects to be characterized by an increase in the cardiovascular effects and pupillary diameter, euphoria, mild changes in perceptions, and memory impairment. In the case of mephedrone, it was possible to calculate a correlation between single orally administered doses of mephedrone and the Cmax achieved in the blood. Oral doses J. Clin. Med. 2022, 11, 1004 13 of 19 J. Clin. Med. 2022, 11, x FOR PEER REVIEW 19 of 26 of mephedrone and their respective Cmax in the blood showed a moderate correlation with a Pearson’s r of 0.8353 and a coefficient of determination of 0.6977 (p value of 0.0193) (Figure 3). Mephedrone 300 Cmax in blood (ng/mL) 200 100 0 0 50 100 150 200 250 Oral dose (mg) Figure 3. Correlation between oral mephedrone dose and the maximum concentration reached Figure 3. Correlation between oral mephedrone dose and the maximum concentration reached in in blood. blood. 3.3. Methylone 3.3. Methylone Only one study concerning methylone administration in humans was found in the literature Only one(Table 3) [63]. study This observational concerning methylonestudy was carriedin administration out in naturalistic humans settings, was found in the where eight literature participants (Table selected 3) [63]. This their oral methylone observational study wasdoses from carried outbetween 100 to 300 in naturalistic mg settings, (mean dose 187.5 mg) according to their experience with psychostimulant where eight participants selected their oral methylone doses from between 100 to 300 mguse (Poyatos, 2021).dose (mean A total of six 187.5 mg)participants according to self-administered their experiencea single oral dose of 75 oruse with psychostimulant 100(Poyatos, mg of MDMA. Concentrations of methylone were analyzed in the oral fluid, obtaining 2021). A total of six participants self-administered a single oral dose of 75 or 100 mg a Cmax of of 15,514.0 and a Tmax of 2 h. The self-administration of methylone produced an increase in MDMA. Concentrations of methylone were analyzed in the oral fluid, obtaining a Cmax the systolic blood pressure and heart rate, accompanied by psychostimulant-like effects of 15,514.0 and a Tmax of 2 h. The self-administration of methylone produced an increase such as “stimulation”, “high”, and “good effects”. in the systolic blood pressure and heart rate, accompanied by psychostimulant-like ef- fects 3.4. such as “stimulation”, “high”, and “good effects”. Diethylpropion Regarding diethylpropion, five publications (six studies) were retrieved (Table 4) [64–68]. 3.4. Diethylpropion Among the selected studies, diethylpropion was administered to compare it to d-amphetam ine Regarding [65]; d-amphetamine and lisdexamfetamine diethylpropion, five publications [68];(six pipradrol studies)and amobarbital were retrieved[64]; and 4) (Table dexamphetamine, phenmetrazine, and caffeine [64] in four studies. [64–68]. Among the selected studies, diethylpropion was administered to compare it to Two studies [65]; d-amphetamine assessed participant preferences d-amphetamine for diethylpropion [68]; and lisdexamfetamine compared to placebo pipradrol andoramo- d- amphetamine. This type of research is considered the paradigm of abuse potential barbital [64]; and dexamphetamine, phenmetrazine, and caffeine [64] in four studies. assessment. Diethylpropion Two produced studies assessed effects that participant were qualitatively preferences similar, butcompared for diethylpropion less intense, to to pla- those of d-amphetamine, with euphoria, increased blood pressure and body temperature, cebo or d-amphetamine. This type of research is considered the paradigm of abuse po- and decreased food intake being observed. Some adverse effects such as anxiety, irritability, tential assessment. dry mouth, and insomnia did, however, appear within the first three months of treatment. Diethylpropion produced effects that were qualitatively similar, but less intense, to those of d-amphetamine, with euphoria, increased blood pressure and body temperature, 4. Discussion and decreased To the bestfood intake of our being observed. knowledge, Some this is the first adverse review systematic effects that suchis as anxiety, aimed irrita- at inves- bility, tigating and comparing the abuse-related effects and pharmacokinetic profiles of cathinone of dry mouth, and insomnia did, however, appear within the first three months treatment. and other synthetic derivatives such as mephedrone, methylone, and diethylpropion. Our search was focused on cathinone, which is the main compound of the khat plant, and 4.three Discussion synthetic cathinones, one of which was approved for therapeutic purposes and two others To that are considered the best substancesthis of our knowledge, of abuse. Information is the first regarding systematic reviewthe abuse that potential is aimed at in- of synthetic cathinones is scarce despite representing the second largest group vestigating and comparing the abuse-related effects and pharmacokinetic profiles of monitored by the European cathinone Union and other Early Warning synthetic System derivatives andastheir such relevant impact mephedrone, on public methylone, health and dieth- and security. Synthetic cathinones have been related to several cases of intoxication and ylpropion. Our search was focused on cathinone, which is the main compound of the fatalities over the years [69]. The variety of these compounds on the market is constantly khat plant, and three synthetic cathinones, one of which was approved for therapeutic growing; nevertheless, few components of this group have been researched in humans. purposes and two others that are considered substances of abuse. Information regarding the abuse potential of synthetic cathinones is scarce despite representing the second largest group monitored by the European Union Early Warning System and their rele- vant impact on public health and security. Synthetic cathinones have been related to several cases of intoxication and fatalities over the years [69]. The variety of these com- J. Clin. Med. 2022, 11, 1004 14 of 19 Moreover, the abuse potential of synthetic cathinones assessed in various preclinical animal models has only been reviewed recently [70]. The studies included in this systematic review provided data about the subjective effects related to the abuse potential of cathinone and some of its synthetic derivatives. They employed validated methods recognized by the FDA and Health Canada for the assessment of abuse potential [1]. Most of the studies evaluated acute reinforcing effects of substances through ARCI and/or VAS, whereas others incorporated VESSPA, POMS, and additional specific questionnaires. Self-administration studies about drug preference were also included, and they directly evaluated whether the substance had rewarding or reinforcing properties. Drug discrimination questionnaires, such as the pharmacological class identification questionnaire, were used in some studies to assess whether the drug had effects that were similar to other known drugs of abuse. 4.1. Cathinone In the majority of studies involving cathinone, the selected route of administration was chewing khat leaves for 1 h. As it has been previously mentioned, this is, by far, the most popular way of cathinone administration due to its traditional background in several African and West Asian countries. Cathinone that was ingested by khat-chewing demonstrated slower pharmacokinetics and the delayed onset of pharmacological effects compared to when cathinone was contained in capsules. This was mainly due to the delayed release of the alkaloid from the leaf matrix during mastication [4]. During chewing, the buccal mucosa was responsible for most of the absorption of the three alkaloids [20]. Such absorption allows the drug to enter directly into systemic circulation, bypassing the gastrointestinal tract and first-pass metabolism in the liver. A second absorption of the swallowed juice, however, takes place in the stomach or small intestine. In some studies, cathine and norephedrine, the main metabolites of cathinone as well as the components of the khat plant [71], were analyzed. Although these metabolites are active compounds and may contribute to psychoactive effects, their action is less potent than that of cathinone [37,72]. 4.2. Mephedrone According to our search, mephedrone is the most investigated synthetic cathinone in humans. Mephedrone users reported consuming this substance as a substitute for MDMA due to its similar pharmacological effects. The pharmacological profile and pharmacokinet- ics of mephedrone were evaluated following oral and intranasal administration, both of which are considered the most conventional routes. In terms of oral administration, mephedrone was employed in comparison with MDMA, which was used as a prototypical psychostimulant reference [57]. Under controlled conditions, an oral dose of 200 mg mephedrone produced noticeable cardiovascular effects and induced stimulant-like and pleasurable effects that were comparable to those produced by MDMA. In comparison to 100 mg of MDMA, the pharmacological effects of mephedrone had an earlier onset and faster disappearance. This event may be related to the brief elimination half-life of mephedrone, which could lead to a compulsive consumption pattern to maintain the desired effects in real life conditions. Mephedrone administration has been also studied in combination with alcohol, the substance it is most commonly combined with on the nightlife scene. In this study, 200 mg of mephedrone was administered in combination with 0.8 g/kg alcohol or placebo [58,59]. The concomitant administration of mephedrone and alcohol amplified the cardiovascular effects and induced more intense and prolonged feelings of euphoria and well-being associated with mephedrone. In turn, mephedrone reduced the drunkenness and sedation produced by alcohol, although this apparently improved state was not reflected in the psychomotor performance. In general, such improved subjective effects could suggest the greater abuse potential of the simultaneous consumption of mephedrone and alcohol in addition to a heightened risk of serious adverse effects associated with both. J. Clin. Med. 2022, 11, 1004 15 of 19 The most popular mephedrone administration route is insufflation, and few studies have analyzed the pharmacokinetics of mephedrone and its metabolites in human plasma and oral fluid after intranasal administration [48,49,62]. As expected, mephedrone concen- trations reached its maximum levels in the blood earlier after the intranasal administration of 100 mg (Tmax of 0.88 ± 0.35 h) [49] compared to the oral administration of the same dose (Tmax of 1 h ranging from 1 to 2 h) in laboratory conditions [60]. This rapid absorption produces fast and short-lasting pharmacological effects, which often lead to a pattern of repetitive use in users intending to prolong the desired effects. In an observational study comparing these two routes, oral self-administration produced greater and larger effects on some subjective measures [62]. The authors did, however, comment that the subjective effects after intranasal self-administration could be underestimated due to the first evalua- tion (at 1 h) being conducted after the expected maximum subjective effects were induced. Regarding the oral fluid concentrations of mephedrone, those were considerably higher after intranasal administration compared to oral administration [62]. 4.3. Methylone In a similar manner, methylone, another synthetic cathinone of abuse potential com- parable to mephedrone, has been shown to produce the prototypical psychostimulant and empathogenic effects associated with MDMA. These include euphoria, stimulation, perception alteration, energy increase, and sociability, although to a lesser extent. The results suggest that methylone induced a similar profile of effects to its non-β-analogue MDMA and mephedrone [62,63], both of which were also administered in naturalistic conditions but showed lower intensity of effects. 4.4. Diethylpropion In contrast to cathinone, mephedrone, and methylone, which are considered sub- stances of abuse, diethylpropion, due to its relatively lower abuse potential compared to amphetamine, has been commercialized as an appetite suppressant and obesity treat- ment under the trade names of Tenuate® and Tepanil® . Tenuate® has, however, currently been discontinued on the North American market according to the FDA. The efficacy of diethylpropion for the treatment of overweight and obese patients has been previously discussed [44,73,74]. Most studies regarding diethylpropion have focused on its therapeutic effects, for in- stance, as an anorectic agent. A few other studies have, however, evaluated the abuse potential of this synthetic cathinone i compared to other substances, such as d-amphetamine [65,66] and lisdexamfetamine [68]. One of them aimed to assess participant preferences between diethylpropion and d-amphetamine at different doses and to measure the reinforcing properties of these drugs. Although the results demonstrated that the subjects gener- ally preferred both amphetamine and diethylpropion to placebo, diethylpropion seemed to show weaker reinforcing properties in comparison to amphetamine [66]. In terms of psychotropic effects, diethylpropion produced effects that were qualitatively similar to those of d-amphetamine, with feelings of euphoria and increased blood pressure being observed, although with less intensity [65,68]. Compared to lisdexamfetamine, there were no statistically significant differences in terms of abuse-related liking scores [68]. In a study evaluating diethylpropion, healthy participants received a single oral dose of 75 mg, and its pharmacokinetics were assessed according to the metabolizer profile, distinguishing among slow, intermediate, normal, and fast metabolizers [47]. The means of the main pharmacokinetic parameters obtained from each metabolizer phenotype were significantly different, with an approximately threefold variation between the slowest (Cmax 11.07 ng/mL and AUC0-t 48.84 ng/mL·h) and fastest (Cmax 4.12 ng/mL and AUC0-t 15.30 ng/mL·h) phenotypes. Overall, in terms of pharmacological effects, cathinone, diethylpropion, mephedrone, and methylone shared a similar stimulant profile to other recreational substances, such as MDMA and amphetamine [57,63,75]. These substances commonly produce an increase in J. Clin. Med. 2022, 11, 1004 16 of 19 cardiovascular effects and body temperature as well as stimulant and euphorigenic effects. The greater the intensity of the rewarding effects, the higher the abuse potential (cathinone and mephedrone). The correlation between the oral administration dose and Cmax in blood is the only possible method through which mephedrone could be calculated since the pharmacokinetic data of cathinone, methylone, and diethylpropion were insufficient. Doses of mephedrone that were administered orally through capsules and Cmax in the blood presented a signifi- cant moderate to strong correlation. This suggests that the absorption of mephedrone is constant at these evaluated doses, which may prove useful for predicting or extrapolating the Cmax value at any mephedrone dose between the evaluated ranges. 4.5. Limitations This systematic review has some limitations that should be considered. Firstly, only one database, PubMed, was consulted for publication retrieval. Moreover, the search was limited to English. Inclusion was restricted to prospective studies, so the results obtained from retrospective studies, such as surveys about previous consumption, were not accepted. Due to the scarcity of studies about the abuse potential of synthetic cathinones in humans, only those concerning mephedrone, methylone, and diethylpropion were included in this review. The variety of study designs hindered the identification of consistent differences among the compared substances. We included both experimental placebo-controlled trials and observational prospective studies. Whilst it may be a limitation, inclusion was based on the fact that evaluation was performed with similar questionnaires and methods to assess abuse potential. 5. Conclusions In conclusion, despite the large number of existing synthetic cathinones and the constant appearance of other derivatives, research about their abuse potential and phar- macokinetics is still very limited. Mephedrone is the most studied synthetic cathinone used for recreational purposes; little is known, however, about the great majority of other synthetic cathinones. Regardless of their legal status, cathinone and its synthetic derivatives induce a range of desirable and reinforcing effects that may result in some degree of abuse potential. All four substances share a similar psychostimulant profile that is close to the profiles of amphetamines and MDMA. The different intensities of the desirable effects they present may be associated with varying levels of abuse potential. Mephedrone showed a moderate correlation between the administration dose and Cmax in experimental studies administering single oral doses. Further investigation is needed to shed light on the abuse potential of cathinone and its synthetic derivatives to minimize the impact of their consumption on society and to detect and prevent any medical complications associated with their use and abuse. Author Contributions: Conceptualization, L.P., A.T., E.P., C.P.-M., M.T., D.F., R.M. and M.F.; method- ology, L.P., A.T. and M.F.; data curation, L.P., A.T., O.H., M.N.-M. and G.d.l.R.; writing—original draft preparation, M.F., L.P. and A.T.; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript. Funding: This research was partially funded by the Instituto de Salud Carlos III (ISCIII, Fondo Investigación Sanitaria (FIS)-Fondo Europeo de Desarrollo Regional (FEDER)), grant number FIS PI17/01962, FIS PI14/00715 and FIS PI20/00879, and predoctoral PFIS FI18/00179 (L. Poyatos), ISCIII-Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS)-Red de Investigación en Atención Primaria de Adicciones (RIAPAd), grant numbers RD21/0009/0001 and RD21/0009/0004, and Ministerio de Sanidad, Política Social e Igualdad (Plan Nacional sobre Drogas -PNSD), grant number 2018I020. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. J. Clin. Med. 2022, 11, 1004 17 of 19 Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare that they have no conflicts of interest. References 1. Food and Drug Administration (FDA). Assessment of Abuse Potential of Drugs—Guidance for Industry; Food and Drug Administration (FDA): Silver Spring, MD, USA, 2017; pp. 1–37. 2. Directive of the European Parliament and of the Council. 2010/84/EU Directive 2010/84/EU of the European Parliament and the Council of 15 December 2010 Amending as Regards Pharmacovigilance, Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use; European Union: Maastricht, The Netherlands, 2010. 3. Papaseit, E.; Moltó, J.; Muga, R.; Torrens, M.; de la Torre, R.; Farré, M. Clinical Pharmacology of the Synthetic Cathinone Mephedrone. Curr. Top. Behav. Neurosci. 2017, 32, 313–331. [CrossRef] 4. 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