Serotonergic psychedelics, including the recreationally used psilocybin and LSD, have become promising therapeutic agents for the treatment of treatment-resistant depression. While it is generally agreed that they exhibit their antidepressant effects by inducing rapid and sustained neuroplasticity, the molecular mechanisms responsible are widely debated. In particular, the role of the serotonin 5-HT2A receptor, known to mediate the hallucinogenic effects of psychedelics, is under scrutiny. However, many studies remain in conflict on whether action at the receptor is also required for neuroplastic effects. In this narrative review, we examine the available evidence for the involvement of the 5-HT2A receptor in neuroplasticity induction and the possibly antidepressant effects of psychedelics. Firstly, we review the role of decreased neuroplasticity in depression, the evidence for dendrito-, spino- and synaptogenesis promotion by psychedelics, and for its possible regional selectivity. We then discuss the current knowledge on psychedelic action at the 5-HT2A receptor, including its role in promoting hallucinogenic effects. Finally, we critically assess the studies testing the necessity for 5-HT2A signalling for neuroplastic effects and present a model of molecular mechanisms responsible for psychedelic-induced neuroplasticity.

Abstract Comorbid problems often coincide in individuals with autism spectrum disorder (ASD). Many parent-mediated systemic interventions have been developed for children to address these comorbid problems, with varying success. This study presents a systemic parent-mediated intervention, The Essential 5®. The effects of this intervention on comorbid social, cognitive and emotional problems in children with ASD were measured with the Child Behavioral Checklist (CBCL). In this study 952 children (6–16 years) and their parents/caregivers participated. There was a significant reduction on the CBCL total scale after the intervention (F = 504,149; p < .001, η²=.347), both for boys and girls separately. The reduction was found on all scales. When the CBCL was analysed as a clinical DSM-scale, all scales significantly decreased after the intervention for the whole group and for boys and girls separately. Based on the CBCL normative data 60% of the children had t-scores below the clinical range at the end of the intervention, compared to 36.6% before the intervention (χ2 = 11.34, p < 0.01). Therefore, it can be concluded that The Essential 5® intervention is effective in reducing comorbid problem behavior in children with ASD. These results clearly invites for more research into the validity of this intervention.

Nitrous oxide (N2O), used medically as an anaesthetic, has gained popularity as a recreational drug, with rising prevalence particularly among young adults. While its reinforcing and addictive potential remains debated, N2O is proven to be neurotoxic, especially with prolonged, heavy use, which is often unexpected for users. The neurotoxicological mechanism underlying N2O-induced neurotoxicity involves inactivation of vitamin B12 (cobalamin), which disrupts methionine synthesis, essential for maintaining the myelin sheath. This can result in demyelinating diseases, including generalized demyelinating polyneuropathy (GDP). Clinical incidence of N2O-induced peripheral neuropathy is largely unknown, although some research suggests it is not uncommon. Treatment includes immediate cessation of N2O use and vitamin B12 supplementation. Although this treatment often reverses damage, residual symptoms such as limb weakness may persist. Additionally, genetic and dietary factors, such as vitamin B12 deficiency, may heighten individual vulnerability for N2O's detrimental effects.

Sex under the influence of psychoactive substances (SUIPS) has gained much attention in the press and scientific literature over the last years, especially among men who have sex with men (MSM). Concerns have thus far been expressed in relation to short-term physical health risks, like contracting bloodborne diseases, like viruses. However, much less is known about long-term mental health consequences of SUIPS, like depression, anxiety, and substance use disorders (SUD). Therefore, we systematically reviewed literature for evidence on mental health complications of SUIPS in MSM. SUIPS was associated with a lower general mental health status, and higher rates of depression, anxiety disorders and suicide ideation in 15 studies, and higher rates of SUD were found among MSM practicing SUIPS in four studies. Motives of SUIPS were increasing sexual performance, fear of rejection, anxiety, and low self-esteem among others. Furthermore, long-term mental health risks, as associated with some of the most frequently reported psychoactive substances in the context of SUIPS, include psychosis and substance dependence. Therefore, the present findings indicate that SUIPS is associated with mental disorders and that they are probably closely intertwined with motives for SUIPS and the long-term effects of using psychoactive substances. This underlines the need to address the presence of mental disorders in people practicing SUIPS, alongside the physical risks.

BACKGROUND:Preterm care involves clinical measures almost exclusively aimed at keeping the preterm alive and ready for discharge from hospital. Children are then enrolled in clinical follow-up care after this stressful period, but mental or specialised care for parents and child is often not embedded in the routine of a neonatal hospital ward and the family is then dependent on institutions for mental health or child health clinics, that is, regular care that is regionally scattered. This study aimed to investigate experiences of parents with regular care and compare them with parents visiting a fixed, specialised, multidisciplinary institute, outside the hospital walls, for preterm follow-up care.METHODS:A survey was conducted among 56 parents (regular follow-up care N = 26; multidisciplinary follow-up care N = 30) of children born prematurely. The survey consisted out of items like parents' experiences with follow-up care, like the organisation of care, supportive care, environmental support and experienced stress.RESULTS:Parents receiving multidisciplinary follow-up care reported higher levels of satisfaction with organisation of care (F = 5.45; p = 0.023) and supportive care (F = 11.69; p = 0.001) than parents receiving regular follow-up care. Also, it was found that the extent of support from the social environment alleviated stress but only in parents receiving regular follow-up care (ß = -0.47; p = 0.016).CONCLUSIONS:The current study findings indicate that experience with follow-up care is valued higher when receiving multidisciplinary care than regular care, and the degree in environmental support alleviates stress in parents receiving regular care.

Evidence for a claim about nitrous oxide as an addictive substance is far from clear-cut. Back et al.'s article invites a thorough revisit of the DSM-5 criteria to disentangle neuropharmacological evidence and to look at concrete epidemiological data to base an informed opinion on this matter. Substances of dependence activate a common neurobiological route of the mesocorticolimbic dopamine system that classically translates into craving, tolerance and withdrawal symptoms upon discontinuation of the drug, as a recent excellent review has reiterated [1]. Although nitrous oxide has been used and studied since the 19th century, the existence of these symptoms among nitrous oxide users have scarcely, if ever, been reported [2]. Reading Back et al.'s article [3] invites an exploration of the very aspects that comprise addiction and a critical look at the DSM-5 criteria to understand whether or not nitrous oxide is an addictive substance. Unlike other addictive substances, nitrous oxide failed to induce reinforcement in animal studies [3, 4], whereas human studies yielded mixed results at best [5, 6]. As a neuroscientist with more than two decades of experience in the field of addiction, the lack of solid neuropharmacological evidence leaves me sceptical. In some of my own research and based upon older studies, I found evidence of mechanisms of action through which nitrous oxide is able to increase dopaminergic firing [7], either through blockade of the N-methyl-D-aspartate (NMDA)-receptor system or through direct release of endogenous opioids [8, 9]. However, given the extremely short half-life of nitrous oxide, it is doubtful whether these pathways invoke the typical long-lasting mesocorticolimbic changes, as is well known from pioneering work by Volkow and others [1]. In fact, the controversy regarding some of the core addiction traits, such as craving, withdrawal or tolerance, have led to nitrous oxide and other volatiles or fumes to be placed under a separate category of 'inhalant use disorder' in the DSM-5 [10]. Nevertheless, the exercise by Back et al. into the possible addictive properties of nitrous oxide on the basis of DSM-5 criteria is not without merit. Nitrous oxide has an image of being relatively innocent and 'fun' and ideal for social use, especially among younger users [11]. It could also function as an alternative for substances which are deemed too dangerous because of their illicit status [11, 12]. However, binge use has led to decreased vitamin B12 and subsequent physical damage [13, 14]. Therefore, the existence of harmful use is obvious, but this is not the same as addiction. In their exercise, Back et al. found strongest evidence for harmful use (criterion 8), negative social consequences (mainly criterion 6), spending a substantial amount of time using (criterion 3) and using more than intended (criterion 1). However, most evidence is qualitative or anecdotal, something that Back et al. also acknowledge. In light of the fact that mainly young users seem to be attracted to nitrous oxide use, one might regard it as part of risk-taking behaviour, as young people tend to take more uninformed risks anyway. For instance, binge alcohol use is typically prevalent among adolescents and young adults [15], and binge-use is definitely not addiction per se [16]. Hence, the criterion of using more nitrous oxide than intended can also be seen in this light. In addition, it is not always clear from these studies whether social problems were already present or not, so disentangling cause and effect is difficult. Finally, physical harm caused by misuse could very probably be due to uninformed decisions, as many users were not aware of the potentially dangerous consequences of vitamin B12 deficiency [13]. Therefore, my main argument here is that the complex neuropharmacological phenomenon of addiction is not always covered by the mere presence of separate DSM-5 criteria. Finally, my foremost concern about qualifying nitrous oxide as an addictive substance is the absence of epidemiological data. It would stand to reason that if nitrous oxide has addictive properties, following its popularity we would see a clear rise of people in addiction treatment. However, this is not the case; Fildago et al. failed to find any epidemiological data [17], aside from reported case studies, and concluded that it has merely a weak addiction potential, thereby justifying nitrous oxide's separate status in the DSM-5. Taking all evidence together, it would be wise to treat nitrous oxide (and other volatiles) as non-typical substance(s) of misuse and to refrain from the (burdened) term addiction, at least until more convincing evidence emerges. Notwithstanding, it is a worthwhile endeavour to revisit the basics of addiction and to critically reassess substances from time to time, for which I owe gratitude to Back et al. None. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Introduction: The use of anabolic androgenic steroids (AAS) and other image- and performance-enhancing drugs is a growing public health concern. AAS use is associated with various physical and mental harms, including cardiovascular risks, cognitive deficiencies, and dependence. The aim of this study was to determine whether patterns of AAS use and other variables are associated with the presence of an AAS use disorder (AASUD). Methods: An online survey was completed by 103 male AAS consumers visiting gyms. The association of different patterns of AAS consumption (cycling vs. continuous forms of AAS use), psychoactive substance use, mental health disorders, and sociodemographic variables with moderate-severe AASUD (fifth edition of the Diagnostic and Statistical Manual of Mental Disorders ≥4 criteria) was investigated. The associations between duration of AAS use and the AAS dose with moderate-severe AASUD were investigated using logistic regression analysis with moderate-severe AASUD as the dependent variable. Results: Moderate-severe AASUD was present in 25 (24.3%) of the participants. AAS consumers meeting criteria for moderate-severe AASUD, compared to those that did not, in the last 12 months reported a longer duration of AAS use (in weeks), a higher average AAS dose (mg/week), and a greater number of AAS side effects. Duration of AAS use and the AAS dose were the only independent predictors, with an increase of 3.4% in the probability of moderate-severe AASUD with every week increase of the duration of AAS use in the last year (p < 0.05) and an increase in moderate-severe AASUD of 0.1% with every 10 mg increase in the average AAS dose per week (p < 0.05), respectively. Conclusion: Our findings show that moderate-severe AASUD is relatively frequent among male AAS consumers and is positively associated with the duration and average dose of AAS use in the last 12 months.

The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia's, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O's dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity.

BACKGROUND:This paper describes an online survey of men who have sex with men (MSM) and use drugs before or during sex ('chemsex') via injection ('slamming' or 'practising slamsex'). Approximately 15-30% of the MSM population in The Netherlands have practiced chemsex at some point, and 0.5-3.1% of them ever had 'slamsex'. This study investigates which substances are used in The Netherlands during slamsex, the motives for slamming and the health risks involved.METHOD:In total, 175 MSM from The Netherlands, who had used substances before or during sex via injection completed an ad hoc online questionnaire designed for this study.RESULTS:Mean age of respondents was 47.8years. During chemsex, almost every substance was used; the most common substances that were injected (slammed) were 3-methylmethcathinone (3-MMC), methamphetamine, ketamine, 4-methylethcathinone (4-MEC) and mephedrone (4-MMC). Reasons for slamming were mainly to experience a more intense rush and longer sex. Virtually none of the respondents used a condom during slamsex, but needles were almost never shared or used only once. Slammers reported health problems associated with injecting drugs (skin problems, collapsed veins and infections). Of most concern were the psychological symptoms reported by about three-quarters of respondents (e.g. insomnia, sadness, depressed mood, anxiety, suicidal tendencies). About half of respondents reported some degree of loss of control or concerns about their slamming behaviour.CONCLUSION:Results show that slamsex is associated with consciously chosen sexual risk behaviours and risk-avoidance slam behaviours. This study may contribute to the reinforcement of accessible, non-judgmental and well informed prevention and harm reduction activities to support MSM practising slamsex.

Background: GHB (gamma-hydroxybutyric acid; sodium oxybate) is a general anaesthetic that is clinically used for the treatment of narcolepsy, cataplexy, alcohol withdrawal and alcohol relapse prevention. In addition, GHB is recreationally used. Most clinical and recreational users regard GHB as an innocent drug devoid of adverse effects, despite its high dependence potential and possible neurotoxic effects. At high doses, GHB may lead to a comatose state. This paper systematically reviews possible cognitive impairments due to clinical and recreational GHB use. Methods: PubMed and PsychINFO were searched for literature data about the acute and residual cognitive deficits following GHB use. This review is conducted using the PRISMA protocol. Results: A total of 43 reports covering human and animal data on GHB-induced cognitive impairments were eligible and reviewed. This systematic review found no indication for cognitive impairments after clinical GHB use. However, it supports the view that moderate GHB use may result in acute short-term cognitive impairments, whereas regular high-dose GHB use and/or multiple GHB-induced comas are probably neurotoxic resulting in long-term residual cognitive impairments. Conclusion: These results emphasize the need for awareness among clinicians and recreational users to minimize negative health consequences of recreational GHB use, particularly when high doses are used and GHB-induced comas occur.

BACKGROUND AND AIMS:Injecting drug use is a matter of public health concern, associated with risks of overdoses, addiction and increased risk of bloodborne viral transmissions. Self-reported data on substances injected can be inaccurate or subject to bias or drug users might be oblivious to their injected substances or adulterations. Gathering of robust analytical information on the actual composition of substances injected might provide better information about the drugs that are being used. Therefore, this study aimed to analyse the residual content of discarded syringes collected across 7 European cities, collectively called the European Syringe Collection and Analysis Project Enterprise (ESCAPE).METHODS:Used syringes were collected at street automatic injection kit dispensers or at harm-reduction services in Amsterdam, Budapest, Cologne, Glasgow, Helsinki, Lausanne and Paris. Two sampling periods were executed thus far, in 2017 and 2018. Qualitative chemical analysis of the content of used syringes was performed combining gas chromatographic (GC) and ultra(high)performance liquid chromatographic ((U)HPLC) analytical techniques with detection by mass spectrometry (MS).RESULTS:Substances detected most frequently across both campaigns were cocaine, heroin, buprenorphine, amphetamines and synthetic cathinones. In Amsterdam, Cologne, Lausanne and Glasgow heroin and cocaine were the psychoactive substances most often detected, often in conjunction with each other. Helsinki showed a high presence of buprenorphine and amphetamines. In Budapest and Paris, synthetic cathinones were frequently detected. Less synthetic cathinones and cocaine was detected in 2018, whereas buprenorphine was detected almost twice as much. Inner-city variations were found, probably reflecting the types of people who inject drugs (PWID) in different areas of the city.CONCLUSION:Overall, laboratory-confirmed local data on injected substances showed resemblance to national surveys done among PWID. However, the ESCAPE data also showed some interesting differences, showing it can be used for local interventions and complementing existing monitoring data.

Although MDMA (ecstasy) is a relatively safe recreational drug and is currently considered for therapeutic use for the treatment of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD), recreational MDMA use occasionally elicits hyperthermia and hyponatremia, sometimes with a fatal outcome. Specific risk factors for both adverse effects are profuse sweating while vigorously dancing under unfavorable conditions such as high ambient temperatures and insufficient fluid suppletion which result in dehydration. Concomitant use of MDMA and alcohol is highly prevalent, but adds to the existing risk, because alcohol facilitates the emergence of MDMA-induced adverse events, like hyperthermia, dehydration, and hyponatremia. Because of potential health-related consequences of concomitant use of MDMA and alcohol, it is important to identify the mechanisms of the interactions between alcohol and MDMA. This review summarizes the main drivers of MDMA-induced hyperthermia, dehydration, and hyponatremia and the role of concomitant alcohol use. It is shown that alcohol use has a profound negative impact by its interaction with most of these drivers, including poikilothermia, exposure to high ambient temperatures, heavy exercise (vigorous dancing), vasoconstriction, dehydration, and delayed initiation of sweating and diuresis. It is concluded that recreational and clinical MDMA-users should refrain from concomitant drinking of alcoholic beverages to reduce the risk for adverse health incidents when using MDMA.

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Background: The novel phenethylamines 4-fluoroamphetamine (4-FA) and 2,5-dimethoxy-4-bromophenethylamine (2C-B) fall in the top 10 most used new psychoactive substances (NPSs) among high-risk substance users. Various phenethylamines and NPS are also highly used in populations with mental disorders, depression, or attention deficit hyperactivity disorder (ADHD). Moreover, NPS use is highly prevalent among men and women with risky sexual behavior. Considering these specific populations and their frequent concurrent use of drugs, such as antidepressants, ADHD medication, and antiretrovirals, reports on potential interactions between these drugs, and phenethylamines 4-FA and 2C-B, were reviewed. Methods: The authors performed a systematic literature review on 4-FA and 2C-B interactions with antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, duloxetine, bupropion, venlafaxine, phenelzine, moclobemide, and tranylcypromine), ADHD medications (atomoxetine, dexamphetamine, methylphenidate, and modafinil), and antiretrovirals. Results: Limited literature exists on the pharmacokinetics and drug-drug interactions of 2C-B and 4-FA. Only one case report indicated a possible interaction between 4-FA and ADHD medication. Although pharmacokinetic interactions between 4-FA and prescription drugs remain speculative, their pharmacodynamic points toward interactions between 4-FA and ADHD medication and antidepressants. The pharmacokinetic and pharmacodynamic profile of 2C-B also points toward such interactions, between 2C-B and prescription drugs such as antidepressants and ADHD medication. Conclusions: A drug-drug (phenethylamine-prescription drug) interaction potential is anticipated, mainly involving monoamine oxidases for 2C-B and 4-FA, with monoamine transporters being more specific to 4-FA.

Objective: Ecstasy is one of the most commonly used illicit substances in Western countries. The aim of this study is to identify characteristics of ecstasy users in a large population-based sample of adults aged 18-45 years. Method: With generalized estimating equation models we explored the association between self-reported lifetime ecstasy use and urbanicity, educational attainment, health, wellbeing, stress, other substance use, personality traits and psychopathology in a Dutch twin sample (N = 9578, 66.8% female, 18-45 years). We also explored the nature of the association (underlying genetic factors, shared environmental factors or a causal relationship) with the co-twin control method. Results: Lifetime ecstasy users (N = 945, 9.9%) were more often male, younger, living more often in urban areas, higher educated, less satisfied with life and more stressed than non-users. Ecstasy users scored differently on most personality and psychopathology scales compared to non-users and were more likely to have used every other substance we investigated. Whereas smoking tobacco and alcohol use often preceded first use of ecstasy, first ecstasy use often preceded first use of other illicit substances. A combination of scenarios (both causal and environmental/genetic) explained the strong associations between ecstasy and substance use. Conclusions: Ecstasy users differ on many characteristics from non-users, and especially on illicit substance use. Our results indicate that causal effects may play a role in explaining the relationship between ecstasy use and other illicit substance use.

The endocannabinoid system is a complex neuronal system involved in a number of biological functions, like attention, anxiety, mood, memory, appetite, reward, and immune responses. It is at the centre of scientific interest, which is driven by therapeutic promise of certain cannabinoid ligands and the changing legalization of herbal cannabis in many countries. The endocannabinoid system is a modulatory system, with endocannabinoids as retrograde neurotransmitters rather than direct neurotransmitters. Neuropharmacology of cannabinoid ligands in the brain can therefore be understood in terms of their modulatory actions through other neurotransmitter systems. The CB 1 receptor is chiefly responsible for effects of endocannabinoids and analogous ligands in the brain. An overview of the neuropharmacology of several cannabinoid receptor ligands, including endocannabinoids, herbal cannabis and synthetic cannabinoid receptor ligands is given in this review. Their mechanism of action at the endocannabinoid system is described, mainly in the brain. In addition, effects of cannabinoid ligands on other neurotransmitter systems will also be described, such as dopamine, serotonin, glutamate, noradrenaline, opioid, and GABA. In light of this, therapeutic potential and adverse effects of cannabinoid receptor ligands will also be discussed.

Purpose: Substance use disorder often coexists with other psychiatric disorders, resulting in the simultaneous use of recreational and prescription drugs. The authors aimed to identify potential pharmacokinetic and pharmacodynamic interactions between new psychoactive substances of the cathinone class and specific prescription drugs. Methods: The authors performed a systematic literature review on interactions between synthetic cathinones (mephedrone, methylone, methylenedioxypyrovalerone, and alpha-pyrrolidinopentiophenone) and antidepressants (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine), attention deficit hyperactivity disorder (ADHD) medications (atomoxetine, dexamphetamine, methylphenidate, modafinil) or HIV medications. Results: Although no pharmacokinetic interactions have been reported in previous literatures, such interactions are likely to occur. Metabolic pathways of cathinones, antidepressants, and ADHD medications have been shown to overlap, including metabolism via cytochrome P450 enzymes and their inhibition. Consistent with this finding, interactions of bupropion (a cathinone) with antidepressants and ADHD medications have been found to increase their serum concentrations and half-lives. Additionally, limited pharmacodynamic interactions have been reported. However, as cathinones, antidepressants, and ADHD medications have been reported to increase the extracellular monoamine concentration by affecting reuptake transporters, interactions among these compounds are likely. Presumably, even higher monoamine concentrations could be observed when cathinones are combined with prescription drugs with a similar mode of action, as has been reported in animals exposed to duloxetine and bupropion. HIV medications have a different mode of action; thus, they have been reported to be less likely to have pharmacodynamic interactions with cathinones. Conclusions: Clinicians should be aware of possible interactions between synthetic cathinones and prescription drugs, which may increase the risk of drug toxicity or reduce the therapeutic efficacy of the drugs. Qualitative drug screening for cathinones using mass spectrometry methods may aid the early detection of these agents.

4‐bromo‐2,5‐dimethoxyphenethylamine (2C‐B) is a designer drug. In Europe, 2C‐B is easily obtained and used for recreational purposes. It is known for its stimulating effects similar to those of 3,4‐methylenedioxymethamphetamine, although in higher doses it has more hallucinogenic effects. Here, we report a case of 2C‐B ingestion, confirmed by liquid chromatography‐tandem mass spectrometry, in an 18‐year‐old man. The neurological consequences were severe, including the development of serotonin syndrome and severe brain edema. Supportive therapy resulted in a stable condition, although, after several months, the patient still suffered from severe neurological impairment due to the drug‐induced toxicity. This case showed that 2C‐B could not be identified with the drugs of abuse screening routinely used in Dutch hospitals. The use of 2C‐B carries many risks, with potentially profound neurological damage, that both consumers and healthcare physicians are unaware of.

Synthetic cannabinoids (SCs) are a class of new psychoactive substances that have been rapidly evolving around the world throughout recent years. Many different synthetic cannabinoid analogues are on the consumer market and sold under misleading names, like “spice” or “incense.” A limited number of studies have reported serious health effects associated with SC use. In this study, we compared clinical and subclinical psychopathological symptoms associated with SC use and natural cannabis (NC) use.

BACKGROUND:The unprecedented proliferation of new psychoactive substances (NPS) threatens public health and challenges drug policy. Information on NPS pharmacology and toxicity is, in most cases, unavailable or very limited and, given the large number of new compounds released on the market each year, their timely evaluation by current standards is certainly challenging.AIMS:We present here a metabolomics-targeted approach to predict the pharmacological profile of NPS.METHODS:We have created a machine learning algorithm employing the quantification of monoamine neurotransmitters and steroid hormones in rats to predict the similarity of new drugs to classical ones of abuse (MDMA (3,4-methyl enedioxy methamphetamine), methamphetamine, cocaine, heroin and Δ9-tetrahydrocannabinol).RESULTS:We have characterized each classical drug of abuse and two examples of NPS (mephedrone and JWH-018) following alterations observed in the targeted metabolome profile (monoamine neurotransmitters and steroid hormones) in different brain areas, plasma and urine at 1 h and 4 h post drug/vehicle administration. As proof of concept, our model successfully predicted the pharmacological profile of a synthetic cannabinoid (JWH-018) as a cannabinoid-like drug and synthetic cathinone (mephedrone) as a MDMA-like psychostimulant.CONCLUSION:Our approach allows a fast NPS pharmacological classification which will benefit both drug risk evaluation policies and public health.