Cristina Miliano

Introduction: Preclinical and clinical studies reported that 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) can cause adverse effects in the central nervous system (CNS). Recently, preclinical studies have demonstrated that certain psychoactive substances may exacerbate the noxious central effects of MDMA when co-administered, including substances that are contained as adulterants in tablets sold as MDMA in the illegal market. Since the quality and quantity of adulterants in tablets sold as MDMA vary based on factors, such as the year and the geographical region of production, this may result in diverse health risks for people who use MDMA. Objectives: This review provides a concise overview of: i) composition of tablets sold as MDMA in Continental Europe, UK, USA and Australia in the post COVID-19 pandemic period; ii) recent preclinical and clinical findings about the central effects of the psychoactive adulterants most commonly found in tablets sold as MDMA in the above areas; and iii) the possible adverse CNS effects of these adulterants in humans when taken in combination with MDMA. Methods: We systematically searched PubMed, Scopus, and Web of Science for studies published between 2020 and 2025 using terms related to “adulterants”, “MDMA tablets composition,” “COVID-19”. Eligible articles were screened for quality, with emphasis on recent, high-impact contributions. Extracted papers included cytotoxicity studies, neurobehavioral outcomes, and mechanistic insights. Results: Tablets sold as MDMA are frequently and differently adulterated in Continental Europe, the UK, the USA, and Australia. Discussion: The possible interactions between MDMA and psychoactive adulterants contained in tablets sold as MDMA deserve attention, since they may potentially explain some of the noxious neurological and psychiatric effects that have been described in people who use MDMA. Conclusion: Ongoing public health efforts and expansion of drug checking are essential to properly inform MDMA users about the risks associated with psychoactive contaminants, first responders, healthcare professionals, and the general public about the possible detrimental consequences for health associated with the use of MDMA obtained from illicit sources and unintended contaminant consumption.

Chronic nociplastic pain syndromes are characterized by sensitization of peripheral and central nervous systems and exhibit increased incidence in women. However, nonsteroidal anti-inflammatory drugs are ineffective in mitigating nociplastic pain, and current prescription treatments, such as opioids, anticonvulsants, and antidepressants, provide limited therapeutic benefit for these indications. In the current work, we extended previous studies in rats of central Toll-like receptor 4–dependent pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) lipopolysaccharide (LPS). In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and a modest increase in locomotor activity in response to IT LPS. Congruent with our previous observations in male rats, LPS released spinal 12/15-lipoxygenase (12/15-LOX) metabolites (12/15-LMs) in female C57BL/6N mice. Likewise, 12/15-LOX enzymes are basally expressed in multiple tissues and cell types relevant to nociceptive transmission. Systemic inhibition of 12/15-LOX in female C57BL/6N mice with selective inhibitors ML355 (targeting 12-LOX-p) or ML351 (targeting 15-LOX-1) completely reversed allodynia and grip force deficits. 12/15-LMs also produce tactile allodynia when administered spinally (IT) or peripherally (paw intraplantar) at a subthreshold dose in a hyperalgesic priming model, similar to others' observations with a subthreshold dose of the cyclooxygenase metabolite prostaglandin E ₂ . Collectively, these data suggest that 12/15-LOX enzymes contribute to peripheral and central pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and functional outcome measures.

25I-NBOMe (4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) is a synthetic psychedelic compound abused for its ambiguous legal state as a counterfeit lysergic acid diethylamide (LSD). 25I-NBOMe acts as a selective agonist of 5HT_2A receptors leading to hallucinations, intoxications, and fatalities. Here, we assessed the rewarding properties of 25I-NBOMe and its behavioral and neurotoxic acute effects on the central nervous system of C57BL/6J mice. We evaluated the dopamine (DA) levels using in vivo microdialysis in the nucleus accumbens (NAc) shell after 25I-NBOMe (0.1–1 mg/kg i.p.) injection. We also investigated the effects of 25I-NBOMe (0.1–1 mg/kg i.p.) on locomotor activity, reaction time, and prepulse inhibition. Moreover, we assessed the acute 25I-NBOMe (1 µM) effects on synaptic transmission and plasticity in the medial prefrontal cortex (mPFC) by using ex vivo electrophysiology. Our findings suggest that 25I-NBOMe affects the DA transmission in NAc shell at the highest dose tested, increases the reaction time within 30 min after the administration, and disrupts the PPI. In slices, it prevents long-term synaptic potentiation (LTP) in the mPFC, an effect that could not be reverted by the co-administration of the selective 5HT_2A antagonist (MDL100907). Overall, these findings provide valuable new insights into the effects of 25I-NBOMe and the associated risks of its use.

Background and Purpose: Spice/K2 herbal mixtures, containing synthetic cannabinoids such as JWH‐018, have been marketed as marijuana surrogates since 2004. JWH‐018 has cannabinoid CB₁ receptor‐dependent reinforcing properties and acutely increases dopaminergic transmission selectively in the NAc shell. Here, we tested the hypothesis that repeated administration of JWH‐018 (i) modulates behaviour, (ii) affects dopaminergic transmission and its responsiveness to motivational stimuli, and (iii) is associated with a neuroinflammatory phenotype.Experimental Approach: Rats were administered with JWH‐018 once a day for 14 consecutive days. We then performed behavioural, electrophysiological, and neurochemical evaluation at multiple time points after drug discontinuation.Key Results: Repeated JWH‐018 exposure (i) induced anxious and aversive behaviours, transitory attentional deficits, and withdrawal signs; (ii) decreased spontaneous activity and number of dopamine neurons in the VTA; and (iii) reduced stimulation of dopaminergic transmission in the NAc shell while potentiating that in the NAc core, in response to acute JWH‐018 challenge. Moreover, (iv) we observed a decreased dopamine sensitivity in the NAc shell and core, but not in the mPFC, to a first chocolate exposure; conversely, after a second exposure, dialysate dopamine fully increased in the NAc shell and core but not in the mPFC. Finally, selected dopamine brain areas showed (v) astrogliosis (mPFC, NAc shell and core, VTA), microgliosis (NAc shell and core), and downregulation of CB₁ receptors (mPFC, NAc shell and core).Conclusion and Implications: Repeated exposure to JWH‐018 may provide a useful model to clarify the detrimental effects of recurring use of Spice/K2 drugs.

Novel psychoactive substances (NPS) are synthetic substances belonging to diverse groups, designed to mimic the effects of scheduled drugs, resulting in altered toxicity and potency. Up to now, information available on the pharmacology and toxicology of these new substances is very limited, posing a considerable challenge for prevention and treatment. The present in vitro study investigated the possible mechanisms of toxicity of two emerging NPS (i) 4′-methyl-alpha-pyrrolidinoexanophenone (3,4-MDPHP), a synthetic cathinone, and (ii) 2-chloro-4,5-methylenedioxymethamphetamine (2-Cl-4,5-MDMA), a phenethylamine. In addition, to apply our model to the class of synthetic opioids, we evaluated the toxicity of fentanyl, as a reference compound for this group of frequently abused substances. To this aim, the in vitro toxic effects of these three compounds were evaluated in dopaminergic-differentiated SH-SY5Y cells. Following 24 h of exposure, all compounds induced a loss of viability, and oxidative stress in a concentration-dependent manner. 2-Cl-4,5-MDMA activates apoptotic processes, while 3,4-MDPHP elicits cell death by necrosis. Fentanyl triggers cell death through both mechanisms. Increased expression levels of pro-apoptotic Bax and caspase 3 activity were observed following 2-Cl-4,5-MDMA and fentanyl, but not 3,4-MDPHP exposure, confirming the different modes of cell death.

In the last decade, the trend of drug consumption has completely changed, and several new psychoactive substances (NPS) have appeared on the drug market as legal alternatives to common drugs of abuse. Designed to reproduce the effects of illegal substances like cannabis, ecstasy, cocaine, or ketamine, NPS are only in part controlled by UN conventions and represent an emerging threat to global public health. The effects of NPS greatly differ from drug to drug and relatively scarce information is available at present about their pharmacology and potential toxic effects. Yet, compared to more traditional drugs, more dangerous short- and long-term effects have been associated with their use, and hospitalizations and fatal intoxications have also been reported after NPS use. In the era of cyberculture, the Internet acts as an ideal platform to promote and market these compounds, leading to a global phenomenon. Hidden by several aliases, these substances are sold across the web, and information about consumption is shared by online communities through drug fora, YouTube channels, social networks, and smartphone applications (apps). This review intends to provide an overview and analysis of social media that contribute to the popularity of NPS especially among young people. The possibility of using the same channels responsible for their growing diffusion to make users aware of the risks associated with NPS use is proposed.