Amphetamine-related drugs, such as 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine (METH), are popular recreational psychostimulants. Several preclinical studies have demonstrated that, ...besides having the potential for abuse, amphetamine-related drugs may also elicit neurotoxic and neuroinflammatory effects. The neurotoxic potentials of MDMA and METH to dopaminergic and serotonergic neurons have been clearly demonstrated in both rodents and non-human primates. This review summarizes the species-specific cellular and molecular mechanisms involved in MDMA and METH-mediated neurotoxic and neuroinflammatory effects, along with the most important behavioral changes elicited by these substances in experimental animals and humans. Emphasis is placed on the neuropsychological and neurological consequences associated with the neuronal damage. Moreover, we point out the gap in our knowledge and the need for developing appropriate therapeutic strategies to manage the neurological problems associated with amphetamine-related drug abuse.
Rationale
MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD). The primary mechanism of action of MDMA involves the same reuptake ...transporters targeted by antidepressant medications commonly prescribed for PTSD.
Objectives
Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering antidepressant medications, participants who had been randomized to receive active doses of MDMA (75–125 mg) were divided into two groups (taper group (
n
= 16) or non-taper group (
n
= 34)).
Methods
Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary endpoint, and for peak vital signs across two MDMA sessions.
Results
Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the primary endpoint, the non-taper group (mean = 45.7, SD = 27.17) had a significantly (
p
= 0.009) lower CAPS-IV total scores compared to the taper group (mean = 70.3, SD = 33.60). More participants in the non-taper group (63.6%) no longer met PTSD criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean = 12.7, SD = 10.17) had lower depression symptom severity scores (
p
= 0.010) compared to the taper group (mean = 22.6, SD = 16.69). There were significant differences between groups in peak systolic blood pressure (
p
= 0.043) and diastolic blood pressure (
p
= 0.032).
Conclusions
Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy.
•Overview and evaluation of available literature using WBE to detect illicit drugs .•The WBE approach shows an improvement in quality over the recent years.•High cocaine and methamphetamine ...consumption rates are found in the USA.•Relatively low illicit drug consumption is found in the continent of Asia.
Illicit drug use is complex, hidden and often highly stigmatized behaviour, which brings a vast challenge for drug surveillance systems. Drug consumption can be estimated by measuring human excretion products in untreated wastewater, known as wastewater-based epidemiology (WBE). Over the last decade, the application of wastewater-based epidemiology to monitor illicit drug loads increased and WBE is currently applied on a global scale. Studies from over the globe are evaluated with regard to their sampling method, analytical accuracy and consumption calculation, aiming to further reduce relevant uncertainties in order to make reliable comparisons on a global level. Only a limited number is identified as high-quality studies, so further standardization of the WBE approach for illicit drugs is desired especially with regard to the sampling methodology. Only a fraction of the reviewed papers explicitly reports uncertainty ranges for their consumption data. Studies which had the highest reliability are recently published, indicating an improvement in reporting WBE data. Until now, WBE has not been used in large parts of Africa, nor in the Middle East and Russia. An overview of consumption data across the continents on commonly studied drugs (cocaine, MDMA, amphetamine and methamphetamine) is provided. Overall, high consumption rates are confirmed in the US, especially for cocaine and methamphetamine, while relatively low illicit drug consumption is reported in Asia.
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Amphetamine ('Speed'), methamphetamine ('Ice') and its congener 3,4-methylenedioxymethamphetamine (MDMA; 'Ecstasy') are illicit drugs abused worldwide for their euphoric and stimulant effects. ...Despite compelling evidence for chronic MDMA neurotoxicity in animal models, the physiological consequences of such toxicity in humans remain unclear. In addition, distinct differences in the metabolism and pharmacokinetics of MDMA between species and different strains of animals prevent the rationalisation of realistic human dose paradigms in animal studies. Here, we attempt to review amphetamine toxicity and in particular MDMA toxicity in the pathogenesis of exemplary human pathologies, independently of confounding environmental factors such as poly-drug use and drug purity.
Combinations of psychotherapy with antidepressants are gold-standard psychiatric treatments. They operate through complex and interactional mechanisms, not unlike the reemergent paradigm of ...psychedelic-assisted psychotherapy, which promising research suggests may also be highly effective in even challenging populations.
We review the therapeutic mechanisms behind both conventional and psychedelic paradigms, including the evolution of this knowledge and the associated explanatory frameworks. We explore how psychedelics have provided insights about psychiatric illnesses and treatments over the past decades. We discuss limitations to early explanatory models while highlighting and comparing the psychological and biological mechanisms underlying many psychiatric treatments.
A narrative review was conducted based on a search in Medline/Pubmed up to January 1
, 2020, and iterative retrieval of references from recent reviews and clinical trials.
The contextual model of the common factors of psychotherapy provides a powerful perspective on psychotherapy, antidepressants, and psychedelics, as well as 3,4-methylenedioxymethamphetamine (MDMA) and ketamine. It aligns well with key tenets of psychedelic-assisted psychotherapy. Conventional antidepressants and especially psychedelics may improve the efficacy of psychotherapy via neurochemical changes and increased environmental sensitivity. Combined treatments hold significant promise for advancing the knowledge and treatment of many forms of psychopathology.
Abstract
Recent controversies have arisen regarding claims of uncritical positive regard and hype surrounding psychedelic drugs and their therapeutic potential. Criticisms have included that study ...designs and reporting styles bias positive over negative outcomes. The present study was motivated by a desire to address this alleged bias by intentionally focusing exclusively on negative outcomes, defined as self-perceived ‘negative’ psychological responses lasting for at least 72 h after psychedelic use. A strong justification for this selective focus was that it might improve our ability to capture otherwise missed cases of negative response, enabling us to validate their existence and better examine their nature, as well as possible causes, which could inspire risk-mitigation strategies. Via advertisements posted on social media, individuals were recruited who reported experiencing negative psychological responses to psychedelics (defined as classic psychedelics plus MDMA) lasting for greater than 72 h since using. Volunteers were directed to an online questionnaire requiring quantitative and qualitative input. A key second phase of this study involved reviewing all of the submitted cases, identifying the most severe—e.g., where new psychiatric diagnoses were made or pre-existing symptoms made worse post psychedelic-use—and inviting these individuals to participate in a semi-structured interview with two members of our research team, during which participant experiences and backgrounds were examined in greater depth. Based on the content of these interviews, a brief summary of each case was compiled, and an explorative thematic analysis was used to identify salient and consistent themes and infer common causes. 32 individuals fully completed an onboarding questionnaire (56% male, 53% < age 25); 37.5% of completers had a psychiatric diagnosis that emerged
after
their psychedelic experience, and anxiety symptoms arose or worsened in 87%. Twenty of the seemingly severer cases were invited to be interviewed; of these, 15 accepted an in-depth interview that lasted on average 60 min. This sample was 40% male, mean age = 31 ± 7. Five of the 15 (i.e., 33%) reported receiving new psychiatric diagnoses after psychedelic-use and all fifteen reported the occurrence or worsening of psychiatric symptoms post use, with a predominance of anxiety symptoms (93%). Distilling the content of the interviews suggested the following potential causal factors: unsafe or complex environments during or surrounding the experience, unpleasant acute experiences (classic psychedelics), prior psychological vulnerabilities, high- or unknown drug quantities and young age. The current exploratory findings corroborate the reality of mental health iatrogenesis via psychedelic-use but due to design limitations and sample size, cannot be used to infer on its prevalence. Based on interview reports, we can infer a common, albeit multifaceted, causal mechanism, namely the combining of a pro-plasticity drug—that was often ‘over-dosed’—with adverse contextual conditions and/or special psychological vulnerability—either by young age or significant psychiatric history. Results should be interpreted with caution due to the small sample size and selective sample and study focus.
This current review focuses on contributions to amphetamine-type substances (ATS) analysis. This type of synthetic illicit drugs has been increasingly present worldwide reaching 5% of the market on ...illicit drugs in 2019. The increment of their production in many clandestine laboratories and easy distribution among society are two of the main concerns towards the battle against synthetic drugs. Therefore, the first part of this review details the classification and mechanism of action of ATS in the human body. Second, the pharmacological and toxicological effects of ATS on human health are described to motivate the need of early detection of ATS. Subsequently, the most used laboratory-based and portable methods are presented and critically discussed along the review. Finally, a careful discussion on the advantages and disadvantages of portable techniques employed on the field are addressed as potential tools for on-site ATS detection by law enforcement officers.
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•The analytical techniques for the detection of amphetamine-type substances (ATS) are detailed.•The physiological effects of ATS in the human body are introduced.•The most used bench-top analytical techniques including sample preparation are described.•Portable methods for the detection of ATS in the field were compared.•Key challenges and prospects for a proper identification of ATS are discussed.
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has been shown to produce serotonergic damage in the brains of primates, including humans, and of rats. Tryptophan, the ...precursor of serotonin, is primarily degraded through the kynurenine (KYN) pathway, producing among others KYN, the main metabolite of this route. KYN has been reported as an endogenous agonist of the aryl hydrocarbon receptor (AhR), a transcription factor involved in several neurological functions. This study aims to determine the effect of MDMA on the KYN pathway and on AhR activity and to establish their role in the long-term serotonergic neurotoxicity induced by the drug in rats. Our results show that MDMA induces the activation of the KYN pathway, mediated by hepatic tryptophan 2,3-dioxygenase (TDO). MDMA also activated AhR as evidenced by increased AhR nuclear translocation and CYP1B1 mRNA expression. Autoradiographic quantification of serotonin transporters showed that both the TDO inhibitor 680C91 and the AhR antagonist CH-223191 potentiated the neurotoxicity induced by MDMA, while administration of exogenous l-kynurenine or of the AhR positive modulator 3,3′-diindolylmethane (DIM) partially prevented the serotonergic damage induced by the drug. The results demonstrate for the first time that MDMA increases KYN levels and AhR activity, and these changes appear to play a role in limiting the neurotoxicity induced by the drug. This work provides a better understanding of the physiological mechanisms that attenuate the brain damage induced by MDMA and identify modulation of the KYN pathway and of AhR as potential therapeutic strategies to limit the negative effects of MDMA.
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•- MDMA increases hippocampal and plasma KYN levels through activation of hepatic TDO.•- MDMA neurotoxicity is potentiated by a TDO inhibitor and attenuated by KYN + probenecid.•- MDMA induces a short-term increase in hippocampal AhR activation.•- CH-223191, an AhR antagonist, potentiates MDMA-induced serotonergic neurotoxicity.•- DIM, a positive modulator of AhR, attenuates MDMA-induced serotonergic neurotoxicity.
Rapid and efficient identification of the precise isomeric form of new psychoactive substances (NPS) by forensic casework laboratories is a relevant challenge in the forensic field. Differences in ...legal status occur for ring-isomeric species of the same class, thus leading to different penalties and judicial control. Portable systems such as near-infrared (NIR) spectroscopy recently emerged as suitable techniques for the on-scene identification of common drugs of abuse such as cocaine, MDMA and amphetamine. This way, the overall forensic process becomes more efficient as relevant information on substance identity becomes available directly at the scene of crime. Currently, no NIR-based applications exist for the rapid, on-scene detection of NPS isomers. Herein, we present the differentiation of cathinone and phenethylamine-type NPS analogues based on their NIR spectrum recorded in 2 seconds on a portable 1350 – 2600 nm spectrometer. A prior developed data analysis model was found suitable for the identification of the methylmethcathinone (MMC) isomers 2-MMC, 3-MMC and 4-MMC. In 51 mixtures and 22 seized casework samples, the correct isomeric form was detected in all cases except for a few mixtures with an active ingredient content of 10 wt%. These results show the feasibility of on-site NPS detection as presumptive test performed directly at the scene of crime with a small size NIR-spectrometer. Additionally, in the illicit drug analysis laboratory the combination of NIR and GC–MS analysis might be suitable for robust identification of NPS isomers and analogues.
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•Drug isomer differentiation by near-infrared (NIR) spectroscopy is possible.•New psychoactive substances (NPS) analogues yield unique NIR-spectra.•Cathinone-isomers were correctly detected in both mixtures and casework samples.•Analysis of samples through their plastic packaging is feasible.•On-scene drug detection by portable NIR may speed-up the forensic process.
•Rodent studies reveal persisting neurobehavioral effects of adolescent drug exposure.•Ethanol, nicotine and cannabinoid vulnerability is greater in adolescents than adults.•MDMA and methamphetamine ...show a converse age-related vulnerability.•Affected brain regions include those undergoing developmental change at this time.•Alterations include disruptions in cognition, affect, and drug self-administration.
Studies using animal models of adolescent exposure to alcohol, nicotine, cannabinoids, and the stimulants cocaine, 3,4-methylenedioxymethampethamine and methamphetamine have revealed a variety of persisting neural and behavioral consequences. Affected brain regions often include mesolimbic and prefrontal regions undergoing notable ontogenetic change during adolescence, although it is unclear whether this represents areas of specific vulnerability or particular scrutiny to date. Persisting alterations in forebrain systems critical for modulating reward, socioemotional processing and cognition have emerged, including apparent induction of a hyper-dopaminergic state with some drugs and/or attenuations in neurons expressing cholinergic markers. Disruptions in cognitive functions such as working memory, alterations in affect including increases in social anxiety, and mixed evidence for increases in later drug self-administration has also been reported. When consequences of adolescent and adult exposure were compared, adolescents were generally found to be more vulnerable to alcohol, nicotine, and cannabinoids, but generally not to stimulants. More work is needed to determine how adolescent drug exposure influences sculpting of the adolescent brain, and provide approaches to prevent/reverse these effects.
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