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Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood–brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines—amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.

SummaryAmphetamine use leads to impaired skeletal health and elevated risk of osteoporosis. In the current study, we document that maximal strength training (MST), as a part of clinical treatment, works as a countermeasure, improving muscle force generating capacity, body composition, and skeletal health at sites particularly prone to osteoporotic fractures.IntroductionAmphetamine users have attenuated musculoskeletal health. MST with heavy loads, few repetitions, and emphasis on maximal mobilization in the concentric phase may increase muscle force generating capacity and skeletal health. This study investigated if MST-induced improvements in force generating capacity improved bone mineral density (BMD), trabecular bone score, and body composition in amphetamine users participating in 3-months clinical treatment.MethodsOf 40 randomized patients, 23 completed the study: 11 in the supervised training group (TG; 8 men, 3 women, 34 ± 10 years) and 12 in the control group (CG; 9 men, 3 women, 32 ± 8 years). The TG performed hack-squat MST three times a week for 12 weeks with an intensity of ~90% of one repetition maximum (1RM). Both groups attended conventional clinical treatment. Pre-training and post-training, we assessed hack-squat 1RM and rate of force development (RFD), BMD, body composition and trabecular bone score by dual X-ray absorptiometry, and serum bone metabolism markers.ResultsMST induced increases in 1RM (70%) and RFD (86%), and resulted in BMD improvements at lumbar spine (3.6%) and total hip (2.4%); all improvements were different from CG (p < 0.05). Both the 1RM and RFD increases were associated with BMD improvements (lumbar spine: r = 0.73 (1RM), r = 0.60 (RFD); total hip: r = 0.61 (1RM); all p < 0.05). No differences were observed in trabecular bone score or bone metabolism markers.ConclusionsMST improved force generating capacity and skeletal health at sites prone to bone loss in amphetamine users, and advocate that MST should be implemented as a clinical strategy to restore the patients’ musculoskeletal health.

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

Methamphetamine use disorder is associated with striatal dopaminergic deficits that have been linked to poor treatment outcomes, identifying these deficits as an important therapeutic target. Exercise attenuates methamphetamine-induced neurochemical damage in the rat brain, and a preliminary observation suggests that exercise increases striatal D2/D3 receptor availability (measured as nondisplaceable binding potential (BPND)) in patients with Parkinson's disease. The goal of this study was to evaluate whether adding an exercise training program to an inpatient behavioral intervention for methamphetamine use disorder reverses deficits in striatal D2/D3 receptors. Participants were adult men and women who met DSM-IV criteria for methamphetamine dependence and were enrolled in a residential facility, where they maintained abstinence from illicit drugs of abuse and received behavioral therapy for their addiction. They were randomized to a group that received 1 h supervised exercise training (n=10) or one that received equal-time health education training (n=9), 3 days/week for 8 weeks. They came to an academic research center for positron emission tomography (PET) using [(18)F]fallypride to determine the effects of the 8-week interventions on striatal D2/D3 receptor BPND. At baseline, striatal D2/D3 BPND did not differ between groups. However, after 8 weeks, participants in the exercise group displayed a significant increase in striatal D2/D3 BPND, whereas those in the education group did not. There were no changes in D2/D3 BPND in extrastriatal regions in either group. These findings suggest that structured exercise training can ameliorate striatal D2/D3 receptor deficits in methamphetamine users, and warrants further evaluation as an adjunctive treatment for stimulant dependence.

Patients and psychotherapists often exhibit behavioral, psychological, and physiological similarity. Here, we test whether oxytocin—a neuropeptide that can enhance expressivity and social perception—influences time-lagged “linkage” of autonomic nervous system responses among participants and facilitators during group therapy. Physiological linkage estimates ( n  = 949) were created from ten cohorts, each with two facilitators ( n  = 5) and four to six participants ( n  = 48), over six weekly sessions of group therapy for methamphetamine use disorder. All participants of a cohort received oxytocin or placebo intranasally in a randomized double-blind procedure before each session. Cardiac interbeat intervals (IBI) were measured continuously during sessions to estimate physiological linkage, operationalized as one cohort-mate’s IBI reactivity during one minute predicting another cohort-mate’s IBI reactivity during the following minute. In oxytocin cohorts, participants and facilitators experienced significant physiological linkage to their cohort-mates (i.e., their physiological responses were predicted by the prior responses of their cohort-mates) and significantly more linkage than people in placebo cohorts. Both effects occurred during the first and second sessions but not later sessions. Results suggest that oxytocin may enhance psychosocial processes often associated with linkage—such as social engagement—in groups and highlight oxytocin’s potential to improve group cohesion during group therapy. Clinical Trials Registration: NCT02881177, First published on 26/08/2016.

Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant ( p =0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline ( p <0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.

Methamphetamine (METH) is a widely abused stimulant that affects the central nervous system. The persistent maladaptive conditioned stimuli (CS, drug cues)-drug associative memories represent a primary factor precipitating relapse. Interfering with the reconsolidation of these memories may help disrupt and modify these maladaptive CS-drug associations, potentially reducing their influence on drug-seeking behavior. The present study explored the effect of CS-triggered memory retrieval-extinction on METH craving, potentially offering a new treatment strategy for addiction. This was a single-center, randomized, controlled trial involving individuals with METH use disorder (MUD). Participants completed one of three interventions on consecutive days (days 2 and 3): CS-triggered memory retrieval followed by extinction after a 10-min interval, CS-triggered memory retrieval followed by extinction after a 6-h interval, or extinction without prior retrieval. Self-report cue-induced craving for METH, salivary cortisol and sympathetic responses were measured at baseline (day 1), post intervention (day 4) and two follow-up timepoints (days 34 and 184), with cue-induced craving and salivary cortisol as primary outcomes. Ninety-eight MUD individuals (mean age 28.15 ± 6.31) were analyzed. After two-day’s interventions, cue-induced METH craving (time × cue interaction: F (1,94)  = 60.02, p  < 0.001) reduced in all groups. Results from follow-up data indicated, when the extinction was performed 10 min, but not 6 h after memory retrieval or no retrieval, the intervention decreased experimental cue-induced METH craving (intervention × time × cue: F (2,94)  = 14.32, p  < 0.001; intervention: F (2,94)  = 24.28, p  < 0.001) and saliva cortisol increases (F (2,90)  = 9.51, p  < 0.001), with effects lasting up to 6-month follow-up. The results revealed a substantial reduction in cue-elicited craving and saliva cortisol in the retrieval-10 min-extinction group over the 6-month follow-up. These findings provide compelling evidence that a brief reconsolidation-based intervention can effectively diminish METH-related craving and cortisol levels, underscoring its potential as a supportive measure in METH treatment. Salivary cortisol is a readily accessible and sensitive biomarker for evaluating intervention effects.

In a randomized trial involving participants with methamphetamine use disorder, the response among those who received bupropion and naltrexone was 11 percentage points higher than that among participants who received placebo. Adverse events included gastrointestinal disorders.

Digital interventions can help to overcome barriers to care, including stigma, geographical distance, and a lack of culturally appropriate treatment options. \"We Can Do This\" is a web-based app that was designed with input from cultural advisors and end users to support Aboriginal and Torres Strait Islander people seeking to stop or reduce their use of methamphetamine and increase psychosocial well-being. This study aimed to evaluate the effectiveness of the \"We Can Do This\" web-based app as a psychosocial treatment for Aboriginal and Torres Strait Islander people who use methamphetamine. The web app was evaluated using a randomized waitlist controlled parallel group trial. Participants were Aboriginal and Torres Strait Islander people aged 16 years or older who self-identified as having used methamphetamine at least weekly for the past 3 months. Participants were randomized on a 1:1 ratio to receive either access to the web-based app for 6 weeks or a waitlist control group. Both groups received access to a website with harm minimization information. The primary outcome was days of methamphetamine use in the past 4 weeks assessed at 1, 2, and 3 months post randomization. Secondary outcomes included severity of methamphetamine dependence (Severity of Dependence Scale [SDS]), psychological distress (Kessler 10 [K10]), help-seeking behavior, and days spent out of role due to methamphetamine use. Participants (N=210) were randomized to receive either access to the web-based app (n=115) or the waitlist control condition (n=95). Follow-up was 63% at 1 month, 57% at 2 months, and 54% at 3 months. There were no significant group differences in days of methamphetamine use in the past 4 weeks at 1 the month (mean difference 0.2 days, 95% CI -1.5 to -2), 2 months (mean difference 0.6 days, 95% CI -1 to 2.4 days) or 3 months (mean difference 1.4 days, 95% CI -0.3 to 3.3 days) follow-up. There were no significant group differences in K10 scores, SDS scores, days out of role, or help-seeking at any of the 3 follow-up timepoints. There was poor adherence to the web-based app, only 20% of participants in the intervention group returned to the web-based app after their initial log-in. Participants cited personal issues and forgetting about the web-based app as the most common reasons for nonadherence. We found poor engagement with this web-based app. The web-based app had no significant effects on methamphetamine use or psychosocial well-being. Poor adherence and low follow-up hindered our ability to accurately evaluate the effectiveness of the web-based app. Future web-based apps for this population need to consider methods to increase participant engagement. Australian New Zealand Clinical Trials Registry ACTRN12619000134123p; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376088. RR2-10.2196/14084.

Amphetamine-type stimulants (ATS), synthetic cathinones (SCs) and phenethylamines (PEAs) pose a challenge to toxicology laboratories. Their extensive use and misuse has led to an increase of intoxications and fatal incidents worldwide. So, the need for new analytical methods for their determination in biological samples is crucial for all toxicology laboratories for a better investigation of these cases. The aim of this study was the development and validation of an analytical method for the determination of 9 ATS, 7 SCs and 5 PEAs in whole blood and urine using gas chromatography coupled with mass spectrometry. The samples were pretreated by solid-phase extraction and derivatized with pentafluoropropionic anhydride. Chromatographic separation of the 21 analytes was achieved in less than 11 min. The method was validated according to international guidelines for selectivity, specificity, linearity, limits of detection (LODs) and quantification (LOQs), precision, accuracy and recovery of the method. The LODs of the analytes ranged from 0.70 to 7.0 ng/mL and the values of the LOQs ranged from 2.0 to 20 ng/mL. The linearity of the 21 analytes, according to the group of substances, were 2.0 ng/mL – 0.20 μg/mL, 5.0 ng/mL – 0.50 μg/mL, 10 ng/mL – 0.50 μg/mL and 20 ng/mL – 0.50 μg/mL with R2 values > 0.99. Extraction recoveries were > 80 % for all analytes. Intra and inter day accuracy and precision of the method were within accepted limits. The developed method was applied to post-mortem blood and urine samples of 46 forensic cases sent for toxicological investigation to the Department of Forensic Medicine and Toxicology, School of Medicine, National and Kapodistrian University of Athens. The results of the analyses revealed the presence of methamphetamine, amphetamine, MDMA, MDA, pseudoephedrine, phenylpropanolamine or MBDB in 14 cases. •GC/MS method.•Determination of 21 NPS.•Investigation of NPS forensic cases.