Amphetamine-like Neurochemical and Cardiovascular Effects of α-Ethylphenethylamine Analogs Found in Dietary Supplements.

Dietary supplements often contain additives not listed on the label, including α-ethyl homologs of amphetamine such as N,α-diethylphenethylamine (DEPEA). Here, we examined the neurochemical and cardiovascular effects of α-ethylphenethylamine (AEPEA), N-methyl-α-ethylphenethylamine (MEPEA), and DEPEA as compared with the effects of amphetamine. All drugs were tested in vitro using uptake inhibition and release assays for monoamine transporters. As expected, amphetamine acted as a potent and efficacious releasing agent at dopamine transporters (DAT) and norepinephrine transporters (NET) in vitro. AEPEA and MEPEA were also releasers at catecholamine transporters, with greater potency at NET than DAT. DEPEA displayed fully efficacious release at NET but weak partial release at DAT (i.e., 40% of maximal effect). In freely moving, conscious male rats fitted with biotelemetry transmitters for physiologic monitoring, amphetamine (0.1-3.0 mg/kg, s.c.) produced robust dose-related increases in blood pressure (BP), heart rate (HR), and motor activity. AEPEA (1-10 mg/kg, s.c.) produced significant increases in BP but not HR or activity, whereas DEPEA and MEPEA (1-10 mg/kg, s.c.) increased BP, HR, and activity. In general, the phenethylamine analogs were approximately 10-fold less potent than amphetamine. Our results show that α-ethylphenethylamine analogs are biologically active. Although less potent than amphetamine, they produce cardiovascular effects that could pose risks to humans. Given that MEPEA and DEPEA increased locomotor activity, these substances may also have significant abuse potential. SIGNIFICANCE STATEMENT: The α-ethyl homologs of amphetamine have significant cardiovascular, behavioral, and neurochemical effects in rats. Given that these compounds are often not listed on the ingredient labels of dietary supplements, these compounds could pose a risk to humans using these products.

Potential of the zebrafish model for the forensic toxicology screening of NPS: A comparative study of the effects of APINAC and methiopropamine on the behavior of zebrafish larvae and mice.

The increased diffusion of the so-called novel psychoactive substances (NPS) and their continuous change in structure andconceivably activity has led to the need of a rapid screening method to detect their biological effects as early as possible after their appearance in the market. This problem is very felt in forensic pathology and toxicology, so the preclinical study is fundamental in the approach to clinical and autopsy cases of difficult interpretation intoxication. Zebrafish is a high-throughput suitable model to rapidly hypothesize potential aversive or beneficial effects of novel molecules. In the present study, we measured and compared the behavioral responses to two novel neuroactive drugs, namely APINAC, a new cannabimimetic drug, and methiopropamine (MPA), a methamphetamine-like compound, on zebrafish larvae (ZL) and adult mice. By using an innovative statistical approach (general additive models), it was found that the spontaneous locomotor activity was impaired by the two drugs in both species: the disruption extent varied in a dose-dependent and time-dependent manner. Sensorimotor function was also altered: i) the visual object response was reduced in mice treated with APINAC, whereas it was not after exposure to MPA; ii) the visual placing responses were reduced after treatment with both NPS in mice. Furthermore, the visual motor response detected in ZL showed a reduction after treatment with APINAC during light-dark and dark-light transition. The same pattern was found in the MPA exposed groups only at the dark-light transition, while at the transition from light to dark, the individuals showed an increased response. In conclusion, the present study highlighted the impairment of spontaneous motor and sensorimotor behavior induced by MPA and APINAC administration in both species, thus confirming the usefulness of ZL as a model for a rapid behavioural-based drug screening.

Synthetic cathinone self-administration in female rats modulates neurotransmitter levels in addiction-related brain regions.

Synthetic cathinones are used for their stimulant-like properties. Stimulant-induced neurochemical changes are thought to occur at different times in different brain regions and neurotransmitter systems. This study sought to examine the behavioral and neurochemical effects of α-pyrrolidinopentiophenone (α-PVP) and mephedrone (4MMC) in female rats. Methods probed the chronology of effects of synthetic cathinone exposure. Female rats were trained to self-administer α-PVP, 4MMC, or saline. Drug exposure ceased after 7 days of autoshaping for half of each drug group; the other half self-administered for another 21 days. Amygdala, hippocampus, hypothalamus, PFC, striatum, and thalamus were extracted, and tissue was analyzed with electrochemical detection and liquid chromatography mass spectrometry. Responding was minimal during autoshaping; thus, most infusions were delivered noncontingently in the autoshaping phase. Rats acquired self-administration of α-PVP and 4MMC. Synthetic cathinone administration, and duration of exposure produced several effects on neurotransmitters. α-PVP primarily increased serotonin, 5-hydroxy-3-acetic acid (5-HIAA), norepinephrine, and glutamate in hypothalamus. In contrast, 4MMC decreased serotonin and 5-HIAA in several brain regions. Longer durations of exposure to both synthetic cathinones increased 5-HIAA, norepinephrine, and glutamate in multiple brain regions compared to the short exposure during autoshaping. Notably, both α-PVP and 4MMC produced minimal changes in dopamine levels, suggesting that the dopaminergic effects of these synthetic cathinones are transient. These alterations in neurotransmitter levels indicate that synthetic cathinone use may produce differential neurochemical changes during the transition from use to abuse.

Analysis of legal high materials by ultra-performance liquid chromatography with time of flight mass spectrometry as part of a toxicology vigilance system: what are the most popular novel psychoactive substances in the UK?

Introduction Legal highs also known as novel psychoactive substances mimic the effects of classic drugs of abuse. Challenges to developing screening services for novel psychoactive substances include identifying which novel psychoactive substances are available to target. Using new techniques such as exact mass time of flight can help identify common novel psychoactive substances to target for screening patient samples by routine methods such as tandem mass spectrometry. We demonstrate this strategy working in our own clinical toxicology laboratory after qualitative analysis of 98 suspect materials for novel psychoactive substances by ultra-performance liquid chromatography with time of flight mass spectrometry. Results From July 2014 to July 2015 we received 98 requests to test a range of different suspect materials for novel psychoactive substances including herbs, tobacco, liquids, pills and powders. Overall, 87% of the suspect materials tested positive for novel psychoactive substances, and 15% for controlled drugs. Three common novel psychoactive substances were present in 74% of the suspect materials: methiopropamine, a methamphetamine analogue; ethylphenidate, a cocaine mimic; and the third generation synthetic cannabinoid 5F-AKB-48. For the 55 branded products we tested only 24% of the stated contents matched exactly the compounds we detected. Conclusion Testing suspect materials using ultra-performance liquid chromatography with time of flight mass spectrometry has identified three common novel psychoactive substances in use in the UK, simplifying the development of a relevant novel psychoactive substances screening service to our population. By incorporating this into our routine liquid chromatography tandem mass spectrometry drugs of abuse screen, then offers a clinically relevant novel psychoactive substances service to our users. This strategy ensures our clinical toxicology service continues to remain effective to meet the challenges of the changing drug use in the UK.

LC-MS-MS Analysis of N,α-Diethylphenethylamine (N,α-ETH) and Its Positional Isomer N,ß-Diethylphenethylamine (N,ß-ETH) in Dietary Supplements.

In a previous publication, we reported on the analysis of several dietary supplement/exercise formulas and the quantitation of N,α-diethylphenethylamine (N,α-ETH, 3: ). In this article we report on the reanalysis of these products using LC-MS-MS and GC-MS methods capable of clearly separating the N,α-isomer ( 3: ) from its N,ß-isomer (N,ß-ETH, 4: ). The reanalysis, by both methods, showed that all samples previously reported as containing N,α-ETH ( 3: ) do contain only that isomer with no detectable concentrations of the N,ß-ETH ( 4: ).

Neuronal changes and oxidative stress in adolescent rats after repeated exposure to mephedrone.

Mephedrone is a new designer drug of abuse. We have investigated the neurochemical/enzymatic changes after mephedrone administration to adolescent rats (3×25 mg/kg, s.c. in a day, with a 2 h interval between doses, for two days) at high ambient temperature (26±2 °C), a schedule that intends to model human recreational abuse. In addition, we have studied the effect of mephedrone in spatial learning and memory. The drug caused a transient decrease in weight gain. After the first dose, animals showed hypothermia but, after the subsequent doses, temperature raised over the values of saline-treated group. We observed the development of tolerance to these thermoregulatory effects of mephedrone. Mephedrone induced a reduction of the densities of dopamine (30% in the frontal cortex) and serotonin (40% in the frontal cortex and the hippocampus and 48% in the striatum) transporters without microgliosis. These deficits were also accompanied by a parallel decrease in the expression of tyrosine hydroxylase and tryptophan hydroxylase 2. These changes matched with a down-regulation of D2 dopamine receptors in the striatum. Mephedrone also induced an oxidative stress evidenced by an increase of lipid peroxidation in the frontal cortex, and accompanied by a rise in glutathione peroxidase levels in all studied brain areas. Drug-treated animals displayed an impairment of the reference memory in the Morris water maze one week beyond the cessation of drug exposure, while the spatial learning process seems to be preserved. These findings raise concerns about the neuronal long-term effects of mephedrone.

Inhibition of monoamine oxidase (MAO) by α-ethylphenethylamine and N,α-diethylphenethylamine, two compounds related to dietary supplements.

Phenethylamines can interact with the metabolic enzyme monoamine oxidase (MAO), which can cause neurochemical dysfunction or changes in drug potency. A methamphetamine analog, N,α-diethylphenethylamine (N,α-DEPEA), was recently discovered in athletic performance-enhancing supplements, along with discovery of its metabolite, α-ethylphenethylamine (AEPEA). In vitro inhibition of human recombinant MAO by AEPEA and N,α-DEPEA was evaluated by measuring the fluorescence of 4-hydroxyquinoline produced from MAO substrate, kynuramine. AEPEA competitively inhibited human recombinant MAO A (Ki = 14.0 µM), which was 17-fold stronger compared to MAO B (Ki = 234 µM). Furthermore, N,α-DEPEA was a weak inhibitor of both MAO A (Ki = 251 µM) and MAO B (Ki = 159 µM). Trends regarding MAO A inhibition were explored among structural analogs, yielding the following ranking: amphetamine (Ki = 5.3 µM), AEPEA (Ki = 14.0 µM), methamphetamine (Ki = 17.2 µM), phentermine (Ki = 196 µM), and N,α-DEPEA (Ki = 251 µM). This study provides important data relating chemical structures and biochemical effects for two emerging compounds associated with dietary supplements.

Understanding the risks associated with the use of new psychoactive substances (NPS): high variability of active ingredients concentration, mislabelled preparations, multiple psychoactive substances in single products.

New psychoactive substances (NPS), are now a large group of substances of abuse not yet completely controlled by international drug conventions, which may pose a public health threat. Anxiety, paranoia, hallucinations, seizures, hyperthermia and cardiotoxicity are some of the common adverse effects associated with these compounds. In this paper, three case reports taken from the archive of processed cases of the authors' laboratory are presented and discussed to stress the risks of possible adverse consequences for NPS users: in particular, (i) the risk deriving from the difficulty of predicting the actual consumed dose, due to variability of active ingredients concentration in consumed products, (ii) the risk deriving from the difficulty of predicting the actual active ingredients present in consumed products, as opposed to those claimed by the manufacturer, and (iii) the risk deriving from the difficulty of predicting the actual pharmacological and toxicological effects related to the simultaneous consumption of different psychoactive ingredients contained in single products, whose interactions are mostly unknown. Each of them individually provide a source of concern for possible serious health related consequences. However, they should be considered in conjunction with each others, with the worldwide availability of NPS through the web and also with the incessantly growing business derived from the manipulation and synthesis of new substances. The resulting scenario is that of a cultural challenge which demands a global approach from different fields of knowledge.

The preclinical pharmacology of mephedrone; not just MDMA by another name.

The substituted ß-keto amphetamine mephedrone (4-methylmethcathinone) was banned in the UK in April 2010 but continues to be used recreationally in the UK and elsewhere. Users have compared its psychoactive effects to those of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy'). This review critically examines the preclinical data on mephedrone that have appeared over the last 2-3 years and, where relevant, compares the pharmacological effects of mephedrone in experimental animals with those obtained following MDMA administration. Both mephedrone and MDMA enhance locomotor activity and change rectal temperature in rodents. However, both of these responses are of short duration following mephedrone compared with MDMA probably because mephedrone has a short plasma half-life and rapid metabolism. Mephedrone appears to have no pharmacologically active metabolites, unlike MDMA. There is also little evidence that mephedrone induces a neurotoxic decrease in monoamine concentration in rat or mouse brain, again in contrast to MDMA. Mephedrone and MDMA both induce release of dopamine and 5-HT in the brain as shown by in vivo and in vitro studies. The effect on 5-HT release in vivo is more marked with mephedrone even though both drugs have similar affinity for the dopamine and 5-HT transporters in vitro. The profile of action of mephedrone on monoamine receptors and transporters suggests it could have a high abuse liability and several studies have found that mephedrone supports self-administration at a higher rate than MDMA. Overall, current data suggest that mephedrone not only differs from MDMA in its pharmacological profile, behavioural and neurotoxic effects, but also differs from other cathinones.

A methamphetamine analog (N,α-diethyl-phenylethylamine) identified in a mainstream dietary supplement.

Pharmaceuticals and banned substances have been detected in hundreds of purportedly natural supplements. Recently, several athletes have been disqualified from competition after testing positive for the methamphetamine analog N,α-diethyl-phenylethylamine (N,α-DEPEA). Athletes have claimed they unknowingly consumed the banned stimulant in workout supplements. Three samples from different lot numbers of Craze, a workout supplement, were analyzed to detect the presence and concentration of N,α-DEPEA. Two labs independently identified N,α-DEPEA in the supplement using ultra high performance liquid chromatography (UHPLC) coupled to an LTQ Orbitrap XL mass spectrometer and UHPLC-quadruple-time-of-flight mass (Q-TOF) spectrometer, respectively. The identity of N,α-DEPEA was confirmed using nuclear magnetic resonance and reference standards. Manufacturer recommended servings were estimated to provide 21 to 35 mg of N,α-DEPEA. N,α-DEPEA has never been studied in humans. N,α-DEPEA is a methamphetamine analog; however, its stimulant, addictive and other adverse effects in humans are entirely unknown. Regulatory agencies should act expeditiously to warn consumers and remove N,α-DEPEA from all dietary supplements.

Behavioral pharmacology of designer cathinones: a review of the preclinical literature.

"Bath salts" is one street name for a family of synthetic cathinones that display pharmacological effects resembling cocaine and commonly abused amphetamines. Despite extensive legislation aimed at the criminalization of bath salts, several designer cathinones are gaining a foothold in the illicit drug scene; for example, in the United Kingdom, mephedrone (4-methylmethcathinone, MEPH) is highly popular among drug abusers whereas, in the United States, MDPV (methylenedioxypyrovalerone) and methylone are highly prevalent. To date, knowledge about the hazards of designer cathinones is based mostly on hospital reports and anecdotal evidence derived from online surveys. Despite the paucity of preclinical studies directed toward designer cathinones, a number of invaluable findings arising from those studies are enabling scientists to develop their neuropharmacological profiles. Despite their commonalities in chemical structures, synthetic cathinones possess distinct neuropharmacological profiles and produce different behavioral effects, including unique effects on locomotor activity, learning, anxiety, thermoregulation, and abuse liability. The present review will discuss the behavioral effects of MEPH, MDPV, and methylone and compare those effects to established psychostimulant drugs. The rise in the use of designer cathinones in the United States and abroad justifies further investigations into these compounds, both for a greater understanding of the danger that "bath salts" pose to the public, and to provide insight into replacement cathinones as they emerge onto the market.

Review of detection frequency and type of synthetic cannabinoids in herbal compounds analyzed by Istanbul Narcotic Department of the Council of Forensic Medicine, Turkey.

In recent years, synthetic cannabinoids have been frequently observed in seized materials all over the world. This new generation of designer drugs, mixed with herbal substances, is also known as "Herbal Highs" or "Legal Highs". There are many articles about the history, type and pharmaco-chemical properties of synthetic cannabinoids in the literature; however the number of articles about the frequency of their detection is limited. In this study, we evaluated the type and detection frequency of synthetic cannabinoids in Istanbul and its surrounding area. The reports of the Council of Forensic Medicine-Istanbul Narcotic Department were retrospectively reviewed for the presence of synthetic cannabinoids in herbal compounds sent by the judicial authorities between August 01, 2010 and March 31, 2012. Among 1200 herbal compounds, 1179 of them (98.3%) contained synthetic cannabinoids. Twenty-one samples (1.7%) had other psychoactive substances. The analysis of 1179 samples showed that JWH-018 was present in 1172 (99.4%) of the samples. JWH-081 was found in 777 samples (65.9%) together with JWH-018. Samples had different package names. "Bonzai Aromatic Potpourri" (n = 755; 64.0%) and "Bonzai Plant Growth Regulator" (n = 316; 26.8%) were the most common product names amongst the herbal products in this study. It is clear from the present study and previous studies that brand name of synthetic cannabinoids that dominate the market exhibit regional differences as to the type and detection frequency of synthetic cannabinoids and the content of herbal highs packages. The number and diversity of synthetic cannabinoid compounds have increased dramatically in the drug market in recent years. New, different, potent derivatives appear on the market almost every day and this presents important problems that need to be solved by scientists and judicial authorities working to prevent their harm. These problems include the limited knowledge about their frequency, the lack of analytical data and reference standards for analysis of these new derivates, the lack of information on their toxic effects, and information about the metabolism and metabolites for toxicological analysis in human subjects.

"Bath salts" and "plant food" products: the experience of one regional US poison center.

Abuse of psychogenic substances sold as "bath salts" and "plant food" has escalated in recent years in the United States (USA). Previous reports suggest regional differences in the primary active ß-keto phenylalkylamines found in these products and the corresponding signs and symptoms reported after exposure. Currently, there are only limited studies describing the clinical effects associated with reported "bath salts" exposure in the USA. This study describes the clinical effects associated with "bath salt" and "plant food" exposures as reported to the poison center serving the state of North Carolina (Carolinas Poison Center). We performed a retrospective review of the Carolinas Poison Center database for all cases of reported human exposure to "bath salt" and "plant food" products from 2010 to 2011 with specific attention to clinical effects and routes of exposure. Additionally, we reviewed therapies used, trended the volume of exposure cases reported over the study period, and evaluated the distribution of calls within state counties using descriptive statistics. Carolinas Poison Center received 485 total calls and 409 reported exposure calls regarding "bath salt" or "plant food" products between January of 2010 and December of 2011. The peak of reported exposures occurred in May of 2011. Clinical effects commonly reported in the exposure cases generated from these calls included tachycardia (53.3 %, n = 218), agitated/irritable (50.4 %, n = 206), hallucination/delusions (26.7 %, n = 109), and hypertension (25.2 %, n = 103). In addition to intravenous fluids, common therapies included benzodiazepines (46.0 %, n = 188), sedation (13.4 %, n = 55), alkalinization (3.90 %, n = 16), antihistamine (4.16 %, n = 17), and intubation (3.67 %, n = 15). Haloperidol was the antipsychotic agent used most often to treat agitation (n = 40). Serious complications associated with reported exposure to "bath salt" and "plant food" products included rhabdomyolysis, renal failure, excited delirium syndrome, and death. While treatments have not been empirically determined, sedation with benzodiazepines, aggressive cooling for hyperthermic patients, and use of small doses of antipsychotics for choreoathetoid movements not controlled with benzodiazepines are not likely to be harmful.

'Legal highs'--novel and emerging psychoactive drugs: a chemical overview for the toxicologist.

INTRODUCTION: 'Legal highs' are psychoactive chemicals which are sold from 'head shops', the internet and from street suppliers and may be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes an evaluation of their harm difficult. This review covers the basic chemistry of these novel psychoactive compounds and relates them to endogenous neurotransmitters and existing drugs of abuse. METHODS: A survey of the internet was used to identify websites that are marketing 'legal highs' in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline, 4-fluorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds. This search elicited no citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N,N-diallyl-tryptamine. RESULTS: 'Legal highs' from the phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is cited in the literature on their true chemical identity, pharmacology or toxicology. CONCLUSIONS: 'Legal highs' are gaining in popularity and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new legislation can be used to reduce the supply of these materials, investment in better education for young people on the harms associated with 'legal highs' is needed.

Mephedrone, a new designer drug of abuse, produces acute hemodynamic effects in the rat.

Mephedrone (4-methylmethcathinone) is a new and popular drug of abuse widely available on the Internet and still legal in some parts of the world. Clinical reports are now emerging suggesting that the drug displays sympathomimetic toxicity on the cardiovascular system but no studies have yet explored its cardiovascular effects. Therefore we examined the effects of mephedrone on the cardiovascular system using a combination of in vitro electrophysiology and in vivo hemodynamic and echocardiographic measurements. Patch clamp studies revealed that mephedrone, up to 30 µM, had little effect on the major voltage-dependent ion channels of the heart or on action potentials recorded in guinea pig myocytes. Subcutaneous administration of mephedrone (3 and 15 mg/kg) to conscious telemetry-implanted rats produced dose-dependent increases in heart rate and blood pressure which persisted after pre-treatment with reserpine. Echocardiographic analysis demonstrated that intravenous injection of mephedrone (0.3 and 1mg/kg) increased cardiac function, including cardiac output, ejection fraction, and stroke volume, similar to methamphetamine (0.3mg/kg). We conclude that mephedrone is not directly pro-arrhythmic, but induces substantial increases in heart rate, blood pressure and cardiac contractility and this activity contributes to the cardiovascular toxicity in people who abuse the drug.

Elimination of exemptions for chemical mixtures containing the list I chemicals ephedrine and/or pseudoephedrine. Final rule.

The Drug Enforcement Administration (DEA) is finalizing, without change, the Interim Rule with Request for Comment published in the Federal Register on July 25, 2007 (72 FR 40738). The Interim Rule removed the Controlled Substances Act (CSA) exemptions for chemical mixtures containing ephedrine and/or pseudoephedrine with concentration limits at or below five percent. Upon the effective date of the Interim Rule, all ephedrine and pseudoephedrine chemical mixtures, regardless of concentration and form, became subject to the regulatory provisions of the CSA. DEA regulated the importation, exportation, manufacture, and distribution of these chemical mixtures by requiring persons who handle these chemical mixtures to register with DEA, maintain certain records common to business practice, and file certain reports, regarding these chemical mixtures. No comments to the Interim Rule were received. This Final Rule finalizes the Interim Rule without change.

Initial characterization of PMMA as a discriminative stimulus.

The phenylisopropylamine PMMA or N-methyl-1-(4-methoxyphenyl)-2-aminopropane, a structural hybrid of paramethoxyamphetamine (PMA) and methamphetamine, has been previously shown to unexpectedly lack amphetamine-like or hallucinogen-like stimulus properties in animals. For example, in tests of stimulus generalization, neither a (+)amphetamine stimulus nor a DOM stimulus generalized to PMMA. It has also been shown, however, that stimulus generalization does occur in animals trained to discriminate the designer drug MDMA ("Ecstasy" or N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane) from vehicle. In order to further characterize this unique agent, we trained a group of six Sprague-Dawley rats to discriminate 1.25 mg/kg of PMMA (ED50 = 0.44 mg/kg) from saline vehicle. The PMMA stimulus failed to generalize to the phenylisopropylamine stimulant (+)amphetamine, or to the phenylisopropylamine hallucinogen DOM. Stimulus generalization occurred to (+/-)MDMA (ED50 = 1.32 mg/kg) and S(+)MDMA (ED50 = 0.48 mg/kg). Partial generalization occurred with R(+)MDMA, PMA, 3.4-DMA, and fenfluramine. The PMMA stimulus also generalized to the alpha-ethyl homolog of PMMA (EH/PMMA, ED50 = 1.29 mg/kg). Taken together, the results of these studies suggest that PMMA is an MDMA-like agent that lacks the amphetamine-like stimulant character of MDMA. These findings support our previous suggestion that PMMA be considered the structural parent of the MDMA-like family of designer drugs.

Chronopharmacokinetics and chronopharmacodynamics of dextromethamphetamine in man.

Stimulants, in particular the amphetamines, have been studied as countermeasures to fatigue induced by circadian desynchronosis and extended flight operations. To make recommendations concerning the use of dextromethamphetamine for operational tasks, its chronopharmacokinetic and chronopharmacodynamic profiles and influence on circadian rhythms as a countermeasure to performance deficits and fatigue were studied. Ten male volunteers, divided into two groups of five each, were given 30 mg/70 kg of oral dextromethamphetamine during two test sessions one week apart and were evaluated with cognitive (dichotic listening, pattern recognition, and compensatory tracking), subjective (fatigue scale), and physiologic (blood pressure) testing. Session order was counterbalanced with dextromethamphetamine administration at either 8:40 AM or 8:40 PM during session one and a crossover to the other time during session two. Subjective and cognitive testing was begun 1.5 hours before dextromethamphetamine administration and continued every half hour until 12.5 hours after administration. Blood pressure was measured immediately before behavioral testing. Serum and urine were collected at regular intervals for gas chromatography/mass spectrometer analysis of methamphetamine and one of its metabolites, amphetamine. No differences were found in the day-versus-night pharmacokinetic profile of dextromethamphetamine. Cognitive performance and subjective fatigue improved after daytime administration of dextromethamphetamine in comparison to performance before drug administration. This effect was suppressed during the circadian trough, which occurred approximately 8 hours into the night sessions (4:30 AM). No correlations were seen between serum concentration of methamphetamine and measured behavioral parameters.