Pyrrolidinyl Synthetic Cathinones α-PHP and 4F-α-PVP Metabolite Profiling Using Human Hepatocyte Incubations.

For more than ten years, new synthetic cathinones (SCs) mimicking the effects of controlled cocaine-like stimulants have flooded the illegal drug market, causing numerous intoxications and fatalities. There are often no data on the pharmacokinetics of these substances when they first emerge onto the market. However, the detection of SC metabolites is often critical in order to prove consumption in clinical and forensic settings. In this research, the metabolite profile of two pyrrolidinyl SCs, α-pyrrolidinohexaphenone (α-PHP) and 4''-fluoro-α-pyrrolidinovalerophenone (4F-α-PVP), were characterized to identify optimal intake markers. Experiments were conducted using pooled human hepatocyte incubations followed by liquid chromatography-high-resolution tandem mass spectrometry and data-mining software. We suggest α-PHP dihydroxy-pyrrolidinyl, α-PHP hexanol, α-PHP 2'-keto-pyrrolidinyl-hexanol, and α-PHP 2'-keto-pyrrolidinyl as markers of α-PHP use, and 4F-α-PVP dihydroxy-pyrrolidinyl, 4F-α-PVP hexanol, 4F-α-PVP 2'-keto-pyrrolidinyl-hexanol, and 4F-α-PVP 2'-keto-pyrrolidinyl as markers of 4F-α-PVP use. These results represent the first data available on 4F-α-PVP metabolism. The metabolic fate of α-PHP was previously studied using human liver microsomes and urine samples from α-PHP users. We identified an additional major metabolite (α-PHP dihydroxy-pyrrolidinyl) that might be crucial for documenting exposure to α-PHP. Further experiments with suitable analytical standards, which are yet to be synthesized, and authentic specimens should be conducted to confirm these results.

Influence on the Sweating Function by the Successive Application of Artificial CO2 Bath Salts / 日本温泉気候物理医学会雑誌

  Using healthy volunteers, we examined the influence of emulsified oil and a low concentration of CO2 gas on cutaneous blood flow in the forearm. The forearm of each subject was immersed in 25 liters of warm water containing either 10 ppm emulsified oil or 60 ppm CO2 gas or both. Forearm cutaneous blood flow was measured for 20 minutes. Emulsified oil had no effect on cutaneous blood flow, whereas CO2 gas caused a gradual and significant increase. When CO2 gas was used with emulsified oil, cutaneous blood flow was significantly increased in comparison to CO2 alone, suggesting that emulsified oil enhances the vasodilation caused by CO2. We then prepared bath salts releasing CO2 and emulsified oil, and tested for their influence on sweating function in sixteen healthy adults. Each subject bathed daily 10 minutes either in tap water (control group) or in tap water dissolving bath salts releasing CO2 and emulsified oil (bath-salts group) at 40°C for successive 14 days. A sweating test was performed before and after the session of bathing. In the bath-salts group, the baseline tympanic temperature after successive bathing tended to be lower than that before successive bathing. Although the rise of body temperature during the heat exposure was not different between the groups, sweating rate was significantly greater after successive bathing. The analysis of the rate of sweat expulsion suggested that the greater sweat rate after the successive bathing is mediated by the central mechanism for sweating. Such changes were not observed in the control group. Thus, successive bathing using bath salts that release CO2 and emulsified oil may have a beneficial effect on sweating function.

The Ability of Narcotic Detection Canines to Detect Illegal Synthetic Cathinones (Bath Salts).

Twelve certified narcotic detection canines were tested for their ability to detect confiscated illegal synthetic cathinones (bath salts). These canine teams were randomly assigned to two different groups and each group imprinted on one of two types of bath salts, ethylone and alpha-pyrrolidinovalerophenone (α-PVP), over the period of 1 month; while simultaneously documenting the imprinting procedure. The newly imprinted canines were validated by field testing and found to not only detect the imprinted bath salt to which they were trained, but they were able to detect other bath salts. The imprinting procedure and results are the first scientifically validated studies on the ability of canines to detect these harmful and illegal substances. Analytical headspace analysis using Solid Phase Microextraction (SPME) on several ethylone and α-PVP samples revealed compounds common in both. These compounds can be used to create a safe and reliable synthetic cathinone mimic training aid for canine teams.

Influence on the Sweating Function by the Successive Application of Artificial CO2 Bath Salts / 日本温泉気候物理医学会雑誌

  Using healthy volunteers, we examined the influence of emulsified oil and a low concentration of CO2 gas on cutaneous blood flow in the forearm. The forearm of each subject was immersed in 25 liters of warm water containing either 10 ppm emulsified oil or 60 ppm CO2 gas or both. Forearm cutaneous blood flow was measured for 20 minutes. Emulsified oil had no effect on cutaneous blood flow, whereas CO2 gas caused a gradual and significant increase. When CO2 gas was used with emulsified oil, cutaneous blood flow was significantly increased in comparison to CO2 alone, suggesting that emulsified oil enhances the vasodilation caused by CO2. We then prepared bath salts releasing CO2 and emulsified oil, and tested for their influence on sweating function in sixteen healthy adults. Each subject bathed daily 10 minutes either in tap water (control group) or in tap water dissolving bath salts releasing CO2 and emulsified oil (bath-salts group) at 40°C for successive 14 days. A sweating test was performed before and after the session of bathing. In the bath-salts group, the baseline tympanic temperature after successive bathing tended to be lower than that before successive bathing. Although the rise of body temperature during the heat exposure was not different between the groups, sweating rate was significantly greater after successive bathing. The analysis of the rate of sweat expulsion suggested that the greater sweat rate after the successive bathing is mediated by the central mechanism for sweating. Such changes were not observed in the control group. Thus, successive bathing using bath salts that release CO2 and emulsified oil may have a beneficial effect on sweating function.

Gestational Exposure to the Synthetic Cathinone Methylenedioxypyrovalerone Results in Reduced Maternal Care and Behavioral Alterations in Mouse Pups.

The member of synthetic cathinone family, methylenedioxypyrovalerone (MDPV), is a frequently used psychoactive drug of abuse. The objective of our study was to determine the effect of MDPV (administered from the 8th to the 14th day of gestation) on the behavior of neonatal and adolescent mice, as well as its effect on maternal care. We measured maternal care (pup retrieval test, nest building), locomotor activity (open field test), and motor coordination (grip strength test) of dams, whereas on pups we examined locomotor activity at postnatal day 7 and day 21 (open field test) and motor coordination on day 21 (grip strength test). On fresh-frozen brain samples of the dams we examined the expression of two important peptides implicated in the regulation of maternal behavior and lactation: tuberoinfundibular peptide 39 (TIP39) mRNA in the thalamic posterior intralaminar complex, and amylin mRNA in the medial preoptic nucleus. We detected decreased birth rate and survival of offspring, and reduced maternal care in the drug-treated animals, whereas there was no difference between the motility of treated and control mothers. Locomotor activity of the pups was increased in the MDPV treated group both at 7 and 21 days of age, while motor coordination was unaffected by MDPV treatment. TIP39 and amylin were detected in their typical location but failed to show a significant difference of expression between the drug-treated and control groups. The results suggest that chronic systemic administration of the cathinone agent MDPV to pregnant mice can reduce birth rate and maternal care, and it also enhances motility (without impairment of motor coordination) of the offspring.

Monoaminergic toxicity induced by cathinone phthalimide: An in vitro study.

Bath salts, or synthetic cathinones, have cocaine-like or amphetamine-like properties and induce psychoactive effects via their capacity to modulate serotonin (5-HT) and dopamine (DA). Structurally distinct synthetic cathinones are continuously being generated to skirt existing drug laws. One example of these modified compounds is cathinone phthalimide (CP), which has already appeared on the global market. The lack of toxicological studies on the effects of CP on monoaminergic systems led to the development of the present study in order to generate an acute toxicity profile for CP, and to clarify whether it primarily affects both dopamine and serotonin, like the synthetic cathinones mephedrone and methylone, or primarily affects dopamine, like 3, 4-methylenedioxypyrovalerone (MDPV). For the first time, the toxicity profile of CP (10µM-1000µM) is reported. In pheochromocytoma cells, exposure to CP induced cell death, and altered mitochondrial function, as well as intracellular DA and 5-HT levels; at the same time, reduced glutathione (GSH) levels remained unaffected. This seems to indicate that CP functions like mephedrone or methylone. The role of CP metabolites, the effect of CP induced hyperthermia on neurotoxicity, and its ability to traverse the blood-brain barrier warrant further consideration.

Magnetic nanotherapeutics for dysregulated synaptic plasticity during neuroAIDS and drug abuse.

The human immunodeficiency virus (HIV) is a neurotropic virus. It induces neurotoxicity and subsequent brain pathologies in different brain cells. Addiction to recreational drugs remarkably affects the initiation of HIV infections and expedites the progression of acquired immunodeficiency syndrome (AIDS) associated neuropathogenesis. Symptoms of HIV-associated neurocognitive disorders (HAND) are noticed in many AIDS patients. At least 50 % of HIV diagnosed cases show one or other kind of neuropathological signs or symptoms during different stages of disease progression. In the same line, mild to severe neurological alterations are seen in at least 80 % autopsies of AIDS patients. Neurological illnesses weaken the connections between neurons causing significant altercations in synaptic plasticity. Synaptic plasticity alterations during HIV infection and recreational drug abuse are mediated by complex cellular phenomena involving changes in gene expression and subsequent loss of dendritic and spine morphology and physiology. New treatment strategies with ability to deliver drugs across blood-brain barrier (BBB) are being intensively investigated. In this context, magnetic nanoparticles (MNPs) based nanoformulations have shown significant potential for target specificity, drug delivery, drug release, and bioavailability of desired amount of drugs in non-invasive brain targeting. MNPs-based potential therapies to promote neuronal plasticity during HIV infection and recreational drug abuse are being developed.

Bath Salt-Induced Psychosis: Nursing Assessment, Diagnosis, Treatment, and Outcomes.

PURPOSE: To review what is known about the assessment, diagnosis, treatment, and outcomes of patients with bath salt-induced psychosis. DESIGN AND METHODS: Comprehensive review and synthesis of research, case reports, and state-level data. FINDINGS: Of the 42 case reports found, only 18 confirmed the presence of bath salts through laboratory testing. Twelve of the confirmed cases died. In most of the case reports, law enforcement was involved prior to hospitalization due to bizarre behaviors, delusions, and hallucinations. PRACTICE IMPLICATIONS: Due to the severity of both physical and psychological symptoms in patients in bath salt-induced psychosis, nurses, other healthcare providers, police, and hospital security personnel must work collaboratively to provide safe care.

Stereochemistry and neuropharmacology of a 'bath salt' cathinone: S-enantiomer of mephedrone reduces cocaine-induced reward and withdrawal in invertebrates.

Knowledge about the neuropharmacology of mephedrone (MEPH) applies primarily to the racemate, or street form of the drug, but not to its individual enantiomers. Here, through chemical isolation of MEPH enantiomers and subsequent behavioral characterization in established invertebrate (planarian) assays, we began separating adverse effects of MEPH from potential therapeutic actions. We first compared stereotypical and environmental place conditioning (EPC) effects of racemic MEPH, S-MEPH, and R-MEPH. Stereotypy was enhanced by acute treatment (100-1000 µM) with each compound; however, S-MEPH was less potent and efficacious than racemate and R-MEPH. Both R-MEPH (10, 100, 250 µM) and racemate (100 µM) produced EPC, but S-MEPH was ineffective at all concentrations (10-100 µM). After showing that S-MEPH lacked rewarding efficacy, we investigated its ability to alter three of cocaine's behavioral effects (EPC, withdrawal, and stereotypy). Cocaine (1 µM) produced EPC that was abolished when S-MEPH (100 µM) was administered after cocaine conditioning. Spontaneous withdrawal from chronic cocaine exposure caused a reduction in motility that was not evident during acute or continuous cocaine treatment but was attenuated by S-MEPH (100 µM) treatment during the cocaine abstinence interval. Acute stereotypy produced by 1 mM cocaine, nicotine or racemic MEPH was not affected by S-MEPH (10-250 µM). The present results obtained using planarian assays suggest that the R-enantiomer of MEPH is predominantly responsible for its stimulant and rewarding effects and the S-enantiomer is capable of antagonizing cocaine's addictive-like behaviors without producing rewarding effects of its own.

Potent rewarding and reinforcing effects of the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV).

Reports of abuse and toxic effects of synthetic cathinones, frequently sold as 'bath salts' or 'legal highs', have increased dramatically in recent years. One of the most widely used synthetic cathinones is 3,4-methylenedioxypyrovalerone (MDPV). The current study evaluated the abuse potential of MDPV by assessing its ability to support intravenous self-administration and to lower thresholds for intracranial self-stimulation (ICSS) in rats. In the first experiment, the rats were trained to intravenously self-administer MDPV in daily 2-hour sessions for 10 days at doses of 0.05, 0.1 or 0.2 mg/kg per infusion. The rats were then allowed to self-administer MDPV under a progressive ratio (PR) schedule of reinforcement. Next, the rats self-administered MDPV for an additional 10 days under short access (ShA; 2 hours/day) or long access (LgA; 6 hours/day) conditions to assess escalation of intake. A separate group of rats underwent the same procedures, with the exception of self-administering methamphetamine (0.05 mg/kg per infusion) instead of MDPV. In the second experiment, the effects of MDPV on ICSS thresholds following acute administration (0.1, 0.5, 1 and 2 mg/kg, i.p.) were assessed. MDPV maintained self-administration across all doses tested. A positive relationship between MDPV dose and breakpoints for reinforcement under PR conditions was observed. LgA conditions led to escalation of drug intake at 0.1 and 0.2 mg/kg doses, and rats self-administering methamphetamine showed similar patterns of escalation. Finally, MDPV significantly lowered ICSS thresholds at all doses tested. Together, these findings indicate that MDPV has reinforcing properties and activates brain reward circuitry, suggesting a potential for abuse and addiction in humans.

Monitoring the Internet for emerging psychoactive substances available to Australia.

INTRODUCTION AND AIMS: Novel psychoactive substances are increasingly available, both in traditional storefronts and via the Internet. While some use of such substances has been captured in Australian consumer surveys and wastewater analyses, there is little information about the products that are available to Australia via the Internet. DESIGN AND METHODS: Systematic monthly Internet monitoring for emerging psychoactive substances was conducted between July 2011 and July 2012. Webstores identified through searches were examined to determine if they sold stimulant or psychedelic emerging psychoactive substances to Australia. Internet search numbers for these products were examined over time using commercial tools. RESULTS: In 12 months, 43 unique webstores were identified selling to Australia, averaging two new webstores per month; however, two-fifths had closed within six months. Over 200 unique chemically unspecified products sold by purported effect (e.g. 'charge') were identified over 12 months, averaging 10 new products per month. Almost half of these products had disappeared from the market within six months. Eighty-six unique chemically specified products (e.g. methylenedioxypyrovalerone) were identified over 12 months, averaging four new novel substances per month. Once released, these products typically remained available, with almost 90% still available for purchase over a 6-month period. Almost 40 000 searches for these products emanated from Australia per month. DISCUSSION AND CONCLUSION: This market is fast paced as retailers strive to beat both regulatory processes and competitors. Ongoing attention to these markets, incorporating surveillance of both Internet and traditional storefronts, is crucial as several of the substances identified have demonstrated potential for health and neurological harm.

Investigating the 'bath salt' panic: the rarity of synthetic cathinone use among students in the United States.

INTRODUCTION AND AIMS: Until recently, synthetic cathinones marketed as 'bath salts' were legally sold at convenience stores and online in the USA. Media reports initiated concerns of a growing 'bath salt' epidemic. Despite media attention and the recent legal action banning synthetic cathinones, little is known about its prevalence or users. DESIGN AND METHODS: A self-report survey was administered to 2349 students in 40 randomly selected courses at a large university in the Southeastern United States. The resulting sample was 51.6% female, 68.9% white, 24.4% black, 2.8% Hispanic and 4.0% other races, with a mean age of 20.06 years and median family income of $75 000-99 999. RESULTS: Only 25 (1.07%) of the students reported using synthetic cathinones at least once. Synthetic cathinone use was found to be more common among men (1.68% vs. 0.50% of women, P = 0.005), Hispanics (4.7%) and Native Americans (4.3% vs. 0.89% of whites and 0.72% of blacks, P = 0.002), and student athletes (4.0% vs. 0.90% of non-athletes, P = 0.001), but in each of these groups, synthetic cathinones were used more rarely than marijuana (58.14%, P < 0.001), cocaine (9.08%, P < 0.001), Salvia divinorum (7.89%, P < 0.001), synthetic cannabinoids (14.28%, P < 0.001), methamphetamines (1.92%, P = 0.002), 3,4-methylenedioxy-N-methylamphetamine (MDMA) (12.54%, P < 0.001) and several other drugs and pharmaceuticals. DISCUSSION AND CONCLUSIONS: 'Bath salts' have received a great deal of media attention in the USA, yet the prevalence of synthetic cathinone use among our sample was extremely rare. We suggest that the media attention focusing on synthetic cathinone use as a growing epidemic may be largely misplaced.

Effects of the Bath Salt with Ginseng Powder on Human Body / 日本温泉気候物理医学会雑誌

Ginseng powder was dissolved in the warm water to develop bath salt that contained Ginseng powder (250mg: 1% Ginseng powder, 500mg: 2% Ginseng powder) and it made comparative study of the effects with the tap warm water for seven healthy adults (male 3, female 4, 20.7±0.8 years old). The Ginseng powder of 250mg and 500mg was made so that the bath salt of 25g may become 1% and 2%. The whole body immersion of 15 minutes was done to all subjects under the condition that 1% or 2% cannot be distinguished without tap water bathing.<br>As a result, the warm water with Ginseng powder increased in the changes of the deep thermometer in front of chest between immersion and after bathing, compared with the tap warm water. But there were not significant change of the surface skin temperature on the arm and the tissue blood flow on thigh skin.<br>Therefore, the warm water with Ginseng powder was suspected that the thermo effects and the retaining warmth were good compared with the tap warm water.<br>It seemed that it was possible to use it safely as bath salt for it did not change of the blood pressure, the heart rate, and abnormality of the skin without the case to whom the skin had temporarily flushed, was not additionally recognized.