1-phenyl-2-(1-pyrrolidinyl)-1-pentanone and Substance-Related-Disorders

Flakka (alpha-pyrrolidinovalerophenone, α-PVP) is a new psychoactive substance, chemically close to cathinone, the primary psychoactive alkaloid of khat ( Catha edulis). Like other synthetic cathinones, α-PVP is a potent inhibitor of the dopamine and norepinephrine transporters. Its robust clinical effects include hallucinations, arousal, aggression/violence, and euphoria. In animal models, α-PVP evokes hyperlocomotion and aberrant/stereotypic behaviors. Here, we discuss the history, synthesis, pharmacological mechanisms, metabolism, abuse potential, and societal impact of α-PVP. Today, α-PVP is a tightly controlled substance, currently banned in the United States and other countries worldwide. However, the growing abuse and complex central nervous system (CNS) effects of α-PVP remain poorly understood, necessitating further pharmacological and pharmacogenetic studies of this drug. Its interesting pharmacological profile (co-inhibition of dopamine and norepinephrine, but not serotonin, transporters) also calls for further studies of α-PVP in animal models, to dissect serotonergic from other monoaminergic mechanisms of action of drugs of abuse. Finally, screening α-PVP and related compounds in vivo may foster discovery of new CNS drugs, including developing novel CNS drugs and identifying their molecular targets.

Topics: Animals; Central Nervous System Stimulants; Designer Drugs; Humans; Illicit Drugs; Psychotropic Drugs; Pyrrolidines; Substance-Related Disorders

3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects. Elevations in brain extracellular dopamine produced by MDPV are likely to underlie its locomotor stimulant and addictive properties. MDPV displays rapid pharmacokinetics when injected into rats (0.5-2.0 mg/kg), with peak plasma concentrations achieved by 10-20 min and declining quickly thereafter. MDPV is metabolized to 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) in vivo, but motor activation produced by the drug is positively correlated with plasma concentrations of parent drug and not its metabolites. 3,4-Catechol-PV is a potent uptake blocker at DAT in vitro but has little activity after administration in vivo. 4-OH-3-MeO-PV is the main MDPV metabolite but is weak at DAT and NET. MDPV analogs, such as α-pyrrolidinovalerophenone (α-PVP), display similar ability to inhibit DAT and increase extracellular dopamine concentrations. Taken together, these findings demonstrate that MDPV and its analogs represent a unique class of transporter inhibitors with a high propensity for abuse and addiction.

Topics: Adrenergic Uptake Inhibitors; Animals; Behavior, Animal; Benzodioxoles; Brain; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Humans; Neuropharmacology; Norepinephrine Plasma Membrane Transport Proteins; Psychotropic Drugs; Pyrrolidines; Substance-Related Disorders; Synthetic Cathinone

α-PVP (α-pyrrolidinovalerophenone) and MDPV (3,4-methylenedioxypyrovalerone) are potent abused stimulants that are members of the synthetic cathinone class of drugs. Although these drugs are taken with recreational intent, high doses can lead to unintended adverse effects including agitation, cardiovascular effects, sympathomimetic syndromes, hallucinations, and psychoses. One possible treatment is the use of a vaccine to block or attenuate adverse medical effects. These studies report the preparation of a vaccine that generates high affinity antibodies specific for both drugs and the pharmacological testing of this vaccine in male rats. Alkylation of a hydroxy-α-PVP analog with an appropriate thiol-bearing linker afforded the hapten. When hapten-conjugated carrier protein was mixed with adjuvant, the resulting vaccine stimulated production of antibodies in male Sprague Dawley rats that were found to significantly reduce α-PVP- and MDPV-induced hyperlocomotion as well as to significantly reduce the concentrations of MDPV drugs in critical organs. The novel vaccine produced high affinity antibodies against MDPV, (R)-MDPV, (S)-MDPV, and α-PVP. Cross-reactivity testing against nine structurally similar cathinones showed very limited binding, and no binding to off-target endogenous and exogenous compounds. Antibodies generated by this bi-specific vaccine also significantly shortened the duration of locomotor activity induced by both drugs up to a dose of 5.6 mg/kg in male rats.

Topics: Animals; Antibodies; Benzodioxoles; Dose-Response Relationship, Drug; Drug Design; Male; Motor Activity; Pyrrolidines; Rats; Rats, Sprague-Dawley; Substance-Related Disorders; Synthetic Cathinone; Vaccines

The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP) continues to be abused despite being banned by regulatory agencies. The abused formulation of α-PVP is a racemic mixture consisting of two enantiomers, S-α-PVP and R-α-PVP. In this study, we investigated the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP and its enantiomers in male rats. Racemic α-PVP blocked the uptake of both dopamine and norepinephrine ex vivo, but did not block the uptake of serotonin (5-HT), at their respective transporters. S-α-PVP was slightly more potent than racemic α-PVP, while R-α-PVP was 10 to 20 times less potent at blocking dopamine and norepinephrine uptake. In microdialysis studies, racemic and S-α-PVP increased extracellular dopamine levels in the nucleus accumbens, but not levels of 5-HT. Racemic and S-α-PVP also increased locomotor activity. When tested at the same doses, S-α-PVP produced larger effects than racemic α-PVP. R-α-PVP also increased extracellular dopamine levels and locomotor activity, but only at 30 times higher doses than S-α-PVP. Racemic and S-α-PVP were self-administered by rats at 0.03 mg/kg/injection, whereas R-α-PVP was self-administered at a 10 times higher dose. Dose-effect determinations following acquisition suggested that R-α-PVP was at least 30 times less potent than S-α-PVP. Finally, racemic and S-α-PVP increased blood pressure and heart rate at doses approximately 30 times less than was required for R-α-PVP to produce similar effects. These results show that the neurochemical, behavioral, and cardiovascular effects of racemic α-PVP most likely reflect the actions of S isomer.

Topics: Animals; Arterial Pressure; Dopamine; Heart Rate; Male; Microdialysis; Nucleus Accumbens; Pyrrolidines; Rats; Rats, Sprague-Dawley; Self Administration; Serotonin; Stereoisomerism; Substance-Related Disorders

We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs' effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.

Topics: Amphetamine; Benzodiazepines; Buprenorphine; Designer Drugs; Humans; Male; Masturbation; Middle Aged; Pyrrolidines; Respiratory Insufficiency; Steam Bath; Substance-Related Disorders

Twenty-one cases involving alpha-pyrrolidinovalerophenone (α-PVP) were submitted between 2012 and 2015 to the Western Department of Forensic Science Laboratory. Eighteen suspected impaired driving cases were determined to have α-PVP concentrations <0.005-0.09 mg/L. Three fatalities during this period were determined to have α-PVP concentrations ranging from 0.03 to >20 mg/L. Human use of synthetic cathinones like α-PVP has been reported to induce psychological effects such as delusions, paranoia, hallucinations and deleterious cardiovascular effects. Quantitation was performed using a liquid-liquid extraction with detection by liquid chromatography triple quadrupole mass spectrometry using electrospray ionization in a multiple reaction monitoring mode. The reported behaviors in the 18 suspected impaired driving cases ranged from central nervous system depression to eluding officers in a high speed chase. The mean and median DUID α-PVP concentrations were both 0.030 mg/L. The α-PVP concentrations in the three fatalities were determined to be 0.033, 0.054 and present >20 mg/L. In 18 DUID cases, only 4 cases reported side effects consistent with synthetic cathinones. Two of the three fatalities indicated histories of bath salt and/or recreational drug use. At this time, no correlation can be determined between side effects and α-PVP concentrations.

Topics: Central Nervous System Stimulants; Forensic Toxicology; Humans; Pyrrolidines; Substance Abuse Detection; Substance-Related Disorders

α-Pyrrolidinovalerophenone (α-PVP) is a synthetic cathinone that has been abused in recent years. The clinical presentation of acute α-PVP poisoning has not been well characterized.. To elucidate the clinical features of acute α-PVP poisoning.. This retrospective case series included eight subjects that visited our hospital emergency department (ED) between March 2012 and November 2014 and had analytically confirmed blood α-PVP levels. Data related to subject demographics, clinical history, laboratory findings, blood drug levels, and outcome were collected.. The median age of the eight study subjects was 27 (range; 21-63) years, and six were male. Drug preparations had been administered by rectal insertion (three subjects) or inhalation (five subjects). The time between drug exposure and presentation at the ED was 8.5 (1-24) h and blood α-PVP concentrations ranged from 1.0 to 52.5 ng/ml. Although psychiatric and neurological findings were reported before arrival at the ED in 5/8 and 7/8 subjects, respectively, these were only observed in 1/8 and 2/8 subjects, respectively, at the ED. Symptoms of high body temperature (3/8), tachycardia (5/8), hypertension (3/8), acid-base balance disorder (5/8), coagulopathy (4/6), blood creatinine phosphokinase >190 U/l (6/8), and a blood lactate level > 1.7 mmol/l (5/7) were observed. All subjects survived and were discharged.. This retrospective case series showed that after acute exposure to α-PVP, transient neuropsychiatric findings were accompanied by more persistent sympathomimetic physical findings, disorders of acid-base balance and blood coagulation, high blood creatinine phosphokinase, and hyperlactacidemia.

Topics: Acid-Base Equilibrium; Adult; Blood Coagulation; Creatine Kinase; Female; Humans; Hyperlactatemia; Male; Middle Aged; Pyrrolidines; Retrospective Studies; Substance Abuse Detection; Substance-Related Disorders; Young Adult

An increasing number of new psychoactive substances (NPS) of different chemical classes have become available through marketing and sale over the Internet. This report from the Swedish STRIDA project presents the prevalence, laboratory results, and clinical features in a series of intoxications involving the stimulant NPS α-pyrrolidinovalerophenone (α-PVP), a potent dopamine re-uptake inhibitor, over a 4-year period.. Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden from 2012 to 2015.. In the STRIDA project, blood and urine samples are collected from intoxicated patients with admitted or suspected intake of NPS or unknown drugs presenting to hospitals over the country. Analysis of NPS is performed by mass spectrometry multicomponent methods. Clinical data are collected when caregivers consult the Swedish Poisons Information Centre (PIC), and retrieved from medical records. The severity of poisoning is graded retrospectively using the Poisoning Severity Score (PSS). The inclusion criteria for this study included absence of other stimulants than α-PVP.. During the 4-year study period, 23 intoxications were originally coded as "α-PVP related" out of a total 3743 NPS-related inquiries (0.6%) at the PIC. The present study covered 42 analytically confirmed cases in which α-PVP was the only stimulant detected. The age range of patients was 20-58 (median 32) years, of which 79% were males. The α-PVP concentration in serum was 4.0-606 (median 64; n = 42) ng/mL and 2.0-41,294 (median 1782; n = 25) ng/mL in urine. There was no statistically significant association between the serum α-PVP concentration and urinary α-PVP/creatinine ratio in 25 cases, where both sets of data were available. In 14/42 (33%) cases, α-PVP was the only psychoactive substance identified. In the remaining cases, additional substances comprised opioids, benzodiazepines, and ethanol. The main clinical manifestations were tachycardia (80%), agitation (70%), hypertension (33%), hallucinations (20%), and delirium (18%). Classification of poisoning severity yielded 25 (60%) moderate (PSS 2), 7 (17%) severe (PSS 3), and 2 fatal cases (PSS 4).. In analytically confirmed α-PVP intoxication cases involving no other stimulant drugs, the urine and serum concentrations showed high variability. The clinical features were consistent with a severe sympathomimetic toxidrome. The results further demonstrated that α-PVP prevailed as a drug of abuse after being classified as a narcotic substance, and despite a high incidence of severe poisonings and fatalities. However, the low prevalence of α-PVP cases registered at the PIC suggested that many were unaware of the actual substance they had taken.

Topics: Adult; Analgesics, Opioid; Benzodiazepines; Central Nervous System Stimulants; Creatinine; Delirium; Dopamine Uptake Inhibitors; Ethanol; Female; Hallucinations; Hospitalization; Humans; Hypertension; Illicit Drugs; Male; Middle Aged; Prevalence; Psychomotor Agitation; Pyrrolidines; Retrospective Studies; Substance-Related Disorders; Sweden; Tachycardia; Young Adult

This is the first reported case of α-pyrrolidinovalerophenone (α-PVP), methylone and ethylone in a suspected impaired driving case in the state of Washington. An initial traffic stop by law enforcement was made of a driver due to poor navigation of the roadway. The drug recognition expert (DRE) officer observed slurred speech, bloodshot watery eyes, dilated pupils, involuntary muscle movements and an elevated pulse and blood pressure. The DRE deduced that the driver was likely under the influence of central nervous system (CNS) stimulants, specifically 'bath salts'. Routine testing of the blood did not reveal the presence of alcohol or common drugs of abuse. Upon further review of the officer's report and the unconfirmed identification of α-PVP, blood was sent to NMS Labs in Willow Grove, PA, USA for bath salts and stimulant designer drugs testing. Analysis was conducted by liquid chromatography-time-of-flight mass spectrometry with the following results: 63 ng/mL α-PVP, 6.1 ng/mL methylone and positive for ethylone. These results are consistent with the DRE opinion of driving performance being impaired by a CNS stimulant.

Topics: Adult; Automobile Driving; Central Nervous System Stimulants; Chromatography, Liquid; Designer Drugs; Humans; Male; Mass Spectrometry; Methamphetamine; Pyrrolidines; Substance Abuse Detection; Substance-Related Disorders; Washington