Methylenedioxypyrovalerone

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Methylenedioxypyrovalerone
MDPV.svg
MDPV 3d.gif
Systematic (IUPAC) name
(RS)-1-(Benzo[d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-yl)pentan-1-one
Clinical data
Legal status
Routes Oral, insufflation, intravenous, rectal, vaporization
Pharmacokinetic data
Metabolism Hepatic
Excretion Primarily urine (renal)
Identifiers
CAS number 687603-66-3 YesY
24622-62-6 (HCl)
ATC code ?
PubChem CID 20111961
ChemSpider 16788110 YesY
UNII E7LD6JMR0L N
Chemical data
Formula C16H21NO3 
Mol. mass 275.343 g/mol (freebase)
 N (what is this?)  (verify)

Methylenedioxypyrovalerone (MDPV) is a psychoactive recreational drug with stimulant properties which acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).[1] It was first developed in the 1960s by a team at Boehringer Ingelheim.[2] MDPV remained an obscure stimulant until around 2004 when it was reportedly sold as a designer drug. Products labeled as bath salts containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for Spice and K2 as incense.[3][4]

Incidents of psychological and physical harm have been attributed to MDPV use.[5][6]

Appearance[edit]

The hydrochloride salt exists as a very fine, hygroscopic, crystalline powder that tends to clump to itself, resembling something like powdered sugar. Its color can range from pure white to a yellowish-tan and has a slight odor that strengthens as it colors. Impurities are likely to consist of either pyrrolidine or alpha-dibrominated alkylphenones from either excess pyrrolidine or incomplete amination, respectively, during synthesis. These impurities likely account for its discoloration and fishy (pyrrolidine) or bromine-like odor, which worsens upon exposure to air, moisture, or bases.[7]

Pharmacology[edit]

Methylenedioxypyrovalerone has no record of FDA approved medical use.[8] Reportedly, it has four times the potency of methylphenidate (Ritalin, Concerta),[9] although its pharmacology has only recently been studied in detail.[10] MDPV has been shown to produce robust reinforcing effects and compulsive self-administration in rats, though this had already been provisionally established by a number of documented cases of misuse and addiction in humans, before the animal tests had been carried out.[11]

MDPV is the 3,4-methylenedioxy ring-substituted analog of the compound pyrovalerone, developed in the 1960s, which has been used for the treatment of chronic fatigue and as an anorectic, but caused problems of abuse and dependence. However, despite its structural similarity, the effects of MDPV bear little resemblance to other methylenedioxy phenylalkylamine derivatives such as 3,4-methylenedioxy-N-methylamphetamine (MDMA), instead producing primarily stimulant effects with only mild entactogenic qualities.

Other drugs with a similar chemical structure include α-pyrrolidinopropiophenone (α-PPP), 4'-methyl-α-pyrrolidinopropiophenone (M-α-PPP), 3',4'-methylenedioxy-α-pyrrolidinopropiophenone (MDPPP) and 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP).

Effects[edit]

MDPV acts as a stimulant and has been reported to produce effects similar to those of cocaine, methylphenidate, and the amphetamines. The acute effects may include:[12]

Desired psychological effects[edit]

Description of effects[edit]

The primary psychological effects have a duration of roughly 3 to 4 hours, with after effects such as tachycardia, hypertension, and mild stimulation lasting from 6 to 8 hours.[12] High doses have been observed to cause intense, prolonged panic attacks in stimulant-intolerant users,[12] and there are anecdotal reports of psychosis from sleep withdrawal and addiction at higher doses or more frequent dosing intervals.[12] It has also been repeatedly noted for inducing strong cravings to re-administer.[12][13] Users have reported a compulsive desire to continuously re-dose, even following onset of the unpleasant side effects induced by prolonged use and higher doses.[citation needed]

Reported modalities of intake include oral consumption, insufflation, smoking, rectal and intravenous use. It is supposedly active at 3–5 mg, with typical doses ranging between 5–20 mg.[12]

Chemistry[edit]

MDPV can be prepared by modifying the alkylation-oxidation-bromination-amination route to cathinone analogs. This involves a Grignard alkylation of piperonal, oxidation of the resulting secondary alcohol back into a ketone, alpha halogenation of the aromatic ketone with bromine, and subsequent amination with pyrrolidine.[14]

Possible synthetic route to MDPV from piperonal.

The α,α-dibrominated or α-mono-brominated intermediate from the 3rd step bromination, and left behind by an expedited or incomplete final workup is the most likely contaminant/impurity to be seen in the final product using this method.[7] Bromination is likely to be in excess, since excess pyrollidine amine will form a black precipitate that is difficult to separate.

Such brominated halo are of particular concern to eukaryote macro-biological organisms, and special consideration must be made when preparing MDPV for purposes of long-term biological testing on lab animals, especially in mammals, and especially where the possibility exists for diversion and subsequent ingestion by humans for recreational purposes. Preparation for biological purposes and testing must ensure a complete and thorough workup, including several washes with saturated sodium bicarbonate[7] solution after washing with water to remove the brominated intermediates before final salting of the freebase for recrystallization. Aside from the bromine ion being highly electronegative and reactive, the alkyl-bromine compounds often being alkylating agents, and brominated aromatic derivatives being implicated as hormone disruptors, there also exists the mechanism for bromine substituting for the methyl group in the nitrogenous base 5-methyluracil of DNA, creating the base-analog 5-bromouracil, which can be incorporated into DNA and induce a point mutation via base substitution.[15]}

Metabolism[edit]

MDPV undergoes CYP450 2D6, 2C19, 1A2,[16] and COMT phase 1 metabolism (liver) into methylcatechol and pyrrolidine, which in turn are glucuronated (uridine 5'-diphospho-glucuronosyl-transferase) allowing it to be excreted by the kidneys, with only a small fraction of the metabolites being excreted into the stools.[17] No free pyrrolidine will be detected in the urine.[18]


Molecularly, this is seen as demethylenation of methylenedioxypyrovalerone (CYP2D6), followed by methylation of the aromatic ring via catechol-O-methyl transferase. Then hydroxylation of both the aromatic ring and side chain takes place followed by and oxidation of the pyrrolidine ring to the corresponding lactam, with subsequent detachment and ring opening to the corresponding carboxylic acid.[19]

Detection in biological specimens[edit]

MDPV may be quantitated in blood, plasma or urine by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalized patients or to provide evidence in a medicolegal death investigation. Blood or plasma MDPV concentrations are expected to be in a range of 10–50 μg/L in persons using the drug recreationally, >50 μg/L in intoxicated patients and >300 μg/L in victims of acute overdosage.[20]

Legality[edit]

In the UK, following the ACMD's report on substituted cathinone derivatives,[13] MDPV is a Class B drug under The Misuse of Drugs Act 1971 (Amendment) Order 2010, making it illegal to sell, buy, or possess without a license.[21][22] Penalties include a maximum of five years and/or unlimited fine for possession; up to 14 years and/or unlimited fine for production or trafficking. See list of drugs illegal in the UK for more information.

MDPV is specifically listed as a controlled substance in Finland (listed appendix IV substance as of June 28, 2010),[23] Denmark and Sweden. In Sweden a 33-year-old man has been sentenced to six years in prison by an appellate court, Hovrätt, for possession of 250 grams of MDPV that had been acquired prior to criminalization.[24]

Australia[edit]

In Western Australia, MDPV has been banned under the Poisons Act 1964, having been included in Appendix A Schedule 9 of the Poisons Act 1964 as from February 11, 2012. The Director of Public Prosecutions for Western Australia announced that anyone intending to sell or supply MDPV faces a maximum $100,000 fine or 25 years in jail. Users face a $2000 fine or two years' jail. Therefore anyone caught with MDPV can be charged with possession, selling, supplying or intent to sell or supply.[25]

Canada[edit]

Canadian Health Minister Leona Aglukkaq announced on June 5, 2012 that MDPV would be listed on Schedule 1 of the Controlled Drugs and Substances Act. Other drugs on schedule 1 include cocaine and heroin. This will make possession, trafficking, importing, exporting, and production of MDPV illegal. As of September 26, 2012 MDPV has become illegal in Canada as a Schedule 1 drug. Researchers will still be able to use the drug after applying for an exemption to that status.[26]

United States[edit]

In the United States, MDPV is a DEA federally scheduled drug. On October 21, 2011, the DEA issued a temporary one-year ban on MDPV, classifying it as a schedule I substance. Schedule I status is reserved for those substances with a high potential for abuse, no currently accepted use for treatment in the United States and a lack of accepted safety for use of the drug under medical supervision.[27][28]

Prior to the Federal ban being announced, it was already banned in Louisiana and Florida.[29][30][31][32] On March 24, 2011, Kentucky passed bill HB 121 which makes MDPV, as well as three other cathinones, controlled substances in the state. It also makes it a Class A misdemeanor to sell the drug, and a Class B misdemeanor to possess it.[33]

MDPV is banned in New Jersey under Pamela's Law. The law is named after Pamela Schmidt, a Rutgers University student, murdered in March 2011 by an alleged user of MDPV.[34] A toxicology report later found that no "bath salts" were present in his system.[35]

On May 5, 2011, Tennessee Governor Bill Haslam signed a law making it a crime "to knowingly produce, manufacture, distribute, sell, offer for sale or possess with intent to produce, manufacture, distribute, sell, or offer for sale" any product containing 3,4-Methylenedioxypyrovalerone (MDPV).[36]

On July 6, 2011, the governor of Maine signed a bill establishing fines for possession and penalties for trafficking of MDPV.[37]

On September 7, 2011, the DEA took advantage of its emergency scheduling authority to ban Mephedrone (4-MMC), MDPV, and Methylone (M1). The substances were made illegal to possess and sell for 12 months until the DEA and Department of Health and Human Services determines if these substances should be permanently banned.[citation needed]

On October 17, 2011, an Ohio law banning synthetic drugs took effect barring selling and/or possession of "any material, compound, mixture, or preparation that contains any quantity of the following substances having a stimulant effect on the central nervous system, including their salts, isomers, and salts of isomers" listing ephedrine and pyrovalerone. It also specifically includes MDPV, misspelling the full name as "methyenedioxypyrovalerone".[38][39] Four days after this Ohio law was passed, the DEA's national emergency ban was implemented.[27]

On December 8, 2011, under the Synthetic Drug Control Act, the US House of Representatives voted to ban MDPV and a variety of other synthetic drugs which had been sold legally in stores.[40]

Documented misuse[edit]

In April 2011, two weeks after they went missing, two men in northwestern Pennsylvania were found dead in a remote location on government land. The official cause of death of both men was hypothermia, but toxicology reports later confirmed that both Troy Johnson, 29, and Terry Sumrow, 28, had ingested MDPV shortly before their deaths. "It wasn't anything to kill them, but enough to get them messed up," the county coroner said. MDPV containers were found in their vehicle along with spoons, hypodermic syringes and marijuana paraphernalia. In April 2011, an Alton, Illinois, woman apparently died from an MDPV overdose.[41] In May 2011, The CDC reported a hospital emergency department (ED) visit after the use of "bath salts" in Michigan. One person was reported dead on arrival at the ED. Associates of the dead person reported that he had used bath salts. His toxicology results revealed high levels of MDPV in addition to marijuana and prescription drugs. The primary factor contributing to death was cited as MDPV toxicity after autopsy was performed.[42] An incident of hemiplegia has been reported.[43]

Overdose treatment[edit]

Physicians often treat MDPV overdose cases with anxiolytics, such as benzodiazepines, to lessen the drug-induced activity in the brain and body.[44] In some cases, general anesthesia was used because sedatives were ineffective.[45]

Treatment in the emergency department for severe hypertension, tachycardia, agitation, or seizures consists of large doses of lorazepam in 2–4 mg increments every 10–15 minutes intravenously or intramuscularly. If this is not effective, haloperidol is an alternative treatment. It has been found that the use of any beta blockers to treat hypertension in these patients can cause an unopposed peripheral alpha-adrenergic effect with a dangerous paradoxical rise in blood pressure.[46]

Alternatively, the antihypertensive drug clonidine can be used to treat symptoms of MDPV intoxication. Clonidine has been used clinically in the treatment of acute stimulant intoxication and withdrawal,[47] and is sometimes prescribed to reduce the side effects of stimulant medications used to treat ADHD.[48]

References[edit]

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External links[edit]