Methylenedioxypyrovalerone (abbreviated MDPV, and also called monkey dust[3]) is a stimulant of the cathinone class that acts as a norepinephrine–dopamine reuptake inhibitor (NDRI).[4][5] It was first developed in the 1960s by a team at Boehringer Ingelheim.[6] Its activity at the dopamine transporter is six times stronger than at the norepinephrine transporter and it is virtually inactive at the serotonin transporter.[4] MDPV remained an obscure stimulant until around 2004 when it was reportedly sold as a designer drug. In the US, products containing MDPV and labeled as bath salts were sold as recreational drugs in gas stations, similar to the marketing for Spice and K2 as incense, until it was banned in 2011.[7]
Appearance
The hydrochloride salt exists as a very fine crystalline powder; it is hygroscopic and thus tends to form clumps, 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—respectively, from either excess pyrrolidine or incomplete amination 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.[8]
Pharmacology
Methylenedioxypyrovalerone has no record of FDA approved medical use.[9] It 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 were carried out.[10][11]
The primary psychological effects have a duration of roughly 3 to 4 hours, with aftereffects such as tachycardia, hypertension, and mild stimulation lasting from 6 to 8 hours.[13] High doses have been observed to cause intense, prolonged panic attacks in stimulant-intolerant users,[13] and there are anecdotal reports of psychosis from sleep withdrawal and addiction at higher doses or more frequent dosing intervals.[13] It has also been repeatedly noted to induce irresistible cravings to re-administer.[13][14]
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.[13]
When assayed in mice, repeated exposure to MDPV causes not only an anxiogenic effect but also increased aggressive behaviour, a feature that has already been observed in humans. As with MDMA, MDPV also caused a faster adaptation to repeated social isolation.[15]
A cross-sensitization between MDPV and cocaine has been evidenced.[16] Furthermore, both psychostimulants, MDPV and cocaine, restore drug-seeking behavior with respect to each other, although relapse into drug-taking is always more pronounced with the conditioning drug. Moreover, memories associated with MDPV require more time to be extinguished. Also, in MDPV-treated mice, a priming-dose of cocaine triggers significant neuroplasticity, implying a high vulnerability to its abuse.[17]
Long-term effects
The long-term effects of MDPV on humans have not been studied, but it has been reported that mice treated with MDPV during adolescence show reinforcing behavior patterns to cocaine that are higher than the control groups. These behavioural changes are related to alterations of factor expression directly related to addiction. All this suggests an increased vulnerability to cocaine abuse.[18]
Molecularly, this is seen as demethylenation of methylenedioxypyrovalerone (CYP2D6), followed by methylation of the aromatic ring via catechol-O-methyl transferase. Hydroxylation of both the aromatic ring and side chain then takes place, followed by an oxidation of the pyrrolidine ring to the corresponding lactam, with subsequent detachment and ring opening to the corresponding carboxylic acid.[22]
Detection in biological specimens
MDPV may be quantified 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 overdose.[23]
Legality
In 2010, a 33-year-old Swedish man was 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
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
Canadian Health Minister Leona Aglukkaq announced on June 5, 2012, that MDPV would be listed on Schedule I of the Controlled Drugs and Substances Act, which was realized on September 26, 2012.[26]
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 substances with a high potential for abuse, no currently accepted use for treatment in the United States and a lack of accepted safety standards for use under medical supervision.[30]
Before the federal ban was announced, MDPV was already banned in Louisiana and Florida.[31] 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.[32]
MDPV is banned in New Jersey under Pamela's Law. The law is named after Pamela Schmidt, a Rutgers University student who was murdered in March 2011 by an alleged user of MDPV.[33] A toxicology report later found no "bath salts" in his system.[34]
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 MDPV.[35]
On July 6, 2011, the governor of Maine signed a bill establishing fines for possession and penalties for trafficking of MDPV.[36]
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.[37] Four days after this Ohio law was passed, the DEA's national emergency ban was implemented.[30]
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 that had been legally sold in stores.[38]
Documented fatalities
In April 2011, two weeks after being reported 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.[39]
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.[40] An incident of hemiplegia has been reported.[41]
A total of 107 non-fatal intoxications and 99 analytically confirmed deaths related to MDPV between September 2009 and August 2013 were reported by nine European countries.[2]
Treatment in the emergency department for hypertensive emergency, 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 is suggested that the use of beta blockers to treat hypertension in these patients can cause an unopposed peripheral alpha-adrenergic effect with a dangerous paradoxical rise in blood pressure.[44]Electroconvulsive therapy (ECT) has been shown to improve persistent psychotic symptoms associated with repeated MDPV use.[45][46]
^US 3478050, Koppe H, Ludwig G, Zeile K, "1-(3',4'-methylenedioxy-phenyl)-2-pyrrolidino-alkanones-(1)", issued November 1969, assigned to CH Boehringer Sohn AG and Co and KG Boehringer Ingelheim GmbH.
^Slomski A (December 2012). "A trip on "bath salts" is cheaper than meth or cocaine but much more dangerous". JAMA. 308 (23): 2445–7. doi:10.1001/jama.2012.34423. PMID23288310.
^Brandt SD, Freeman S, Sumnall HR, Measham F, Cole J (September 2011). "Analysis of NRG 'legal highs' in the UK: identification and formation of novel cathinones". Drug Testing and Analysis. 3 (9): 569–75. CiteSeerX10.1.1.687.9467. doi:10.1002/dta.204. PMID21960541.
^Westphal F, Junge T, Rösner P, Sönnichsen F, Schuster F (September 2009). "Mass and NMR spectroscopic characterization of 3,4-methylenedioxypyrovalerone: a designer drug with alpha-pyrrolidinophenone structure". Forensic Science International. 190 (1–3): 1–8. doi:10.1016/j.forsciint.2009.05.001. PMID19500924.
^Coppola M, Mondola R (January 2012). "3,4-methylenedioxypyrovalerone (MDPV): chemistry, pharmacology and toxicology of a new designer drug of abuse marketed online". Toxicology Letters. 208 (1): 12–5. doi:10.1016/j.toxlet.2011.10.002. PMID22008731.
^ abcdef"Report on MDPV"(PDF). Drugs of Concern. DEA. May 2013. Archived(PDF) from the original on June 11, 2016. Retrieved June 27, 2016.
^ ab"Consideration of the Cathinones"(PDF). Advisory Council on the Misuse of Drugs. March 31, 2010. Archived(PDF) from the original on September 16, 2016. Retrieved June 27, 2016.
^Duart-Castells L, López-Arnau R, Buenrostro-Jáuregui M, Muñoz-Villegas P, Valverde O, Camarasa J, et al. (January 2019). "Neuroadaptive changes and behavioral effects after a sensitization regime of MDPV". Neuropharmacology. 144: 271–281. doi:10.1016/j.neuropharm.2018.10.005. hdl:2445/148191. PMID30321610. S2CID53208116.
^Duart-Castells L, López-Arnau R, Vizcaíno S, Camarasa J, Pubill D, Escubedo E (May 2019). "7,8-Dihydroxyflavone blocks the development of behavioral sensitization to MDPV, but not to cocaine: Differential role of the BDNF-TrkB pathway". Biochemical Pharmacology. 163: 84–93. doi:10.1016/j.bcp.2019.02.004. hdl:2445/130480. PMID30738029. S2CID73433868.
^Duart-Castells L, Blanco-Gandía MC, Ferrer-Pérez C, Puster B, Pubill D, Miñarro J, et al. (June 2020). "Cross-reinstatement between 3,4-methylenedioxypyrovalerone (MDPV) and cocaine using conditioned place preference". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 100: 109876. doi:10.1016/j.pnpbp.2020.109876. PMID31991149. S2CID210896469.
^Strano-Rossi S, Cadwallader AB, de la Torre X, Botrè F (September 2010). "Toxicological determination and in vitro metabolism of the designer drug methylenedioxypyrovalerone (MDPV) by gas chromatography/mass spectrometry and liquid chromatography/quadrupole time-of-flight mass spectrometry". Rapid Communications in Mass Spectrometry. 24 (18): 2706–14. Bibcode:2010RCMS...24.2706S. doi:10.1002/rcm.4692. PMID20814976.
^Michaelis W, Russel JH, Schindler O (May 1970). "The metabolism of pyrovalerone hydrochloride". Journal of Medicinal Chemistry. 13 (3): 497–503. doi:10.1021/jm00297a036. PMID5441133.
^Meyer MR, Du P, Schuster F, Maurer HH (December 2010). "Studies on the metabolism of the α-pyrrolidinophenone designer drug methylenedioxy-pyrovalerone (MDPV) in rat and human urine and human liver microsomes using GC-MS and LC-high-resolution MS and its detectability in urine by GC-MS". Journal of Mass Spectrometry. 45 (12): 1426–42. Bibcode:2010JMSp...45.1426M. doi:10.1002/jms.1859. PMID21053377.
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^Penders TM, Gestring RE, Vilensky DA (November 2012). "Intoxication delirium following use of synthetic cathinone derivatives". The American Journal of Drug and Alcohol Abuse. 38 (6): 616–7. doi:10.3109/00952990.2012.694535. PMID22783894. S2CID207428569.
^Penders TM, et al. (December 2013). "Electroconvulsive Therapy Improves Persistent Psychosis After Repeated Use of Methylenedioxypyrovalerone ("Bath Salts")". The Journal of ECT. 29 (4): 59–60. doi:10.1097/YCT.0b013e3182887bc2. PMID23609518. S2CID45842375.
