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The Next Big Bath Salt....Flakka

6/30/2015

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Alpha-PVP (aka “Flakka” or “Gravel”)

Introduction:
-Also referred to as Alpha-pyrrolidinovalerophenone, alpha-pyrrolidinopentiophenone, (RS)-1-phenyl-2-(1-pyrrolidinyl)-1-pentanone
-Cathinone is a natural stimulant found in the khat plant
-Synthetic cathinones, aka “Bath salts”, refer to a collective group of compounds that are highly potent stimulants and are similar to MDMA, cocaine, and methamphetamine
-The most common compound found in bath salts is MDPV (3,4-methylenedioxypyrovalerone)
-Alpha-PVP is not a “second generation bath salt”; it was actually first synthesized in the 1960’s
-Alpha-PVP has been recently been linked to multiple reported deaths in Florida
-Alpha-PVP was added to the controlled substance list in the USA in 2014

Structure:
-Alpha-PVP typically comes in a crystal form
-Formula: C15H21NO
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Pharmacology/Pharmacokinetics:
-Alpha-PVP’s mechanism of action is believed to involve inhibition of the reuptake of norepinephrine, dopamine, and serotonin
-Rat studies have showed that alpha-PVP is both an uptake blocker of norephinephrine/dopamine and stimulates dopamine release

Absorption/Distribution/Metabolism/Excretion:
Absorption
-Can be taken orally, sublingually, injected, vaporized, or intranasal
-Onset of desired effects (euphoria) in 5-30 minutes and lasts for 1-3 hours.  However, the undesired side effects (including psychosis) can last days
Distribution
-Postmortem studies have found alpha-PVP uniformly distributed among multiple tissues (blood, brain, muscle, CSF, lung, kidney, and liver)
Metabolism
-Six phase I metabolites have been identified
-Lactam is the major metabolite
Excretion
-A study of postmortem alpha-PVP levels showed the highest concentrations were found in urine and the lowest concentrations were found in the liver → suggesting the drug is excreted chiefly by the renal system

Significant Drug/Drug Interactions:
-Co-ingestion of alcohol, other stimulants, and other illicit drugs has been shown to enhance the effects of the drugs
-A large proportion of the fatal cases of alpha-PVP have involved co-ingestions of multiples drugs and alcohol

Toxicity/Mechanism of Toxicity:
-LD50 has not been determined
-The potency and efficacy of alpha-PVP and MDPV are very similar in rat studies
-Rat studies showed increased locomotor signs with doses ranging from 1mg/kg to 30mg/kg
-A few case reports of drug-related fatalities with serum alpha-PVP levels have been reported:  0.1mg/L, 0.29mg/L, 0.52mg/L, 0.901mg/L
-All serum levels determined by liquid-mass-mass spectrometry method
-There is a significant overlap between concentrations tolerated by individuals and those reported in drug-related fatalities → alpha-PVP concentration alone does not determine toxicity

Clinical Toxicity/Presentation:
-Increased dopamine causes euphoria, increased activity, and hyperstimulation
-Increased norepinephrine increases heart rate and blood pressure
-Increased serotonin can cause hallucinations, delirium, and paranoia
-Severe agitated delirium and aggressive behavior have been reported
-Life threatening severe toxicity: Serotonin syndrome, hyperthermia, hypotension, rhabdomyolysis, acute renal failure, liver failure, cardiac dysrhythmias, seizures
-Chronic exposure:  May lead to physical and psychological dependence with withdrawal symptoms

Laboratories/Where it is made:
-Mainly manufactured in China and India and then shipped to America by legal delivery companies
-Unknown if manufactured in America currently

Treatment/Management:
-Treatment is symptomatic and supportive
-Benzodiazepines for sedation/delirium/seizures/tachycardia/hypertension
-IVF’s for dehydration frequently indicated
-GI decontamination is not recommended.  Single dose of activated charcoal may be considered for possible co-ingestion, but usually not clinically indicated.  Hemodialysis is not effective for elimination.
-Labs: Obtain electrolytes, renal function, hepatic enzymes, and CPK level
-Serum drug levels are NOT clinically useful and NOT readily available
-Obtain EKG and continuous cardiac monitoring
-Frequent temperature monitoring and institute cooling measures as warranted (Hyperthermia is an indicator of severe toxicity)
-Dispo:  Minimal observation of 6-8 hours.  If patient has persistent CNS stimulation, persistent tachycardia, seizures, or dysrhythmias →then warrants admission
-Poison center should be consulted

By: Dr. Patrick Jackson

References:
  1. Aarde S, Creehan K, Vandewater S, et. al.  In vivo potency and efficacy of the novel cathinone alpha-PVP and 3,4-methylenedioxypyrovalerone: self-administration and locomotor stimulation in male rats.  Psychopharmacology.  2015
  2. Eiden C, Mathieu O, Cathala P, et. al.  Toxicity and death following recreational use of 2-pyrrolidino valerophenone.  Clin Toxicol.  51(9):899-903, 2013.
  3. “Flakka” (alpha-PVP).  National Institute of Drug Abuse.  April 6, 2015.  http://www.drugabuse.gov/drugs-abuse/emerging-trends
  4. Gatch M, Dolan S, & Forster M.  Comparative behavioral pharmacology of three pyrrolidine-containing synthetic cathinone derivatives.  J Pharmacol Exp Ther.  2015.
  5. Jones S.  Trending now: Flakka/Gravel/Alpha-PVP, and what you need to know.  Drug Policy Alliance.  April 10, 2015.  http://www.drugpolicy.org/blog/trending-now-flakka-gravel-alpha-pvp-and-what-you-need-know 
  6. Kaizaki A, Tanaka S, & Numazawa S.  New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron.  The Journal of Toxicological Sciences.  39(1):1-6, 2014.
  7. Logan B.  Emerging designer drug monograph: Alpha-PVP.  SOFT Designer Drug Monographs.  2013.  http://www.soft-tox.org/files/Designer_Drugs/Alpha-PVP.pdf
  8. Marinetti L & Antonides H.  Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: Method development, drug distribution and interpretation of results.  J Anal Toxicol.  37(3):135-146, 2013.
  9. Marusich JA, Antonazzo KR, Wiley JL, et. al.  Pharmacology of novel synthetic stimulants structurally related to the “bath salts” constituent 3,4-methylenedioxypyrovalerone (MDPV).  Neuropharmacology.  87:206-213, 2014.
  10. Negreira N, Erratico C, Kosjek T, et. al.  In vitro phase I and phase II metabolism of alpha-pyrrolidinovalerophenone (alpha-PVP), methylenedioxypyrovalerone (MDPV) and methedrone by human liver microsomes and human liver cytosol.  Anal Bioanal Chem.  2015
  11. Sauer C, Peters F, Haas C, et. al.  New designer drug alpha-pyrrolidinovalerophenone (PVP): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques.  Journal of Mass Spectrometry.  44(6):952-964, 2009.  
  12. Waugh L, Bailey K, Clay D, et. al.  Deaths involving the recreational use of alpha-PVP.  AAFS Proceedings. Abstract presentation.  2013.
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