Flakka Drug: Symptoms, Side Effects & Complications

Each standard was transferred to a volumetric flask and diluted to volume with tissue buffer to create stock solutions. A stock solution containing approximately 10 μg/ml of analyte was then diluted to encompass a concentration range from 1000 to 0.5 ng/ml. Ultra-high pressure liquid chromatography (UPLC) coupled with ECD was used to simultaneously measure DA, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-HT, 5-hydroxy-3-acetic acid (5-HIAA), and NE.

Brain Dissection

• In SH-SY5Y neuroblasts, only 4-F-PVP and 4-MeO-PVP used at 300 μM caused a slight elevation of extracellular LDH activity.
• Despite these challenges, flakka holds promise in neuroscience research and potential therapeutic applications.
• Considered a new psychoactive substance (NPS), Flakka is part of a collection of black-market, lab-made drugs imported to the United States from China.
• Importantly, the more lipophilic PV8 and PV9 evoked changes in the membrane fluidity across a broader concentration range than PVP, an observation that is in line with the fact that disturbances were found in the internal, highly lipophilic part of the membrane but not in the external polar head-groups.
• The desired psychostimulatory effects include raised alertness and awareness, improved mood, impression of increased motivation, energy, and euphoria (Zawilska and Wojcieszak 2017).
• Small, but significant changes in DA levels for LgA groups compared to naïve were found in select brain regions where α-PVP decreased DA levels in thalamus, whereas 4MMC increased DA levels in hypothalamus and thalamus.

All self-administration and neurotransmitter data for these three rats were excluded from graphs and analyses. 4-Methylmethcathinone (4MMC; mephedrone) releases dopamine (DA), norepinephrine (NE), and serotonin (5-HT) (Baumann et al., 2012; Cameron et al., 2013; Simmler et al., 2013). In contrast, α-PVP inhibits uptake of DA and NE transport (Glennon and Young, 2016; Koob and Volkow, 2010; Marusich et al., 2014). Both α-PVP and 4MMC cause hyperactivity and stereotyped behavior (Gatch et al., 2015;Gregg and Rawls, 2014; Marusich et al., 2014; Marusich et al., 2012; Marusich et al., 2016), and α-PVP also produces toxic effects not observed with cocaine or methamphetamine (Marusich et al., 2014). Α-PVP and 4MMC are readily self-administered by rats, attesting to their reinforcing effects (Aarde et al., 2015; Creehan et al., 2015; Gannon et al., 2018; Marusich et al., 2019a; Marusich et al., 2019b; Marusich et al., 2013; Nguyen et al., 2017a; Nguyen et al., 2016; Vandewater et al., 2015).

• It may, however, cause an excited delirium resulting in wild, unpredictable, and severely violent behavior in those under this drug’s influence.
• PV9 and its substituted analogs produced significant cytotoxicity in all analyzed cell lines, with profound effects observed after 24 h incubation at concentrations of 200 and 300 μM (Fig. 6).
• This caused people most at risk, poor desperate drug addicts and homeless people, to use it instead of more expensive drugs like cocaine or methamphetamines.
• Flakka is a highly potent drug that can be snorted, injected, eaten, smoked, or vaporized in e-cigarettes.
• PVP and its analogs caused only benign disruption of SH-SY5Y and H9C2(2-1) cell membranes, while PV8 and PV9, and their substituted derivatives, evoked marked damages.
• Although many synthetic cathinone derivatives exist, 3,4-methylenedioxypyrovalerone (MDPV), mephedrone, or methylone, initially comprised approximately 98% of all synthetic cathinones encountered in US drug seizures (United States Department of Justice, 2011a).

Treating Flakka Abuse

All other data comparing saline versus α-PPP were analyzed by unpaired t-test, and corrected for multiple comparisons by the Bonferroni method to maintain the probability of making a type 1 error at 5%. Flakka, also known as the “flakka drug” or “flakka zombie drug,” is primarily composed of alpha-pyrrolidinopentiophenone (alpha-PVP), which is an artificial stimulant that falls under the category of synthetic cathinones, commonly referred to as bath salts. Flakka is a highly potent drug that can be snorted, injected, eaten, smoked, or vaporized in e-cigarettes.

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The report demonstrates, for the first time, that changes of fluidity of the interior part of plasma membrane contribute to the cytotoxicity of pyrovalerone derivatives, in addition to the previously reported mechanisms. As with neurochemistry, there has been little study of the persistent effects of synthetic cathinone exposure on learning, memory, and behavior. A recent study examined the effects of binge-like self-administration of MDPV using five 96-hour self-administration sessions in rats. Three weeks after the last session, the subjects showed both neurodegeneration and deficits in NOR performance (Sewalia et al. 2018). We report that, five days after exposure to α-PPP, mice exhibited decreased exploratory behavior as well as significantly impaired Y-maze performance.

Studies

Changes in DA levels in striatum and thalamus are hypothesized to occur during the binge and intoxication stage because activation of the mesolimbic DA system produces acute reinforcing properties of psychostimulants (Koob and Volkow, 2010). Furthermore, the dorsal striatum is involved in escalation of drug taking and compulsive behaviors (Clark et al., 2013; Willuhn et al., 2012). LgA, but not ShA, synthetic cathinone self-administration elevated DOPAC and HVA levels in striatum compared to saline and synthetic cathinone ShA levels (Fig. 5), encompassing the binge and intoxication stage of Koob and Volkow’s model. Interestingly, while the metabolites were altered, DA levels only changed in striatum and thalamus for 4MMC and α-PVP LgA groups, respectively, compared to saline ShA. These findings are consistent with a past study showing that ShA 4MMC self-administration did not alter DA, DOPAC, or HVA in striatum (Motbey et al., 2013). Thus, LgA synthetic cathinone self-administration for 21 days models most neurochemical changes predicted by the Koob and Volkow hypothesis for the binge and intoxication stage.

Fig. 1.

Flakka, also recognized as alpha-Pyrrolidinopentiophenone (α-PVP), is a synthetic cathinone acknowledged for its potent psychoactive effects. Initially intended for medicinal use, flakka has become popular as a recreational substance due to its affordability and stimulant properties. Despite these challenges, flakka holds promise in neuroscience research and potential therapeutic applications.

Links to NCBI Databases

Long incubation times were applied in order to show whether the cytotoxicity of studied compounds increase with time, which is relevant since the common abuse pattern of synthetic cathinones includes long sessions during which multiple doses are administered (Zawilska and Wojcieszak 2013). The effects of α-PPP on serotonin levels are somewhat surprising, as it has reported selectivity for the dopamine and norepinephrine transporters over the serotonin transporter (Eshleman et al. 2017). However, we used a relatively high dose regimen to ensure near maximal levels of toxicity, and α-PPP likely loses some selectivity alpha-pyrrolidinopentiophenone function at such doses.