As with other stimulant drugs, Flakka greatly increases the activity of the neurotransmitter dopamine in the brain. This trips the brain’s reward pathway, causing a euphoric high and priming a person to feel cravings to repeat the experience in the future. Our findings are in line with those published by Matsunaga et al. (2017), demonstrating that cytotoxicity of pyrovalerones increases with the elongation of the α-carbon side-chain. Importantly, our results suggest that the risk of intoxication with pyrovalerones, resulting from their cytotoxic properties, could be positively related to the length of their aliphatic side-chain.

The NOR test has been proposed to measure recognition memory by allowing mice to explore novel and familiar objects (Antunes and Biala 2012). Each animal had a familiarization (training) session with a pair of identical objects (~ 5 cm long x 5 cm wide x 10 cm high) placed 5 cm away from the walls but adjacent in the open field. 6 hours after familiarization (Leger et al. 2013), each mouse was tested in the same box with a novel object replacing one of the familiar objects.Familiarization and testing sessions lasted 10 minutes, were video recorded, and were assessed offline.

The plate was sealed and mixed again at 1000 RPM for 4 min on an Eppendorf MixMate orbital shaker prior to analysis. Ark Behavioral Health Is an accredited drug and alcohol rehabilitation program, that believes addiction treatment should not just address “how to stay sober” but needs to transform the life of the addict and empower him or her to create a more meaningful and positive life. We are dedicated to transforming the despair of addiction into a purposeful life of confidence, self-respect and happiness. We want to give recovering addicts the tools to return to the outside world completely substance-free and successful. Ark Behavioral Health offers 100% confidential substance abuse assessment and treatment placement tailored to your individual needs.

What are the symptoms of flakka abuse?

Self-administration of α-PVP during LgA conditions had no effect on 5-HT in any brain region but increased 5-HIAA in all brain regions compared to naïve. In contrast, self-administration of 4MMC during LgA conditions decreased 5-HT in all brain regions except thalamus and decreased 5-HIAA in most brain regions compared to naïve (Table 1 and Fig. 3). 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. The most striking effects of condition were large elevations of DOPAC and HVA levels in striatum that were noted following LgA self-administration of both α-PVP and 4MMC.

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The mobile phase consisted of 50 mM sodium phosphate, 47 mM citric acid, 0.14 mM EDTA, 0.64 mM octanesulfonic acid, and 5% methanol, with a flow rate of 0.4 ml/min. The detector was set to sequentially deliver potentials of −150 mV, alpha-pyrrolidinopentiophenone function 150 mV, 400 mV, and 600 mV.

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). The maximal cytotoxic effect increases with the elongation of the α-aliphatic side-chain, which can cause major health problems, as longer-chain substances produce less pronounced stimulatory effects and hence are used in higher doses. Additionally, the presented findings implicate the presence of disturbances in the plasma membrane fluidity as another important factor underlying the cytotoxicity of α-pyrrolidinophenones. Results obtained using LDH assay further confirm the impact of the side-chain length on the cytotoxicity of pyrrolidinophenones. 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.

For self-administration data, autoshaping data were analyzed with separate mixed factors ANOVAs (day x lever x sex) to compare active and inactive lever presses, with day and lever as within-subjects factors, and sex as a between-subjects factor. The additional 21 days of self-administration were also analyzed with separate mixed factors ANOVAs (day x lever x sex), which compared responses on the active and inactive levers. If the assumption of circularity was violated, the Geisser-Greenhouse Adjustment was employed.

Moreover, at least for dopamine, these changes do not appear to be related to changes in neurotransmitter production or metabolism, as we did not detect any changes in dopamine turnover, suggesting that they are related to poisoning of the dopamine system rather than temporary changes in dopamine metabolism. Notwithstanding these findings, much work remains to be completed to elucidate the role of sex, age, species, strain, dose, drug class,structural modification, and pharmacological mechanism in the putative neurotoxicity effects of cathinones, including the second-generation pyrrolidines. Stimulant-induced neurochemical changes may occur at different times for different brain regions or neurotransmitter systems. This study sought to examine the behavioral and neurochemical effects of extended access to α-pyrrolidinopentiophenone (α-PVP) and 4-methylmethcathinone (4MMC). Male and female Sprague-Dawley rats were trained to self-administer α-PVP (0.1 mg/kg/infusion) or 4MMC (0.5 mg/kg/infusion) through autoshaping, and then self-administered for 21 days during 1 h (short access; ShA) or 6 h (long access; LgA) sessions. Amygdala, hippocampus, hypothalamus, prefrontal cortex (PFC), striatum, and thalamus were extracted, and tissue was analyzed with electrochemical detection and liquid chromatography mass spectrometry.

Synthetic cathinones first appeared in Europe in the mid 2000s and in the United States around 2009, and their use led to numerous reports of abuse, bizarre behavior, toxicity, and death (Prosser and Nelson, 2012; Rosenbaum et al., 2012). The rise in popularity of synthetic cathinones is linked to their ease of procurement over the internet and in gas stations, smoke shops, and novelty stores (Spiller et al., 2011). Synthetic cathinones have been falsely marketed as numerous products, the most recognizable being “bath salts,” and are typically labeled “not for human consumption” or “for research purposes only” to evade drug laws (United States Department of Justice, 2011c).

Extending incubation time to 72 h increased the cytotoxicity at 300 μM, leading to the decrease of the viability by 91% for SH-SY5Y, 97% for Hep G2, 98% for RPMI 2650, and 63% for H9c2(2-1). Moreover, a broader concentration range was found to elicit a significant drop in the viability for the Hep G2 (25–300 μM) and H9c2(2-1) (10–300 μM) cell lines, compared to 24-h exposure (Fg. 4c). Cell viability and mitochondrial function were measured by assessment of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction by mitochondrial dehydrogenases after 24- and 72-h exposure to the drugs. A solution of MTT (0.5 mg/ml) was added to the cells, and the culture was incubated for a further 3-h at 37 °C. After aspiration of culture medium, formazan crystals were dissolved in DMSO, and its absorbance was measured at 570 nm using Bio-Rad microplate reader model 680; this value being proportional to the number of cells with intact mitochondria. The mean values for each group were obtained by subtracting the mean OD of the positive control (1% (v/v) Triton-X100, added 30 min before MTT) from the value.

Flakka is the street name for the synthetic cathinone called alpha-pyrrolidinopentiophenone (Alpha-PVP). It is also notable that both α-PPP (Eshleman et al. 2017) and MDPV (Simmler et al. 2013) function as reuptake inhibitors rather than substrate-based releasers, and the mechanism of action of methylone appears to include both reuptake inhibition and substrate-based release (Simmler et al. 2013). Although α-PPP and MDPV are amphetamine derivatives, their pharmacological mechanism of action is closer to cocaine than to amphetamines.

What is Flakka? Is it Safe?

Muscle tissue begins to break down, releasing proteins and other cellular products into the bloodstream, in a process called rhabdomyolysis. The result of the cellular products and proteins released during rhabdomyolysis and dehydration can impair the filtering function of the kidneys, leading to renal failure and death. In addition, such agitation may trigger Taser use or other methods that have the potential to harm the individual when law enforcement personnel have to intervene. Frozen tissues were weighed, sonically disrupted in 100 µl of 0.3 N HClO4 and centrifuged for 10 minutes at 4ºC to remove cellular debris. A 100 µl aliquot of the supernatant was placed in an WPS-3000TBSL autosampler maintained at 10ºC, and 10 µl was injected onto a Thermo Scientific (Waltham, MA) Hypersil BDS C18 column (35ºC) with Thermo Scientific Dionex Test Phase running at a flow rate of 0.5 mL/min. Coulometric detection was accomplished with a Thermo Scientific Dionex 6011RS electrode cell, and the signal analyzed on a Thermo Scientific Dionex Chromeleon CDS processing platform.

Fig. 3.

Likewise, adolescent rats exposed to methylone exhibited persistent depletions of serotonin and deficits in reference memory (Lopez-Arnau et al. 2014). However, mephedrone and methylone have also been reported to not persistently deplete brain monoamine content (Baumann et al. 2012). The Koob and Volkow hypothesis of drug abuse posits that treatment needs may differ based on the amount of drug consumed over time, and that stimulant-induced neurochemical changes may occur at different times for different brain regions or neurotransmitter systems (Koob and Volkow, 2010).

Fig. 1.

In contrast, it had no significant effect on elevated plus maze performance or object discrimination in the novel object recognition test. The locomotor-stimulant effects of α-PPP were comparable to cocaine (30mg/kg), and α-PPP (80mg/kg) did not induce hyperthermia. The present study suggests that 21 days of LgA self-administration models the neurochemistry of the beginning stages of the Koob and Volkow model of dysregulated drug intake (Koob and Le Moal, 2005, 2008; Koob and Volkow, 2010). Most past research using the escalation model of self-administration has used 21 sessions (Anker et al., 2010; Gipson et al., 2011; Kitamura et al., 2006; Marusich et al., 2010; Wee et al., 2007a), or fewer. The identified studies that used more than 21 sessions of self-administration (Ahmed and Koob, 1999; Belin et al., 2009; Greenwell et al., 2009a; Greenwell et al., 2009b) provided very little information on the neurochemical changes that occur beyond 21 sessions. Thus, future research should extend the duration of self-administration past 21 sessions to examine what neurochemical changes transpire and if increasing neurochemical dysregulation occurs with continued drug use as hypothesized.

• Brains were sliced into 1 mm thick coronal sections, and these slices were placed flat on a cold plate over ice.
• Flakka is a highly potent drug that can be snorted, injected, eaten, smoked, or vaporized in e-cigarettes.
• Treatment with PV9 for 24 h caused a significant decrease in the survival of Hep G2 and RPMI 2650 (10–300 μM), SH-SY5Y (100–300 μM), and H9c2(2-1) (200 and 300 μM) cells.
• Our findings are in line with those published by Matsunaga et al. (2017), demonstrating that cytotoxicity of pyrovalerones increases with the elongation of the α-carbon side-chain.

Despite this, few studies have examined the effects of synthetic cathinones on neurochemistry. As noted previously, when methylone is administered to adolescent rats in a warm ambient environment, it induces an acute hyperthermic response and persistent depletions of serotonin and deficits in reference memory. These decrements were also selective, as there were no changes in dopamine levels or spatial memory (Lopez-Arnau et al. 2014). An interesting recent study reported the effects of exposure to MDPV, methylone, or mephedrone, using the same dosing regimen that we used in the present study (30–40 mg/kg, QID, q2h, IP), in female C57BL/6 mice, housed at five per cage.

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In the United States, flakka is classified as a Schedule I controlled substance under the Controlled Substances Act. Schedule I drugs are defined as substances with a high potential for abuse, no currently accepted medical use in treatment, and a lack of accepted safety for use under medical supervision. On January 22, 2013, the US DEA published a request for information specifically regarding 8 additional synthetic cathinones, 2 of the most prominent being 4-methyl-N-ethcathinone (4-MEC) and α‐pyrrolidinopentiophenone (α-PVP) (DEA, 2013). Their similarity in chemical structure suggests that α-PVP and 4-MEC likely emerged as replacements for MDPV and mephedrone, respectively (Figure 1). Rats were surgically implanted with chronic indwelling jugular catheters under general anesthesia as previously described (Marusich et al., 2019a; Marusich et al., 2019b). Catheters were flushed daily with saline prior to the session, and with 0.2 ml of a solution containing 0.96% gentamicin, 2.88% heparin, and 96.2% saline after the session to maintain patency.

Rats were given 7 days to recover from surgery before commencement of ICSS procedures, during which they received daily injections of 2.5mg/mL meloxicam (0.15mL volume) to minimize postsurgical discomfort. Law enforcement and community activists were instrumental in limiting the damage done by the drug’s dangerous effects. Most reports of flakka after 2016 turned out to be other similar chemicals in the bath salt family. Flakka is a dangerous drug that has many bad side effects, mostly including changes in behavior or mood.