Flakka Drug: Symptoms, Side Effects & Complications

Effective treatment typically includes a combination of medical detoxification, behavioral therapies, and ongoing support to manage cravings and prevent relapse. Researchers have not thoroughly clinically studied the long-term effects of flakka, but renal failure can occur that is irreversible. In some of the documented delusions, individuals’ experiences are of a typical paranoia, where the drug users feel they are being chased by a large group of people trying to kill them. These patients are a threat to themselves, the people around them, and the first responders (police, EMS) who are there to help them. It is common to hear reports that it takes multiple people to restrain and sedate these patients. Rescue crews and emergency department staff need to give sedatives to these patients to calm them and make them safe.

Use of synthetic cathinones, which are designer stimulants found in “bath salts,” has increased dramatically in recent years. Following governmental bans of methylenedioxypyrovalerone, mephedrone, and methylone, a second generation of synthetic cathinones with unknown abuse liability has emerged as replacements. One limitation is that the neurotransmitter data for LgA and naïve were analyzed at a different time than those for ShA.

Citing imminent threats to public health and safety, the US Drug Enforcement Administration (DEA) used their emergency scheduling authority to temporarily classify these 3 drugs (now often referred to as first-generation bath salts) as Schedule I substances in October of 2011 (United States Department of Justice, 2011b). As of 2013, these first-generation synthetic cathinones are now permanently classified as Schedule I substances in the United States (United States of America, 2012; United States Department of Justice, 2013a). The test subjects were male Swiss Webster mice (Charles River Laboratories; Wilmington, MA) that weighed 27–33 grams and ranged in age from 2–3 months.

Drugs and Chemicals

These drugs are all related to a broader group of chemical compounds known as synthetic cathinones, chemically similar to a substance found in the khat plant, which is known for its amphetamine-like stimulant effects. Some brand names of synthetic cathinones include Bliss, Vanilla Sky, Lunar Wave, Cloud Nine, and White Lightning. Flakka is the street name for the synthetic cathinone called alpha-pyrrolidinopentiophenone (Alpha-PVP). 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.

2. Drugs

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.

• Exploration was defined as sniffing the object or orienting the head towards the object while the subject was within 1 cm of distance from the object.
• Male, Swiss-Webster mice were exposed to α-PPP (80mg/kg) using a binge-like dosing regimen (QID, q2h).
• 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).
• Finally, thalamus and amygdala were removed from the third section (Chiu et al., 2007; Honkanen, 1999).
• Exposure of cells to 300 μM of PVP reduced their viability by 48% (SH-SY5Y), 55% (Hep G2), 61% (RPMI 2650), and 44% (H9c2(2-1)) of the respective control values (Fig. 2a).
• Synthetic cathinones altered DA metabolite levels in a few select locations in the brain compared to saline.

The epicenter of the flakka epidemic was Broward County, Florida, which includes the city of Fort Lauderdale. Body weight and rectal temperature were recorded at baseline, immediately prior to each injection, and two hours after the last injection. Temperature was measured by inserting a lubricated probe 1.5 cm into the rectum and recording the readout from a connected TH-8 Thermalert temperature monitor (Physitemp Instruments; Clifton, NJ, USA) after the signal reached steady state. 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. A 10-μl aliquot was injected onto a Luna Omega 2.1 x 150 mm column (Phenomenex, Torrance, CA) coupled to a LPG-3400RS pump, WPS-3000TBRS autosampler, and a CoulArray electrochemical detector. 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.

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• Results reported for methylenedioxypyrovalerone (MDPV) and methylone were obtained from previous publications (Watterson et al., 2012, 2014).
• The longer side-chain α-pyrrolidinophenones and their fluoro- and methoxy-analogs produce more pronounced maximal cytotoxicity, with regard to mitochondrial activity and cell membrane integrity, than the five-carbon α-PVP and its substituted derivatives.
• Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography.
• Furthermore, α-PVP LgA, but not 4MMC LgA, elevated 5-HIAA/5-HT in PFC compared to α-PVP ShA and saline ShA.
• In the present study, to elucidate the persistent effects of exposure to α-PPP, we examined the effects of administration of α-PPP on neurochemistry and behavior.

Exposure to 4-F-PVP for 24 h led to a marked, concentration-dependent reduction in the survival of SH-SY5Y (10–300 μM), Hep G2 (10–300 μM), RPMI 2650 (10–300 μM), and H9c2(2-1) (25–300 μM) cell lines. The greatest reduction in the viability, i.e., by 53% of the control value, was observed in RPMI 2650 cells, while reductions by 45, 47, and 45% of control values were observed in SH-SY5Y, Hep G2, and H9c2(2-1) cells, respectively (Fig. 2b). Incubation of cells with 4-F-PVP for 72 h resulted in a marked, concentration-dependent decline in the survival of all cell lines, with the maximal effect at the similar level in SH-SY5Y (reduction by 60%), Hep G2 (reduction by 54%), RPMI 2650 (reduction by 59%), and H9c2(2-1) (reduction by 46%) (Fig. 2b). 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.

The role of serotonin systems in working and recognition memory is an area ripe for additional research. In this study, we document persistent effects of the second-generation pyrrolidine synthetic cathinone α-PPP on behavior and neurochemistry. We document that, consistent with previous studies of amphetamine derivatives (Murnane et al. 2012), α-PPP acutely decreases body weight over the course of a standard 6-hour dosing regimen.

2.2. Effects of synthetic cathinone ShA vs saline ShA.

Each experiment included a positive control of 1% (v/v) Triton-X100, as recommended by the manufacturer. Results are expressed as a percentage value of the positive control group, considered as 100% cytotoxicity. Bath salts, in general, are psychoactive synthetic drugs (designer drugs) made in large quantities in foreign drug labs.

Both 4MMC and α-PVP produce robust functional changes in the DA system, albeit by different mechanisms of action, releasing DA, or blocking DA transport, respectively (Baumann et al., 2012; Cameron et al., 2013; Glennon and Young, 2016; Marusich et al., 2014; Simmler et al., 2013). Overall, there were few neurochemical differences following self-administration of a DA uptake inhibitor versus a DA releaser, and the magnitude of the differences between effects of these synthetic cathinones was small (Fig. 3 and 4). This suggests that synthetic cathinones may lead to similar neuroplasticity, regardless of the mechanism of action. In contrast, the amount of drug access during self-administration (ShA vs. LgA) is a pivotal factor in the neurochemical effects of synthetic cathinones. After 24-h incubation PVP caused significant reductions in the survival of SH-SY5Y (25–300 μM), Hep G2 (10–300 μM), RPMI 2650 (50–300 μM), and H9c2(2-1) (10–300 μM) cell lines.

However, mephedrone and methylone have also been reported to not persistently deplete brain monoamine content (Baumann et al. 2012). Male, Swiss-Webster mice were exposed to α-PPP (80mg/kg) using a binge-like dosing regimen (QID, q2h). Behavior was assessed 4–5 days after the dosing regimen, and neurochemistry was assessed the following day. Behavior was studied using the elevated plus maze, Y-maze, and novel object recognition tests. Regional levels of dopamine, serotonin, norepinephrine, and the major dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the prefrontal cortex and striatum using high-pressure liquid chromatography. Additional experiments assessed the time courses of the effects of α-PPP on locomotor activity and core temperature using telemetry.

Drugs

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. A Thermo Scientific CoulArray Multi-Channel ECD alpha-pyrrolidinopentiophenone function Array system (model 5600A; Thermo Scientific, Waltham, MA, USA) was used to analyze neurotransmitter concentrations. The array detector contained 16 coulometric electrochemical cells that provided quantitation of multiple neurotransmitters and metabolites simultaneously. An Agilent 1100 HPLC System (Santa Clara, CA, USA) and an Applied Biosystems API 4000 Triple Quadrupole liquid chromatography mass spectrometer (LC-MS) with Turbo Ion Spray source (Foster City, CA, USA) were used for quantitation of GLU. Exposure of Hep G2 cells to PVP, PV8, and PV9 for 15 min significantly lowered the fluorescence anisotropy of the DPH probe, which is negatively related to the fluidity of the inner part of the cell membrane.

LgA α-PVP groups showed sex differences in self-administration on one day (Fig. 1), but this effect did not persist into other days of the study. Thus, the similarity in α-PVP intake across sexes was akin to that found in previous studies (Aarde et al., 2015; Javadi-Paydar et al., 2018). The similarity in 4MMC self-administration for both sexes is also consistent with past studies, which showed no sex difference in acquisition of 4MMC self-administration (Creehan et al., 2015; Vandewater et al., 2015). Sex differences in ShA saline self-administration were noted (Fig. 2) but were only statistically different for two days. The dosing consisted of a regimen of 4 unit doses of 80 mg/kg of α-PPP or saline administered over an 8 hour period with each dose separated by 2 hours.

Spontaneous alternations were calculated as the percentage of the total arm entries minus two composed of triads containing entries into all arms. Brain tissue samples were weighed and placed in cryovials containing stainless steel grinding balls. Supernatant was then transferred to a 96 well plate for analysis by electrochemical detection (ECD). SH-SY5Y (ATCC® CRL-2266™), Hep G2 (ATCC® HB-8065™), and RPMI 2650 (ATCC® CCL-30™) cell lines were purchased from Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ, Braunschweig, Germany). H9c2(2-1) (ATCC® CRL-1446™) cell line was purchased from the European Collection of Cell Cultures (ECACC, Porton Down, UK).

All graphical data presentations were created using GraphPad Prism 7.0 (GraphPad Software Inc.; La Jolla, CA). The time courses of the telemetry data (locomotor activity and core temperature) comparing saline versus α-PPP were integrated by standard area under the curve analysis in GraphPad, and then analyzed by repeated measures one-way analysis of variance, with post-hoc comparisons by Tukey’s test. 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%. Chemical structures of the traditional psychostimulants methamphetamine (METH) and methylenedioxymethamphetamine (MDMA), first-generation synthetic cathinones methylenedioxypyrovalerone (MDPV) and methylone, and second-generation synthetic cathinones α‐pyrrolidinopentiophenone (α-PVP) and 4-methyl-N-ethcathinone (4-MEC). This study sought to examine effects of long access (LgA) to α-PVP and 4MMC, using procedures similar to those employed for ShA exposure (Marusich et al., 2019a; Marusich et al., 2019b).

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). 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).