What is Flakka Alpha-PVP: Risks, addiction & treatment

The results are expressed as percentages of the negative control group values, these values being considered 100% viable. Statistical analyses were conducted using NCSS (Number Cruncher Statistical Systems, Kaysville, Utah, USA). In most instances, data from naïve and LgA groups (present study) were statistically analyzed separately from ShA groups (Marusich et al., 2019a; Marusich et al., 2019b) because the neurotransmitter assays were conducted at different times for these studies. Additionally, one male 4MMC ShA and saline ShA rat were exposed to the incorrect infusion volume.

Substituted analogs differ from native PV8 as they affect H9c2(2-1) cell viability even after 24 h. 4-F-PV8 applied for 24 h markedly reduced the viability of SH-SY5Y (100–300 μM), Hep G2 (50–300 μM), RPMI 2650 (10–300 μM), and H9c2(2-1) (200 and 300 μM) cell lines, with the greatest reduction by 42% (SH-SY5Y), 77% (Hep G2), 79% (RPMI 2650), and 72% (H9c2(2-1)) (Fig. 4b). Cell viability was significantly decreased in SH-SY5Y (25–300 μM; maximal reduction by 83%), Hep G2 (50–300 μM; maximal reduction by 97%), RPMI 2650 (10–300 μM; maximal reduction by 97%), and H9c2(2-1) cells (10–300 μM; maximal reduction by 79%) (Fig. 4b). PVP and its substituted counterparts produced only benign damage to the cell membranes after 48 h incubation (Fig. 3).

Figure 1.

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. All analyses of self-administration data were examined for circularity using Mauchly’s test. If the assumption of circularity was violated, the Geisser-Greenhouse Adjustment was employed. Examples of behavioral therapy include cognitive-behavioral therapy, contingency management and motivational incentives. Flakka is a highly addictive and dangerous drug, otherwise known as alpha-PVP alpha-pyrrolidinopentiophenone function (alpha-pyrrolidinopentiophenone.) It is an amphetamine-like stimulant that belongs to the cathinone drug class. Cathinones are man-made, or synthetic drugs containing cathinone, a naturally occurring stimulant found in the khat plant.

Alpha-PHP appeared on the Japanese illicit drug market in 2014 and, two years later, α-PiHP was identified for the first time in China. They were placed in schedule II on the list of Psychotropic Substances under International Control in 2020 and in March 2023, respectively. Both cathinones have no therapeutic potential for medical use and therefore are abused for recreational habits, which can lead to fatalities. The most frequent adverse effects reported are cardiac, psychiatric, and neurologic, and fatal intoxications have already been described. In Portugal, their consumption and consequent seizures are more prevalent on the archipelagos, which has been aggravating the health situation. In conclusion, these types of substances are a challenge for forensic toxicology since they are easily synthesized, modified, and placed on the market.

Fig. 1.

Synthetic drugs are illicitly created to produce substances that differ slightly from legal drugs. Flakka originally became popular as a new synthetic drug in South Florida with people looking for a cheap high. Flakka is the latest in a selection of synthetic drugs used in the United States.The illegal substance can sell on the streets for as little as five dollars a hit.

Figure 2.

• Some bath salts may be more potent than Flakka, others less, and there is really no way of telling beforehand.
• These NPS drugs are generally classified as Schedule I controlled substances with no accepted medical use and a high potential for abuse and addiction.
• Some brand names of synthetic cathinones include Bliss, Vanilla Sky, Lunar Wave, Cloud Nine, and White Lightning.
• It is also possible that Koob and Volkow’s hypothesized neurochemical changes are dependent on drug contingency, dose, or other methodological considerations.
• In contrast, since it was first time reported in 2016, α-PiHP was placed in schedule II in March 2023 through the Convention of Psychotropic Substances of 1971 by the INCB.
• In contrast, both LgA and ShA 4MMC self-administration decreased 5-HT and 5-HIAA levels in most brain regions.
• Nowadays, the number of NPSs on the global market is increasing, after several years of stabilization, due to traffickers who continue to sustain their production.

In SH-SY5Y neuroblasts, only 4-F-PVP and 4-MeO-PVP used at 300 μM caused a slight elevation of extracellular LDH activity. In H9c2(2-1) cells the effect was more pronounced and significant at 200 and 300 μM for PVP and 100–300 μM for 4-F-PVP and 4-MeO-PVP. The strongest effect was observed at 300 μM of 4-F-PVP and 4-MeO-PVP, being 43 and 45% of positive control cytotoxicity, respectively (Fig. 3). PVP and its fluoro- and methoxy-substituted derivatives produced moderate and concentration- and time-dependent decline in the viability of SH-SY5Y, Hep G2, RPMI 2650, and H9c2(2-1) cells measured as mitochondrial activity. The observed effects varied among the studied cell lines and the tested compounds (Fig. 2).

ICSS Apparatus

All self-administration and neurotransmitter data for these three rats were excluded from graphs and analyses. 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). Neurotransmitter levels were measured to investigate if neuronal signaling changed as a function of duration of synthetic cathinone exposure and modeled different stages of drug abuse (Koob and Volkow, 2010). 4MMC shows escalation of self-administration during LgA conditions (Nguyen et al., 2017b; Watterson et al., 2014). Both Flakka and bath salts are incredibly dangerous when abused, causing harmful side effects, overdose, death, and are addiction-forming. The adverse effects of Flakka abuse, its damaging nature to physical and mental health, and the potential for overdose all make Flakka a highly dangerous drug.

Prominent sex differences emerged for NE levels in amygdala, hippocampus, PFC, and striatum for ShA groups (Fig. 4). There were also large sex differences in GLU levels in PFC, and 5-HIAA levels in striatum and thalamus for ShA groups (Fig. 4). Sex differences in neurochemistry in LgA groups were largely confined to 5-HIAA levels (Fig. 3). Future studies are needed to determine why there were vast sex differences in the neurochemistry of ShA groups that seemed to dissipate in the LgA groups. New Psychoactive Substances (NPSs) are characterized as substances in a pure or prepared form that are not under the 1961 and 1971 European Union Conventions and can jeopardize public health. They are rapidly emerging and spreading through the market, triggering social and public health risks 1.

Although the doses were located at similar points on the dose-effect curves (Aarde et al., 2015; Gannon et al., 2017; Nguyen et al., 2016), it is unknown if the results of this study will generalize across doses. Alpha-PHP is a synthetic stimulant drug from the cathinones group which was developed in the 1960s 19. In April of 1967, the United States Patent Office published a patent document related to α-pyrrolidine ketones and synthesis methods of their novel substances, including the α-PHP compound. It was identified in material seized from the Japanese illicit drug market in 2014, and was implicated in drug-related intoxication deaths a few years later 21,22. On the other hand, α-PiHP is an α-PHP chain isomer and was first reported internationally in 2016 by Liu et al., who identified and characterized it analytically along with eight synthetic cathinones in seized materials in China 23. In December of the same year, α-PiHP was formally submitted to the Early Warning System of EMCDDA, and in 2019, its concentration in biological specimens was determined for the first time in an intoxication case 24.

PV9 and its substituted analogs caused profound disruption of cell membranes in all assessed cell lines (Fig. 7). The effect was always significant at 200 and 300 μM for all drugs and cell lines; in addition, the membrane integrity of RPMI 2650 cells was also significantly affected by all drugs at 100 μM. Moreover, 4-MeO-PV9 also damaged the membranes of SH-SY5Y and Hep G2 cells when administered at 100 μM. All PV9 analogs produced a maximal effect of at least 70% of the positive control group in SH-SY5Y, Hep G2, and RPMI 2650 cells, while the maximal effect of PV9 derivatives in H9c2(2-1) cells always exceeded 65% of the positive control (Fig. 7). One limitation is that the neurotransmitter data for LgA and naïve were analyzed at a different time than those for ShA.

• Within the pyrovalerone derivatives subgroup, the most prominent compound is 3,4-methylenedioxypyrovalerone (3,4-MDPV), since after its appearance on the market, many others began to emerge 13.
• 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).
• 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.
• Self-administration of 4MMC produced widespread decreases in 5-HT and 5-HIAA levels compared to saline self-administration, whereas self-administration of α-PVP had little effect on serotonergic levels compared to saline.
• Synthetic cathinones are also labeled as ‘not for human consumption.’ These labels help hide the real reason for the product’s existence, so the drugs distribute easily.

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. There were two scenarios in which neurotransmitter data were excluded from graphs and analyses.