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). For the first time in history, the number of unregulated novel psychoactive substances on international drug markets now exceeds those under international control (United Nations, 2013). One of the most problematic classes of novel psychoactive substances to emerge are synthetic cathinones, comprising approximately 18% of all unregulated substances in international markets (United Nations, 2013).

Flakka is the street name for the synthetic cathinone called alpha-pyrrolidinopentiophenone (Alpha-PVP). This study confirms that pyrovalerone cathinones are endowed with the prominent cytotoxicity. 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.

Flakka (Alpha-PVP) Overview, Effects, Abuse, Addiction, & Treatment

• 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).
• Many studies measure the neurochemical effects of stimulants of abuse during direct drug effects (Ahmed et al., 2004; Mantsch et al., 2004), which does not provide information on lasting brain changes.
• Since 2008, each year has seen the introduction of a number of novel synthetic cathinone derivatives into the dynamic, clandestine NPS market, in an attempt to circumvent legal restrictions (EMCDDA 2017; Majchrzak et al. 2018; Zawilska and Wojcieszak 2017).
• Serum specimens were used for α-PHP quantitation, and in some cases, since it was absent, meconium in newborn cases, blood from the femoral vein, and urine were analysed.
• In 2022, worldwide, 1184 NPSs were identified (cumulative number of the previous 16 years), although they presented a lower consumption rate than traditional drugs 4.
• Most reports of flakka after 2016 turned out to be other similar chemicals in the bath salt family.

Alpha-PHP is known as a recreational drug of abuse and has no pharmacological therapeutic purpose. Thus, it can be abused through oral, nasal, sublingual, rectal, or intravenous application. The following table shows the relationship between the consumed dose and the proportion of the effect triggered through the various routes of administration (Table 1) 19. 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. Consequently, the prevalence of their use is higher, especially in younger age groups 4,5. 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.

• Three other metabolites, two phase I and one phase II, are also abundant and come from the combination of keto reduction and isoalkyl chain hydroxylation (M3), the cleavage of the ring and carboxylation (M4), and the glucuronidation of M1 (M5) 87.
• Agitated patients can go into a state called “excited delirium,” which is a medical emergency.
• Furthermore, the dorsal striatum is involved in escalation of drug taking and compulsive behaviors (Clark et al., 2013; Willuhn et al., 2012).
• As reported before his demise, the man was agitated and acting strange, and afterwards, he lost consciousness 34.
• The observed effects varied among the studied cell lines and the tested compounds (Fig. 2).
• Instead of omitting these values from graphs and analyses, we substituted a value of 0.005 ng/mg, which is halfway between zero and the level of quantitation of 0.01 ng/mg.

Figure 4.

First, there were a few cases in which amygdala samples had very elevated levels of DA, DOPAC, and HVA. Because of the closeness of amygdala and striatum in the brain, it is likely that a small amount of striatum was inadvertently included as part of the amygdala sample. Second, an unknown peak interfered with the integration of the DOPAC or NE peak in select samples of PFC and hypothalamus. Additionally, in some samples of thalamus, DOPAC levels were below the level of quantitation. Instead of omitting these values from graphs and analyses, we substituted a value of 0.005 ng/mg, which is halfway between zero and the level of quantitation of 0.01 ng/mg. 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.

What Is the Difference Between Drug Abuse and Substance Abuse?

PV8, 4-F-PV8, and 4-MeO-PV8 inflicted significant damage to the membranes of SH-SY5Y and RPMI 2650 cells at 200 and 300 μM, and to H9c2(2-1) cells when applied at 100 to 300 μM. Moreover, 4-F-PV8 and 4-MeO-PV8, but not PV8, disrupted Hep G2 cell membranes at 200 and 300 μM. The most pronounced cytotoxicity was observed after treatment of Hep G2 cells with 4-MeO-PV8 (71% of positive control toxicity) (Fig. 5). 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).

Flakka (Zombie Drug) vs. Bath Salts

The euphoric high from flakka abuse can last from hours to days, depending on the dosage. The legal status of flakka remains a moving target as authorities try to keep pace with the evolving synthetic drug market. It is an ongoing challenge, as each time one type of bath salt is made illegal, the drug labs change the chemical structure slightly and a new drug that is technically not illegal is created. In the case of flakka, the new chemical is called alpha-pyrrolidinopentiophenone or alpha-PVP. Drug users take flakka to get a feeling of euphoria, a heightened sense of awareness, stimulation, and energy. Word on the street is that flakka (also called gravel or flocka) is a combination of heroin and crack cocaine, or heroin and methamphetamines, but in reality, flakka is just a newer-generation version of a type of synthetic drug called bath salts (MDPV).

Materials and Methods

On the other hand, the incubation of cells with PV8 and its analogs, containing an additional two carbon atoms, reduced cell viability by a maximum of 70–80% after 24 h, and by more than 90% after 72 h. Further elongation of the side-chain increased the cytotoxic activity, as observed in the tests on PV9 and its substituted analogs. Incubation for 72 h with the highest tested doses (200 and 300 μM) resulted in almost complete extinction of cell viability in all but the H9C2(2-1) cell lines. To date, α-PiHP is not known to have any therapeutic potential in medical use and has abuse liability and psychostimulant properties similar to other synthetic cathinones such as α-PHP 25.

Α-Pyrrolidinopentiothiophenone (also known as α-PVT) is a synthetic stimulant of the cathinone and thiopropamine (thiophenylpropylamine) families that has been sold online as a designer drug.123 It is an analogue of α-PVP where the phenyl ring has been replaced by thiophene. Edmund has an extensive background in addiction research and medical writing, working collaboratively with doctors, substance use disorder specialists, and clinical experts across all content on Recovered. As well as inducing psychotic episodes, Flakka may also cause hyperthermia, liver and renal failure, hypertension, narrowing of the blood vessels, irregular heartbeat, stroke, heart attack, suicidal ideation, coma, and death. Flakka also has a high potential for overdose, especially when vaporized as the exact amount being taken is hard to quantify. The onset of a Flakka overdose is often rapid and can cause heart problems, aggressive behavior, and psychosis. Ark Behavioral Health offers 100% confidential substance abuse assessment and treatment placement tailored to your individual needs.

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 was added to the Schedule I list in 2014 by the Drug Enforcement Administration (DEA). This was part of an effort to curb the abuse of synthetic drugs, which were becoming increasingly popular and causing significant health issues. Taken together, we predict that α-PVP possesses a potential for compulsive abuse (ie, addiction) that is roughly similar to that of METH and MDPV but much greater than that of 4-MEC, methylone, and MDMA. Accordingly, we also predict that 4-MEC will have a relatively lower potential for compulsive use than that of MDPV and METH, would be most similar to methylone and MDMA (ie, episodic use), and may exert primarily entactogenic effects.

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 alpha-pyrrolidinopentiophenone function 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.