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.
Grapp et al. researched α-PHP intake in 29 forensic and clinical cases, of which two were newborns. 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. The predominant symptoms in the reported cases were aggressive behaviour and resistance to the authorities, coupled with a delayed physical response and drowsiness 32. Adamowicz et al. reported a case of α-PiHP intoxication and achieved its determination in biological specimens. Before death, the person was agitated, running, wheezing, hallucinating, and talking to himself 24.
- Self-administration of α-PVP and 4MMC induced plasticity in neural circuitry that may be driving compulsive drug taking or producing a deficit state for normal reward, thereby increasing motivation to continue self-administration (Koob and Le Moal, 2005).
- 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.
- In addition, the lack of effective legislation also favours the national and international dissemination of such substances.
- Thus, it can be abused through oral, nasal, sublingual, rectal, or intravenous application.
- In the concentration range of 10–300 μM, significant cytotoxic effects were observed in SH-SY5Y, Hep G2, and RPMI 2650 cells after 24-h incubation, and in SH-SY5Y and RPMI 2650 cells after 72-h incubation.
- The most frequent adverse effects reported are cardiac, psychiatric, and neurologic, and fatal intoxications have already been described.
The cytotoxic activity of PVP was potentiated by extension of the incubation time alpha-pyrrolidinopentiophenone function to 72 h. 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). This is clear when considering α-PHP and α-PiHP, as they are only identified as positional isomers because they both exert identical effects. In addition, the lack of effective legislation also favours the national and international dissemination of such substances. Therefore, further studies need to be carried out so that NPS data are always up to date, and more comprehensive legislation needs to be implemented for better control.
Teen Drug Abuse
One of the largest differences in DOPAC/DA was observed in amygdala where females showed greater change from DA to DOPAC than males, regardless of the self-administration condition. For 5-HIAA/5-HT ratios, LgA self-administration of both synthetic cathinones lowered 5-HIAA/5-HT compared to ShA groups. Furthermore, α-PVP LgA, but not 4MMC LgA, elevated 5-HIAA/5-HT in PFC compared to α-PVP ShA and saline ShA.
Flakka (Alpha-PVP)
Slope and ED50 values from previously published data (Watterson et al., 2012, 2014) were also calculated (Table 1) but were not compared statistically because of the possibility of cohort effects. In contrast to the minor sex differences in self-administration behavior, sex differences in neurochemical changes were more widespread. Notably, sex differences in neurochemistry were more abundant for ShA than LgA groups, and the cause of this is unknown.
Prescription Drug Abuse
In contrast, other studies measured neurochemical effects several days after the last drug exposure (Briand et al., 2008; Hadlock et al., 2011; Schwendt et al., 2009), which may be during withdrawal. Brain tissue was collected approximately 24 h after the last drug exposure in this study and the past companion studies (Marusich et al., 2019a; Marusich et al., 2019b). While effects on DA were largely absent in this study, self-administration of either synthetic cathinone altered 5-HT and 5-HIAA levels. The serotonergic effects of 4MMC were expected because it releases 5-HT (Baumann et al., 2012).
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.
Figure 2.
Supernatant was then transferred to a 96 well plate for analysis by electrochemical detection (ECD). Some bath salts may be more potent than Flakka, others less, and there is really no way of telling beforehand. Flakka, a street name for the inexpensive and dangerous “designer drug” Alpha-PVP, is one such newcomer. In accordance with each route of administration, the latency and action time are different. Thus, in Table 2 is described the effect duration considering the various routes of α-PHP consumption 19.
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Α-PVP does not have functional serotoninergic effects (Marusich et al., 2014), but α-PVP surprisingly increased 5-HIAA levels in several brain regions under LgA conditions. It is unclear if these unexpected serotonergic effects are a result of α-PVP binding to 5-HT1A (Rickli et al., 2015). Furthermore, it was noteworthy that 4MMC decreased 5-HT and 5-HIAA levels, whereas α-PVP increased 5-HIAA levels. The decreased 5-HIAA levels in striatum for 4MMC ShA groups compared to saline ShA groups is consistent with a past study; however, the present study produced slightly higher levels of 5-HT and 5-HIAA in striatum for both 4MMC and saline ShA groups than the past study (Motbey et al., 2013).
Adverse effects
- The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) was monitoring about 930 NPSs at the end of 2022, with synthetic cathinones representing the second largest group of substances monitored until 2021 5.
- Identifications of synthetic cathinones in seized drug products (DEA, 2017, 2019; NDEWS, 2018b) and identification of new synthetic cathinones are rising in some parts of the U.S. (NDEWS, 2019).
- Using a discrete trials current intensity threshold intracranial self-stimulation procedure, the present study assessed the effects of 2 common second-generation synthetic cathinones, α‐pyrrolidinopentiophenone (0.1–5mg/kg) and 4-methyl-N-ethcathinone (1–100mg/kg) on brain reward function.
- In H9c2(2-1) cells, the viability was reduced by 76–78% at 200 μM and by approximately 96% at 300 μM, irrespective of the incubation time.
- 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.
- This assessment is based on the drug’s potent effects, its ability to alter brain chemistry, and comparisons with other synthetic drugs like bath salts.
This will often be part of inpatient or outpatient treatment programs which include a course of behavioral therapy to help manage addiction, identify causes and triggers of addiction, and treat any co-occurring mental health disorders. 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.
To our knowledge, there are currently no published studies directly assessing the potential abuse liability of the second-generation synthetic cathinones α-PVP or 4-MEC. The present study revealed that, similar to methamphetamine in the present study and to MDPV and methylone in previous studies (Watterson et al., 2012, 2014; Bonano et al., 2013), both α-PVP and 4-MEC dose-dependently decreased ICSS thresholds in a discrete trials current threshold procedure. ICSS threshold reductions are commonly accepted as indicative of facilitated brain reward function and the interoceptive rewarding effects of drugs of abuse and thus provide evidence of abuse potential in humans (Vlachou and Markou, 2011). At the highest doses tested, α-PVP (5mg/kg), 4-MEC (100mg/kg), and METH (3mg/kg) no longer decreased but instead produced increased ICSS thresholds (although these increases were not significant for α-PVP or 4-MEC).
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.