What is mdpv used for

Figure 4a shows that i. The rise in extracellular dopamine produced by 0. Figure 4c and d illustrate the effect of MDPV and cocaine on locomotor activity in rats. In these experiments, rats receive s. The threshold dose of MDPV capable of stimulating significant stereotypy is 0. It is important to note that MDPV is more efficacious than cocaine in both locomotor assays. We assessed cardiovascular actions of MDPV in conscious rats bearing surgically implanted telemetric devices Tella et al, The data in Figure 4e and f demonstrate that s.

Effects of MDPV and cocaine on extracellular dopamine in nucleus accumbens, locomotor activity and cardiovascular parameters in conscious rats. For microdialysis studies a, b , rats received i. Vehicle controls received i. For locomotor studies c, d , rats received s. For the cardiovascular measurements e, f , rats bearing surgically implanted telemetric sensors received s. The primary goal of the present study was to provide a systematic evaluation of the mechanism and pharmacological effects of MDPV, a primary constituent of psychoactive bath salts sold on the internet and in retail shops Ross et al, ; Spiller et al, A variety of designer cathinone derivatives and other substances eg, caffeine can be found in bath salts products, but MDPV is the main compound detected in biological fluids from patients admitted to emergency departments for bath salts overdose in the United States Borek and Holstege, ; Kyle et al, ; Murray et al, ; Spiller et al, We found that MDPV is a catecholamine-selective transporter blocker that is much more potent than cocaine when assessed using in vitro transporter assays.

In contrast to other bath salts compounds like mephedrone and methylone, MDPV is not a transporter substrate. Thus, MDPV displays a profile of monoamine transporter activity that is similar to the structurally related compound pyrovalerone Meltzer et al, ; Tidjane Corera et al, ; Vaugeois et al, Consistent with the potent blockade of dopamine uptake, MDPV inhibits dopamine clearance in mouse striatal slices and elevates dialysate dopamine concentrations in rat nucleus accumbens.

Importantly, MDPV is at least 10 times more potent than cocaine in assays measuring motor hyperactivity and cardiovascular stimulation in vivo. A critical secondary aim of the present study was to ascertain whether MDPV functions as a monoamine transporter substrate ie, like amphetamine or blocker ie, like cocaine.

This distinction in molecular mechanism is essential to determine for at least three reasons: 1 transporter substrates, but not blockers, are translocated into cells and evoke non-exocytotic release of transmitters via reverse transport Rothman and Baumann, a ; Sitte, Freissmuth, ; 2 transporter substrates, but not blockers, are known to produce long-term deficits in monoamine neurons that are often viewed as neurotoxicity Baumann et al, ; Fleckenstein et al, ; and 3 there are conflicting reports in the literature regarding the precise interactions of designer cathinones with monoamine transporters Baumann et al, ; Cozzi et al, ; Hadlock et al, ; Martinez-Clemente et al, ; Nagai et al, ; Sogawa et al, Our results from in vitro experiments in synaptosomes confirm that uptake inhibition assays can identify drugs which interact with transporter proteins.

However, uptake assays cannot discriminate between drugs which act as blockers or substrates because both types of drugs are fully efficacious in their ability to reduce the accumulation of [ 3 H]transmitter in synaptosomes see Figure 2a , c, and e. Results from the release assays, on the other hand, uncover obvious differences among the various drugs tested see Figure 2b , d, and f. The data with mephedrone and methylone agree with the published findings showing that these bath salts compounds are transporter substrates and not blockers Baumann et al, ; Nagai et al, ; Sogawa et al, Based on previous observations, we surmised that the apparent releasing effects of MDPV and cocaine are secondary to uptake blockade, rather than substrate activity per se.

For example, we have shown that established uptake blockers like GBR and indatraline display low-efficacy releasing effects in synaptosomes Rothman and Baumann, a ; Rothman et al, In the presence of transporter blockers, the leak is unmasked and gives the illusion of drug-induced release.

In support of this notion, Scholze et al demonstrated that the serotonin uptake blocker imipramine evokes low-efficacy efflux of [ 3 H]serotonin from HEK cells expressing human SERT. Thus, monensin clearly differentiates the mechanism of efflux produced by amphetamine from that produced by MDPV. The present results also highlight the utility of monensin as a reliable tool to discriminate transporter substrates from blockers in cells stably expressing transporter proteins.

Our in vitro data reveal a clear mechanistic dichotomy among the most common bath salts constituents: namely, ring-substituted analogs of methcathinone like mephedrone and methylone act as transporter substrates, whereas pyrrolidinophenones like MDPV act as transporter blockers.

There are notable differences in transporter selectivity across this group of compounds as well. Mephedrone and methylone are non-selective transporter substrates that produce neurochemical effects akin to those produced by MDMA Baumann et al, ; Kehr et al, By contrast, MDPV is a catecholamine-selective uptake blocker. Such findings suggest that ring-substituted analogs of methcathinone will produce MDMA-like behavioral effects, while pyrrolidinophenones will be more stimulant-like in their profile of actions.

In agreement with this proposal, recent findings in rats have shown that wheel-running behavior produced by mephedrone is MDMA-like, while that produced by MDPV is more methamphetamine-like Huang et al, Additional investigations are warranted to compare the effects of ring-substituted cathinones and pyrrolidinophenones in animal models and in human subjects under controlled laboratory conditions.

Using fast-scan cyclic voltammetry, we found that MDPV exhibits powerful dose-related effects on dopamine clearance. As is typically observed in cyclic voltammetry experiments, uptake inhibition results in a large increase in the magnitude of evoked dopamine signal and a profound broadening of the dopamine decay curve Schmitz et al, The mechanistic explanation for the heightened efficacy of MDPV in the slice preparation is not known, but we hypothesize that the potency of MDPV might be a critical factor.

Owing to its high potency at DAT, MDPV may display a slow dissociation from the site ie, persistent binding , thereby augmenting and extending its pharmacological effects.

In fact, previous voltammetric studies have shown that high-affinity dopamine uptake blockers like nomifensine and GBR produce marked inhibition of dopamine clearance that mirrors the effects of MDPV shown here Bull et al, ; Schmitz et al, It also remains possible that MDPV interacts with non-transporter sites of action, which further enhance its effects on dopamine clearance, and this proposal warrants examination.

In vivo microdialysis methods were used to compare the effects of MDPV and cocaine on extracellular dopamine in the nucleus accumbens, a brain region implicated in addictive properties of drugs Bonci et al, ; Willuhn et al, As predicted from the in vitro findings, both drugs elicit dose-related increases in dialysate dopamine, but MDPV is at least 10 times more potent than cocaine in this regard Figure 4a and b.

Furthermore, the rise in extracellular dopamine associated with MDPV is sustained when compared with the short-lived effects of cocaine. It is well established that drug-induced elevations in extracellular dopamine in the nucleus accumbens are involved with locomotor-activating properties of stimulant drugs Ikemoto, ; Pennartz et al, Our previous experiments examining stimulant drug effects in rats have shown strong positive correlations between dialysate dopamine responses and the extent of hyperactivity Baumann et al, ; Zolkowska et al, The present data show that MDPV produces robust dose-related forward locomotion and stereotypy.

Consistent with the voltammetric findings, locomotor effects of MDPV are much greater in magnitude than the comparable effects of cocaine see Figure 4c and d. Collectively, the potent and efficacious actions of MDPV on extracellular dopamine and motor activity suggest a high potential for abuse. A recent study by Watterson et al demonstrates that MDPV is readily self-administered by rats, and the range of self-injected doses 0. Two of the most serious side-effects of bath salts ingestion in human users are acute tachycardia and hypertension Ross et al, ; Spiller et al, Here we compared the effects of MDPV and cocaine on cardiovascular parameters in conscious rats.

Similar to its effects on other in vivo endpoints, MDPV is more potent than cocaine in its ability to increase heart rate and blood pressure.

Our preclinical findings may have important implications for people who take bath salts products for recreational purposes. The potent blockade of dopamine uptake caused by MDPV predicts that the drug has a high risk for abuse, whereas the potent blockade of norepinephrine uptake portends dangerous cardiovascular stimulation.

Patients admitted to emergency departments for bath salts overdose, who have toxicological verification of MDPV consumption, display symptoms, including agitation, psychosis, violent behavior, hyperthermia, and tachycardia Borek and Holstege, ; Kyle et al, ; Murray et al, ; Spiller et al, The constellation of adverse effects produced by high-dose MDPV resembles the life-threatening excited delirium syndrome associated with acute cocaine toxicity Mash et al, ; Ruttenber et al, Accordingly, the preclinical findings in the present study, demonstrating powerful cocaine-like actions of MDPV, suggest that efforts to remediate symptoms of bath salts overdose should aim to manage excessive dopaminergic and noradrenergic stimulation.

It is noteworthy that new legal cathinone-related compounds are being marketed to replace Schedule I drugs like MDPV, mephedrone, and methylone Shanks et al, The designer methcathinone analogs, mephedrone and methylone, are substrates for monoamine transporters in brain tissue.

Neuropsychopharmacology 37 : — In vivo effects of amphetamine analogs reveal evidence for serotonergic inhibition of mesolimbic dopamine transmission in the rat. J Pharmacol Exp Ther : — Psychopharmacology Berl : — The dopamine-containing neuron: maestro or simple musician in the orchestra of addiction?

Trends Pharmacol Sci 24 : — Ann Emerg Med 60 : — Article Google Scholar. Application of fast cyclic voltammetry to measurement of electrically evoked dopamine overflow from brain slices in vitro. Synthetic cathinones are synthetic derivatives of a stimulant found in the khat plant , a flowering plant native to the Horn of Africa and the Arabian Peninsula.

More than individual synthetic cathinones have been identified as illicit drugs, so users can never be certain about a substance from its street name alone. This class also includes drugs you may have heard of before including ephylone the dangerous drug detected recently via pill testing at an Australian music festival , methylone, and mephedrone. Read more: Weekly Dose: ephylone, the dangerous designer stimulant found at Groovin the Moo.

MDPV was developed by pharmaceutical firm Boehringer Ingelheim in the mids as a central nervous system stimulant.

But development never got far enough for it to be tested on humans. It first reappeared in internet drug forum discussions around , and became increasingly prevalent in the United States, Europe and elsewhere over the following years. In serum demethylenyl-oxo-MDPV was present at low levels maximum value Figure 3 shows that the groups had equivalent body temperatures at the 8.

VEH rats' temperatures remained steady at about Figure 3. At both testing-onsets, rats showed a normal pattern of locomotor habituation progressively diminishing activity over the session which was not disturbed by any dose MDPV.

Figure 4. VEH white. Shown alongside 5 min bins on the x axis are minutes elapsed since drug administration. Example trajectory patterns are shown in C. Figure 5. Mean T centre A and mean thigmotaxis B over 30 min tested 15 or 60 min after drug administration: sc. Figure 6. Our biotransformation study detected a number of metabolites in sera and tissues, however at very low levels.

As previous studies have shown we found a small increase in temperature in individually-housed rats, which was exacerbated by crowded cage conditions. The highest concentrations of MDPV in serum, brain, and lung tissue were recorded at 30 min followed by a rapid decline, suggesting that in all cases, the actual peaks were prior to our first measurement.

Previous pharmacokinetic data in rats which were not published at the time of our data collection showed peak plasma concentrations of MDPV at 10—20 min post-administration [ 29 , 30 ].

Novellas et al. From 30 min and the following 2 h, the brain concentration was approximately twice that in the sera.

Evidence suggests a kinetic profile of fast onset and relatively short duration, consistent with our short-lasting peak behavioural effects, and with estimates of the onset and duration of subjective effects in humans [ 25 , 28 ].

MDPV's short duration may have a causal role in re-dosing and escalating use shown in human and rodent studies , and together with fast penetration of the brain [ 30 ] these characteristics are indicative of MDPV's addictive potential [ 36 ]. We observed levels of MDPV that were approximately four times higher in lungs than in sera. Rapid transition of substances such as drugs from blood to lungs is characteristic of parenterally administered cationic compounds with a lipophilic profile [ 75 ].

The rapidity and magnitude of accumulation is partly a consequence of the relatively large volume of blood flowing to the lungs in compared to other organs, such as the brain, where molecules become trapped by lysosomes and mitochondria and accumulate in lung tissue as gradually eluting pools [ 75 ]. In consequence, accumulation in, and elimination from lung tissue is usually rapid, which was supported by our data, where lung concentrations of MDPV declined more quickly than in the brain.

The relevance if any of drug accumulation in the lungs for MDPV toxicity is unclear; pyrrolidinophenone toxicity primarily involve CNS and cardiovascular related problems [ 13 , 56 ]. These urinary metabolites were at concentrations approximately three to four times higher than the parent drug.

Other metabolites were detected in urine, serum, brain and lung but again at very low concentrations. Taken together with pharmacokinetic findings here and previous studies [ 30 — 32 , 72 ], MDPV appears to be cleared from sera and tissues relatively rapidly here almost undetectable by 6 h , and by 24 h only very small amounts of MDPV in the form of metabolites remain in the body the majority having been excreted in urine. Our sample size for the biotransformation study was small, and there was variability in the data, both of which may have contributed to the observation of lower concentrations, and few metabolites than other studies have shown previously.

As in our pharmacokinetic study, we found peak temperatures at our earliest measurement time-point 30 min post-administration , therefore, we cannot exclude the possibility that temperatures were increased prior to this. A number of findings have been published now that demonstrate that environmental crowding and hotter ambient temperatures can exacerbate drug-induced hyperthermia [ 70 , 73 , 76 , 77 ]. MDPV increases brain and body temperature in mice at high ambient temperatures and under conditions of social interaction [ 21 , 43 , 44 ], perhaps due to combined DAT-mediated hyperactivity and NET-mediated sympathomimetic effects [ 20 , 22 ], although recent research has also implicated 5-HT [ 21 ].

On the other hand, although MDPV toxicity and fatalities in humans have been documented [ 7 , 34 — 39 , 41 ], they remain relatively uncommon given the prevalence of cathinone use. In our behavioural studies, the 15 min testing-onset synchronised with peak serum and brain concentrations as well as their initial decline. Effects over testing-onsets showed that locomotor effects related to declining systemic levels of MDPV, e. Had testing continued, hyperlocomotion may have been observed as brain drug concentrations diminished, as previously reported [ 45 , 52 ].

MDPV's potent stimulatory effects most likely relate to its potent DAT inhibition, coupled with its lack of capacity to increase extracellular 5-HT which can attenuate DA-induced locomotor effects [ 4 ].

Rats usually avoid the aversive centre of the open field which is brighter more and open preferring to spend time in the periphery next to the arena walls. The spatial characteristics of locomotor behaviour in this paradigm can provide some indication of drug effects on emotionality with increased exploration of the centre suggesting decreased emotionality anxiolytic-like effects and vice versa.

In our experience, effects on T centre and thigmotaxis are usually but not always the inverse of one another, however, whilst related, T centre may be more sensitive to effects on emotionality, and thigmotaxis to locomotor stereotypy. MDPV has been shown previously to increase exploration in mice [ 53 ], as well as induce stereotypy at a range of doses in rats and mice [ 30 , 45 , 53 , 72 ].

Stimulant-typical stereotypies emerge in a systematic manner [ 30 , 72 , 82 ], which was shown here, and, with MDPV, are reversible with the typical antipsychotic a DA D2 antagonist , haloperidol e. A specific disruption of PPI i.

Evidence to date has shown that other ring-substituted cathinones and stimulants can disrupt PPI, but usually only at higher doses [ 61 — 69 ]. Although different cathinones and stimulants operate via different DA-ergic mechanisms i. Moreover, cathinone-induced PPI deficits and stimulant-typical psychomimesis can be reversed with typical and atypical antipsychotics [ 30 , 86 ] which have DA D2 receptor antagonism in common [ 87 ], suggesting a role for this receptor subtype specifically [ 63 ].

Our findings indicate that the duration of psychological symptoms is likely to be short, which suggests that in cases of acute MDPV intoxication, adverse psychological effects may pass relatively quickly. Behavioural findings have relevance to recreational users who, in striving for stimulatory effects may take large amounts of MDPV, unaware that this will only delay rather than increase stimulation which is modest, in any case and induce adverse psychological and physical effects instead, with risks of toxicity especially if taken in combination with other drugs increasing with dose.

Thus even our lowest dose, whilst within the range used by people, was nevertheless a high dose, in the range associated with unwanted effects [ 25 ]. Responsible and occasional use of sensible doses of MDPV alone is probably relatively low-risk for most healthy people.

However, users should be aware that MDPV's acute effects may create interactions between their activity levels, environmental and social circumstances and potentiate temperature dysregulation. These are simply, as yet, unknown, and data will only emerge in years to come. The short-lasting behavioural effects and pharmacokinetics shown here are consistent with existing evidence that MDPV has characteristics that encourage risky use such as re-dosing, binge or poly-drug use, 36 as well as significant addictive potential.

All authors made a substantial contribution to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work. All authors were involved in drafting the work or revising it critically for important intellectual contents. All authors gave final approval for the current version of the work to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Analysis of first and second generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry.

J Anal Toxicol. Trends and Developments, Luxembourg World Drug Report. Curr Topics Behav Neurosci. Sociology 36 — J Med Toxicol. Perhaps the most dangerous side effect of MDPV is the uncompromisingly strong, physical, and psychological cravings it creates. This is what keeps people coming back for more. While MDPV is addictive, few individuals battle this addiction for long because of the high risk for overdose, death, and criminal activity that leads to jail time.

Addiction to MDPV will most certainly cause health problems, as well as damage relationships, careers, finances, lifestyles, and general well-being. Getting help for someone often requires outside intervention from medical professionals, judges, friends, family, employers, and others.