Intoxications in the STRIDA project involving a panorama of psychostimulant pyrovalerone derivatives, MDPV copycats

Abstract

Context: An increasing number of new psychoactive substances (NPS) of different chemical classes have become available through marketing and sale over the Internet. This report from the Swedish STRIDA project presents the prevalence, laboratory results, and clinical features in intoxications involving 11 stimulant pyrovalerone NPS derivatives over a 5-year period.

Study design: Case series of consecutive patients with admitted or suspected intake of NPS presenting to Swedish hospitals for emergency treatment from January 2011 to March 2016.

Patients and method: Blood and urine samples were collected from intoxicated patients presenting to hospitals all over Sweden. Analyses of NPS and other drugs of abuse were performed by immunochemical and liquid chromatography–mass spectrometry multi-component methods. Clinical data were collected during consultation with the Swedish Poisons Information Centre (PIC), and retrieved from medical records. The study involved analytically confirmed cases with 11 pyrovalerone drugs.

Results: During the study period, 114 intoxications were detected that involved any of 11 new pyrovalerone drugs. In addition to these new pyrovalerone derivatives, 3,4-methylenedioxypyrovalerone (MDPV) was detected in 17 of the cases and α-pyrrolidinovalerophenone (α-PVP) in 45 cases. Identification was made according to forensic standards and comprised the following substances: 4F-α-PVP, α-PHP, PV8, 4Me-PPP, α-PBP, 4F-PV8, α-PPP, MDPHP, α-PVT, 4Cl-α-PVP, and 4F-α-PHP. The three most frequently detected drugs were α-PBP, MDPHP, and 4F-α-PVP. The age range of patients was 16–66 (median 30) years and 84% were males. The substance concentrations in urine and serum were highly variable, ranging from 1 ng/mL to 300 µg/mL. Poly-drug use was common with only 8 of 114 cases (7%) involving one pyrovalerone drug. The additional substances comprised other NPS and classical psychoactive drugs. The patients showed a variety of clinical signs; agitation, delirium, hallucinations, excessive motor activity, seizures, tachycardia, hypertension, and/or hyperthermia.

Conclusions: In analytically confirmed NPS-related intoxications, 11 new pyrovalerone derivatives in addition to MDPV and α-PVP were found. The clinical features were consistent with a sympathomimetic toxidrome, but the urine and serum concentrations were highly variable. The results demonstrated that many novel pyrovalerone stimulants were introduced on the recreational NPS drugs market. Analytical investigations were necessary to obtain this information.

Keywords:

• Pyrovalerone derivatives
• new psychoactive substances
• illicit drugs
• intoxications
• liquid chromatography–mass spectrometry

Introduction

The worldwide occurrence and concern about new psychoactive substances (NPS) used as “legal” recreational drugs is well established [1]. NPS comprise agents with a wide range of pharmacological effects of which some are psychostimulants. This NPS sub-group is considered especially dangerous and known to cause intoxications requiring emergency treatment, and even lead to fatal outcome [2–4].

The pyrovalerone drugs comprise a group of phenylethylamine and cathinone derivatives many of which were originally developed as therapeutic drug candidates but later appeared on the NPS market [5]. Indeed the parent compound of this group, pyrovalerone, is a psychostimulant drug used in a pharmaceutical product in the 1960s for treatment of lethargy, fatigue and obesity [6]. Following reports of misuse, pyrovalerone was withdrawn from the market [7] and eventually banned as a narcotic substance by the WHO in 1971 [8].

More recently, 3,4-methylenedioxypyrovalerone (MDPV) was the first pyrovalerone derivative that occurred as an NPS and it got widespread use even after being regulated. MDPV has been reported to replace amfetamine on the illicit drug market in some places [9,10]. However, MDPV soon got attention as a highly dangerous drug, as it was involved in severe intoxications [11,12]. MDPV later appeared to be replaced on the recreational drug market by the structural analogue α-pyrrolidinovalerophenone (α-PVP) [13].

In 2006, in search for medications to treat cocaine abuse, the neurochemical profiles of a number of pyrovalerone analogs with different substituents on the benzene ring were investigated [5]. The pyrovalerones were demonstrated to be potent selective dopamine uptake inhibitors [5], thereby showing potential of becoming misused as psychostimulants [14], whereas their effect on serotonin release was suggested to be much weaker [15]. Other studies of pyrovalerone analogs have demonstrated that synthetic cathinones may act as dopamine releasing (i.e., amfetamine-like) or as dopamine uptake inhibiting (cocaine-like) agents [15,16]. α-PVP was reported to show a similar cocaine-like mechanism of action and potency as MDPV [17].

MDPV became established on the recreational drug market as a well-known trade name, similar to “Spice” and “Ecstasy”. Many of the structural pyrovalerone variants introduced to replace MDPV were often marketed under the same name [18], but, as many of them share the same pharmacological effect and mechanism of action, this was not evident or known by the drug users. Even the Swedish Poisons Information Centre (PIC) stated that MDPV was a drug that had come to stay [19], but this was based on self-reported information collected during consultations and not analytically confirmed.

The STRIDA project has monitored the occurrence and health hazards of a wide range of NPS in Sweden, through evaluation of analytically confirmed serious adverse events presenting in emergency departments (ED) or intensive care units (ICU) [20,21]. Since the start of the project in 2010, many novel psychostimulants have been identified and the associated toxicity data reported together with analytical data. One observation was that individual substances are rapidly replaced on the open online NPS market in response to substance regulation [22], which in Sweden is done individually.

This investigation from the STRIDA project presents analytically confirmed intoxications associated with 11 selected NPS pyrovalerone analogues (Figure 1, Table 1) appearing in 2011–2016 and which were introduced as “MDPV copycats”.

Figure 1. Chemical structures of the 11 studied pyrovalerone derivatives together with the parent compounds α-PVP and MDPV.

Table 1. Monoisotopic and exact masses of monitored protonated molecular ions of the 11 pyrovalerones, together with information on their appearances as recreational drugs and classification in Sweden. Information on MDPV and α-PVP is also included for comparison.

Substance (alternative name)	Mono-isotopic mass	Exact mass (M + H^+)^+	Discussed on a Swedish Internet forum since	EU seizures reported by the EMCDDA since	Classified in Sweden since	Classified as^a
α-PPP	203.1310	204.1383	January 2009	2009	February 2013	N
4Me-PPP (MPPP)	217.1467	218.1539	August 2011	2010	January 2015	N
α-PBP	217.1467	218.1539	June 2013	2011	January 2015	N
α-PVT	237.1187	238.1260	September 2013	2013	January 2015	H
4F-α-PVP	249.1529	250.1602	September 2013	2014	January 2015	N
4Cl-α-PVP	265.1233	266.1306	August 2015	2015	August 2016	H
α-PHP (PV7)	245.1780	246.1852	May 2014	2014	January 2015	H
4F-α-PHP	263.1685	264.1758	August 2015	2015	August 2016	H
MDPHP	289.1678	290.1751	July 2014	2014	June 2015	N
PV8 (α-PEP, α-PHPP)	259.1936	260.2009	June 2013	2013	January 2015	H
4F-α-PEP (4F-PV8)	277.1842	278.1915	April 2014	2014	January 2016	H
α-PVP			August 2011	2012	February 2013	N
MDPV			September 2006	2008	February 2010	N

^a N: Narcotics; H: harmful to health.

Methods

Reference materials

Eleven pyrovalerone derivatives were covered in this investigation (Figure 1, Table 1): α-pyrrolidinopropiophenone (α-PPP), reference material from LGC Standards AB (Borås, Sweden); 4-methyl-α-pyrrolidinopropiophenone (4Me-PPP), α-pyrrolidinobutiophenone (α-PBP), 4-fluoro-α-pyrrolidinopentiophenone (4F-α-PVP), α-pyrrolidinohexiophenone (α-PHP), α-pyrrolidinoheptiophenone (PV8), and 4-fluoro-α-pyrrolidinoheptiophenone (4F-PV8), reference materials from Cayman Chemical Co (Ann Arbor, Michigan. USA); α-pyrrolidinopentiothiophenone (α-PVT), 4-chloro-α-pyrrolidinopentiophenone (4Cl-α-PVP), and 3,4-methylenedioxy-α-pyrrolidinohexiophenone (MDPHP), reference materials from the National Forensic Centre (NFC, Linköping, Sweden) characterized by spectroscopic techniques; 4-fluoro-α-pyrrolidinohexiophenone (4F-α-PHP), reference material originated from a webshop purchase and was characterized by nuclear magnetic resonance (NMR) analysis at the Medical Products Agency laboratory (Uppsala, Sweden). The tentative concentrations of stock solutions made from non-certified materials were assigned by comparison of chromatographic peak areas in the following way: MDPHP was compared with MDPV, α-PVT with α-PHP, and 4F-α-PHP and 4Cl-α-PVP with 4F-α-PVP.

Intoxication cases

The PIC receives telephone inquiries regarding acute poisonings from both health care providers and the public from all over Sweden. Intoxicated patients with admitted or suspected intake of NPS, or of unknown drugs of abuse, presenting at ED or ICU are recruited to the STRIDA project. Approximately half of the PIC cases are successfully recruited to the project. On admission to the hospital, blood and urine samples were requested for toxicological investigation; venous blood was used for preparation of serum, and urine was collected in tubes without additives according to established routines for drug testing. No consent from the patient was needed. The specimens were stored refrigerated until sent to the Karolinska University Laboratory, Department of Clinical Pharmacology (Stockholm).

During the consultation with caregivers, personnel at the PIC record, whenever possible, data on the reported or suspected psychoactive substance and/or product brand name involved, the dose, time of intake, and route of administration. Afterwards, a copy of the medical record with full documentation of symptoms and treatments was requested. For the scientific evaluation, all clinical and laboratory data were anonymized and linked to the individual case only by a code number. For the present investigation, cases with analytical findings in urine or serum specimens of any of the 11 studied analytes during the period from January 2011 to March 2016 were included. Serum was only analyzed, if a urine sample was missing or otherwise decided.

The STRIDA project is conducted in accordance with the Helsinki Declaration, and it has been approved by the regional ethical review board (Nr. 2013/116–31/2).

Analytical investigations

On arrival to the laboratory, serum and urine specimens were stored refrigerated until taken for analysis, which was initiated within 24 h. Storage of specimens over longer time was done at –70 °C. Measurement of psychoactive substances in urine and serum was carried out as detailed elsewhere [23,24], using an electrospray ionization liquid chromatography–tandem mass spectrometry (LC–MS/MS) multi-component method based on recording signals for two product ions for each analyte in positive selected reaction monitoring (SRM) mode. The method is regularly updated with new substances, as they emerge on the recreational drugs market and reference material becomes available. From November of 2014, the analytical investigation of NPS has been performed using LC–high resolution MS (LC-HRMS) on a Thermo Q Exactive instrument operating at 70,000 resolution power [24].

For the analysis of urine, a 100-µL aliquot was diluted 5-fold with 400 µL internal standard solution (methamphetamine-d5 in 0.1% formic acid). Serum samples were prepared by mixing 100 µL serum with 50 µL internal standard (pethidine-d5) solution, followed by addition of 400 µL acetonitrile. After mixing and centrifugation, 300 µL of the supernatant was transferred to autosampler vials. The injection volume was 2 µL. Calibrators were prepared from blank samples. The measuring range covered 1.0 ng/mL to 1.0 µg/mL. Quantifications above the upper limit were done following dilution of samples with blank matrix. The exact mass of monitored protonated molecular ions of the 11 studied substances are listed in Table 1.

Immunochemical screening for classical drugs of abuse was performed using CEDIA, DRI and EIA reagents on an Olympus 640 or 680 Analyzer (Thermo Fisher Diagnostics), as detailed elsewhere [20,21].

Results

In addition to MDPV and α-PVP, 11 other NPS pyrovalerone drugs (Figure 1) were detected in urine or serum samples from 114 intoxicated patients in the STRIDA project. This comprises 4.5% of the 2545 ED/ICU cases enrolled during the study period, and 12% of the cases concerning a pyrovalerone drug. Analytical identification was based on agreement with reference materials and LC–MS analytical data that fulfilled the chromatographic and MS criteria according to forensic standards. An example chromatogram for one substance, α-PPP, is shown in Figure 2, together with product ion mass spectral data. The measured substance concentrations are given in Table 2.

Figure 2. Chromatograms from the analysis of α-PPP in a urine sample from one selected case of intoxication. The analysis was performed with LC–HRMS in scan mode and in MS/MS mode for identification. Comparison was made with certified reference substance.

Table 2. Urine and serum concentrations of pyrovalerone NPS in intoxication cases.

	Urine concentration (ng/mL)			Serum concentration (ng/mL)
Substance	median	range	N	median	range	N
α-PPP	13	4–102	8	–	–	0
4Me-PPP	2095	1290–2900	2	–	–	0
α-PBP	14	2–13,200	37	14	2–436	6
α-PVT	43	4–7380	11	184	8–1060	4
4F-α-PVP	48	1–24,600	17	33	23–43	2
4Cl-α-PVP	5220	–	1	–	–	0
α-PHP	68	1–300,000	11	6	4–10	3
MDPHP	34	2–5960	19	8	3–136	7
4F-α-PHP	97	11–10400	7	15	3–28	2
PV8	20	2–1270	8	–	–	0
4F-PV8	14	3–182	5	–		0

The age range of patients was 16–66 (median 30) years and 84% were males. In the 114 patients testing positive for any of the investigated substances, a total of 149 pyrovalerone findings were made: α-PBP was the most common (n = 43) followed by MDPHP (26), 4F-α-PVP (19), α-PVT (15), α-PHP (14), α-PPP (8), 4F-α-PHP (8), PV8 (8), 4F-PV8 (5), 4Me-PPP (2), and 4Cl-α-PVP (1). Nineteen patients tested positive for two pyrovalerones, 8 patients for three, and one patient had a combination of five substances: α-PBP, α-PVT, 4F-α-PVP, α-PHP, and PV8. MDPV was detected as an additional substance in 17 cases and α-PVP in 45 cases.

In 23 cases (20%), one of the studied pyrovalerone derivatives was specifically named during PIC consultation and/or in the medical record, of which the most common were α-PHP (9 cases) and 4F-α-PVP (5 cases). These reports were consistent with the analytical results in 89% and 100% of the cases, respectively. However, the most common (n = 22) suspected toxic agent at consultation of the positive patients was MDPV. Indeed, MDPV was present as an additional substance in 7 (32%) of those 22 suspected cases. No specific drug name was given in 41 (36%) cases.

A combination of several psychoactive substances was a typical finding in the patients, and only 8 cases appeared to be single substance exposures according to the analytical results. Of these cases, four involved MDPHP, and one each α-PBP, α-PVT, 4F-α-PVP, and α-PHP. Details of these 8 cases are presented in Table 3. Only one of these single substance exposed patients developed pronounced clinical symptoms associated with a sympathomimetic/stimulant toxidrome. In the other 106 cases (93%), the patients had combined a pyrovalerone drug with other NPS and/or classical drugs. In 68 cases, more than one of the investigated and/or the established (i.e. MDPV and α-PVP) pyrovalerone substances were found. Classical stimulants (amfetamines, MDMA, and cocaine) were detected in 24 cases, depressants (buprenorphine, opioids, and ethanol) in 59, and benzodiazepines in 33 cases.

Table 3. Details of the 8 single drug intoxication cases.

	Substance concentrations, ng/mL
Substance	Serum	Urine	Creatinine in urine, mmol/L	Sampling time after admission (from drug intake)	Drug experience	Symptoms for seeking hospital	Clinical observations	Treatment	PSS
α-PBP	161	305	1.4	1 h (2 h)	Opiates, MDPV	General body pain, breathing difficulties, tingling in legs after injection	RLS 1, mild agitation, paresthesia, muscle pain, hypothermia (35.9 °C/96.6 °F)	Diazepam 5 mg iv	2
MDPHP	<1.0	48	8.2	1 h (–)	–	Thorax pain, breathing difficulties and sense of fatigue since 3 weeks	Long latency of response and speech, but tactile hypersensitive		1
MDPHP	6.7	43	12.8	2 h (4–5 h)	2 years experimental drug use	Unpleasant feelings in the thorax region	RLS 1		1
MDPHP	14.3	19	5.8	2 h (4–5 h)	2 years experimental drug use	Euphoria followed by “panic anxiety attack”, including dizziness, blurry vision, breathing difficulties, unpleasant feelings in the thorax region, cold extremities	RLS 1, hypertension (168/77 mmHg)		1
MDPHP	3.8	25	5.4	24 h (–)	Long term misuse of drugs	Psychosis, aggressiveness (police assistance needed)	Hallucinations, aggressiveness, RLS 1	Lorazepam 2.5 mg po	2
4F-α-PVP	43	–	–	Promptly (–)	Misuse of alcohol and other drugs, previously treated for intoxication related to amfetamine	Psychosis, aggressiveness (police assistance needed)	GCS 13, agitation, dilated pupils, hyperthermia (39.3 °C/102.7 °F), tachycardia (150/min), hypertension (148/130 mmHg), CRP 123 mg/L, rhabdomyolysis (S-myoglobin 455 µg/L [on admission]/3162 µg/L [22 h from arrival], P-creatinine 115 µmol/L)	Propofol, midazolam, cold fluids	3
α-PVT	425	–	–	Promptly (9 h)	–	Apathetic, anxiety	GCS 13, mild agitation, muscle spasm in the back, tachycardia (109/min), CRP 22 mg/L		2
α-PHP	1.9	3	8.1	6.5 h (7.5 h)	Misuse of drugs, previously treated for intoxication related to synthetic cannabinoids	Breathing difficulties, palpitation, jaw muscle spasm within 1 h after drug exposure	GCS 15, dilated pupils, paresthesia, hypertension (142/82 mmHg), respiratory alcalosis (pH 7.56, pCO2 3.2 kPa, standard bicarbonate 25 mmol/L)		1

–: Sample or information missing; CRP: C-reactive protein; GCS: Glasgow Coma Scale; iv: intravenous; P: plasma; po: peroral; PSS: Poisoning Severity Score; RLS: Reaction Level Scale; S: serum.

Written documentation by the physician or PIC pharmacist during consultation or in the medical record revealed that the patients showed clinical symptoms commonly seen following exposure to central stimulatory substances, such as agitation, delirium, hallucinations, excessive motor activity, seizures, tachycardia, hypertension, and/or hyperthermia, in 50% of the cases. In 15 (13%) cases, there was information of a depressed state; however, in all but one, CNS depressing agents (e.g., opioids, bensodiazepines, and/or alcohol) were found in the analytical investigation. On admission to the hospital, 12 (11%) patients presented with clinical signs that were not clearly derived from either the CNS stimulating or depressing drugs, or, in a few cases, showed symptoms atypical for an acute drug exposure. In 30 cases (26%), there was no documentation of the clinical state of the patient.

Statistics on PIC inquiries related to the investigated pyrovalerone derivatives during 2012–2016 are listed in Table 4. In Figure 3, their appearance, together with MDPV and α-PVP, in STRIDA cases over time are shown. The times for regulation in Sweden of each substance, either as a narcotic or as hazardous to health, is also indicated. Table 1 provides further information on classification dates and first observed interest from recreational drug users.

Figure 3. Quarterly statistics during 2010–2016 from the STRIDA project of analytically confirmed (in urine or serum) cases of intoxication involving a pyrovalerone derivative. The time for substance regulation in Sweden is indicated by a bold vertical line.

Table 4. Pyrovalerone substances mentioned in telephone inquiries to the Swedish Poisons Information Centre.

	Year
Substances	2012	2013	2014	2015	2016
MDPV	194	208	129	74	34
α-PVP	6	9	3	2	4
Pyrovalerones in this study	0	0	0	0	0
α-PPP	1	2	0	0	0
4Me-PPP	0	0	0	0	0
α-PBP	0	6	2	0	0
α-PVT	0	0	2	0	0
4F-α-PVP	0	0	24	0	0
4Cl-α-PVP	0	0	0	0	4
MDPHP	0	0	0	0	0
α-PHP	0	0	25	8	4
4F-α-PHP	0	0	0	1	5
PV8/α-PEP	0	0	8	3	1
4F-PV8	0	0	1	0	0
Other pyrovalerones
4Cl-α-PHP	0	0	0	0	2
3,4-MeO-α-PVP	0	0	0	1	0
3,4-MeO-α-PHP	0	0	0	5	0
5-DBFPV	0	0	0	0	1
α-PiHP	0	0	0	0	2
5-BPDi	0	0	0	0	1
PV	2	0	9	1	0

Discussion

The present study documented the appearances of an additional 11 pyrovalerone drugs sold as NPS, besides MDPV and α-PVP, in acute intoxication cases presenting for emergency care all over Sweden in 2011–2016. All but one of the additional substances occurred at about the same time, or after, the use of MDPV and α-PVP had peaked [12,18]. An exception to this pattern was 4Me-PPP, which only occurred in two cases in 2011 and 2012. However, in both of these, MDPV was also detected in the urine samples.

Similar to what was earlier found for MDPV and α-PVP, a clear majority of the patients intoxicated by the other pyrovalerone derivatives were males (84%). The median age for MDPV positive cases in the STRIDA project was 35 years, and 32 years for α-PVP [12,18]. In the present study, the median age was slightly lower, 30 years, which is still considerable higher than the median age of 20 years found in other STRIDA cases [20,21]. In the case of MDPV, the higher age range was supposed to relate to the fact that it attracted mainly established users of psychostimulant drugs (i.e. amfetamines) [12]. The impression from the data in Figure 3, that the time for substance classification has less relation to the appearance of intoxications compared with, e.g., NPS fentanyl derivatives [25], might support this assumption. These drug users may simply not be purchasing the drugs on the open web but rather at the illicit drug market from local drug dealers.

The number of individual cases for the 11 substances investigated was always much lower compared with for MDPV and α-PVP, even for the most prevalent substance α-PBP. The potential severe toxicity of “MDPV” received media attention and this might have reduced the interest in these substances among drug users.

Also similar to what was found for MDPV and α-PVP [12,18], the serum concentrations associated with the intoxications were highly variable, ranging from only a few to several thousand ng/mL. The ranges of concentration appeared overlapping with those found for MDPV and α-PVP [12,18]. This may be due to the non-standardized times for sampling but also to the combined use of multiple drugs. In cases with low serum concentrations, it is possible that the analytical findings were more related to previous use rather than causing the actual acute intoxication.

The expected stimulatory clinical symptoms dominated in the patients taking pyrovalerone derivatives, although the great majority of patients tested positive for more than one psychoactive drug. The common use of a combination of pyrovalerones and/or other amfetamine-like drugs, suggests that the primary intention was to achieve a central stimulatory effect rather than using a specific pyrovalerone. Patients' limited awareness of the specific substance taken might also indicate that they were not purchased from a webshop, since these commonly declare the true content (own observation).

A benzodiazepine was often detected in the analytical investigations, together with the pyrovalerone NPS, which was also observed for patients treated after MDPV and α-PVP intoxication [12,18]. However, in most cases, this likely related to standard medications used in critical care of patients presenting with a sympathomimetic/stimulant toxidrome. Therefore, unless immediate sampling for drug testing is done on admission, a falsely high rate of benzodiazepine use may be found. However, as the same substances are also commonly misused, the proportion of benzodiazepines originating from the medical ward or from illegal use is not known. However, NPS, or “designer” benzodiazepines, which are not used in clinical practice, were detected in 16 cases.

The neuropharmacological profiles of pyrovalerone derivatives have been well characterized and they are considered to act mainly as dopamine re-uptake inhibitors, very similar to cocaine [17]. The structure–activity relationship suggests that MDPV and α-PVP show similar potency and that the substituent on the benzene moiety has little importance [5]. The length of the side alkyl chain, however, is more important [17]. The three analogues with shorter chains, i.e., α-PPP, 4Me-PPP, and α-PBP, are less potent than α-PVP, while α-PHP and PV8 are more potent as dopamine re-uptake inhibitors [17]. If a substituent on the benzene ring is less influential on the potency, it can be assumed that 4F-α-PVP, 4Cl-α-PVP, MDPHP, 4F-α-PHP, and 4F-PV8 all possess similar activity as their respective analogues. Alpha-PVT is chemically distinct, as the benzene ring is replaced by a thiophene ring. Recent work has demonstrated rewarding and reinforcing effects of α-PVT, similar to cocaine and methamphetamine [26]. The neuropharmacological profile of α-PVT on biogenic amine transporters was found to be similar to the benzene pyrovalerone drugs but with 15-fold lower potency [27]. A new aspect concerning the danger related to this class of drugs is the cytotoxic effect that is especially associated with an extended alkyl side chain and with substitution of the benzene ring by a thiophene [28]. This calls for awareness not only for acute toxic effects but also for health risks after repeated use.

Our study has some limitations that need to be pointed out. In 26% of the intoxication cases, documentation of the clinical state was missing in the PIC database. The sometimes sparse amount of clinical information communicated to the PIC in several cases is probably due to the project form, where participation in the STRIDA project with free-of-charge drug testing requires an initial phone contact with the PIC, regardless of whether consultation is needed or not. Timing of clinical data acquisition and sample collection was not standardized, and their relation to exposure time was often impossible to determine. Furthermore, the present data most likely underestimated the total number of pyrovalerone intoxications, mainly because health care providers and the public do not report every case of NPS exposures to the PIC. Less than half of the PIC consultations became STRIDA cases since blood and/or urine was not always submitted for analysis. Moreover, the substances used may not have been included in our set of analytes.

Conclusion

This study presented a series of 114 analytically confirmed intoxication cases involving 11 pyrovalerone derivatives that appeared as NPS in addition to the established substances MDPV and α-PVP. The clinical features of these new stimulants were consistent with a sympathomimetic toxidrome, although the urine and serum concentrations showed high variability. The results demonstrated that many different pyrovalerone stimulants were introduced on the recreational drug market at about the same time as MDPV and α-PVP. The analytical investigations were necessary to reveal this information.

Disclosure statement

The authors report no declarations of interest.

Additional information

Funding

This work was supported in part by grants from the Swedish National Institute of Public Health.