Clinical Toxicology (2015), Early Online: 1–8 Copyright © 2015 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2015.1033630
ORIGINAL ARTICLE
Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine Anders Helander,1,2 Olof Beck,1,2 and Matilda Bäckberg3 1Department
of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden of Clinical Pharmacology, Karolinska University Laboratory, Stockholm, Sweden 3Swedish Poisons Information Centre, Stockholm, Sweden
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2Department
Background. Diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) are substances with dissociative effects that were recently introduced for “recreational” purpose through the online-based sale of new psychoactive substances (NPS). A number of analytically confirmed non-fatal intoxications associated with diphenidine or MXP have occurred in Sweden and were included in the STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS and requiring intensive treatment in an emergency room and hospitalization in Sweden. Patients and methods. Blood and urine samples were collected from intoxicated patients presenting at emergency departments all over the country. NPS analysis was performed by multi-component liquid chromatography–mass spectrometry methods. Data on clinical features were collected during telephone consultations with the Poisons Information Centre and retrieved from medical records. Information was also obtained from online drug discussion forums. Case series. Over a 12-month period from January to December 2014, 750 cases of suspected NPS intoxication originating from emergency departments were enrolled in the STRIDA project of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) tested positive for MXP. Co-exposure to several other NPS (e.g., 5-/6-(2-aminopropyl)benzofuran, 2-4-bromomethcathinone, butylone, 3,4-dichloromethylphenidate, 5-methoxy-N-isopropyltryptamine, methiopropamine, and a-pyrrolidinopentiothiophenone), also including other dissociative substances (3-/4-methoxyphencyclidine), and classical drugs of abuse (e.g., cannabis and ethanol) was documented in 87% of these cases. The 17 patients were aged 20–48 (median: 32) years, and 13 (76%) were men. They commonly presented with hypertension (76%), tachycardia (47%), anxiety (65%), and altered mental status (65%) including confusion, disorientation, dissociation, and/or hallucinations. Eight patients (47%) displayed severe intoxication (Poisoning Severity Score 3). The diphenidine- or MXP-positive patients required hospitalization for 1–3 (median: 2) days. In addition to standard supportive therapy, half of the cases were treated with benzodiazepines and/or propofol. Conclusion. The adverse effects noted in analytically confirmed cases of NPS intoxication involving diphenidine or MXP were similar to those reported for other dissociative substances such as ketamine and methoxetamine. However, the high proportion of polysubstance use might have played a role in the intoxication and clinical features in some cases. Keywords Diphenidine; Dissociative drugs; LC–MS; Legal highs; Methoxphenidine; New psychoactive substance; NMDA receptor antagonist; Research chemicals; Severe adverse events; STRIDA project
NPS detected in Europe, according to notifications from the EU Early Warning System operated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and Europol, remained at a relatively stable level of around 10 novel substances per year. Since then, partly in response to legal actions undertaken to regulate individual NPS,2 there has been a steady increase from 24 new substances in 2009 to 101 in 2014.3 Accordingly, each week on average 2 new substances are currently introduced in the European recreational drugs market. In addition to the structurally modified NPS variants (“designer drugs”) that replace the banned ones, there is also an increasing diversity of new and potentially hazardous substances, as other classes of psychoactive substances such as designer benzodiazepines and opioids have started to appear. For example, the NPS opioids MT-45 and AH-7921 have recently been associated with severe adverse responses
Background In the past decade, there has been a dramatic increase in the panel of psychoactive substances used for “recreational” purpose. Besides the classical set of stimulant, sedative, and hallucinogenic drugs of abuse, such as amphetamines, cannabis, cocaine, opiates, and lysergic acid diethylamide, a large number of new psychoactive substances (NPS) mainly of synthetic origin are openly sold by online-based vendors as unregulated drug alternatives (e.g., “legal highs” and “research chemicals”).1,2 Until 2008, the official number of Received 13 January 2015; accepted 20 March 2015. Address correspondence to Prof. Anders Helander, C1:74, Clinical Chemistry, Karolinska University Laboratory Huddinge, SE-141 86 Stockholm, Sweden. Tel: 46 70 4841888. E-mail: anders.helander@ ki.se
1
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2 A. Helander et al. and fatalities.4–6 In addition, designed dissociative anesthetic substances with comparable activity to phencyclidine (PCP), ketamine, methoxetamine (MXE), and dextromethorphan, acting by N-methyl-D-aspartate (NMDA) receptor antagonism, have emerged on the recreational drugs market and are used for their mind-altering effects.7–10 The interest among drug users for this type of compounds has been documented for PCP and ketamine, albeit at a relatively low prevalence,11–13 and also many cases of serious toxicity.14–16 The substituted PCP analogs 3- and 4-methoxyphencyclidine (3- and 4-MeO-PCP) were among the first designer dissociatives introduced as NPS.10,17 More recently, two structurally different dissociative substances, the diarylethylamines diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) (Fig. 1), have been introduced.18,19 Diphenidine and MXP are known from the scientific and patent literature, diphenidine since 1924 and MXP since 1989.9 However, despite documented central nervous system (CNS) effects and resemblance with already controlled substances, neither diphenidine nor MXP are classified drugs in Sweden and both were still available on several websites in February 2015. This report presents laboratory results and clinical characteristics in a case series of analytically confirmed non-fatal intoxications involving diphenidine or MXP in the Swedish STRIDA project.
Methods STRIDA is a collaborative project between the Karolinska University Laboratory, the Karolinska Institutet, and the Swedish Poisons Information Centre that monitors the occurrence and health hazards of newly emerging drugs of abuse in Sweden. Results of blood and urine drug testing are compared with the associated clinical features, among cases of acute NPS intoxication presenting at emergency departments or intensive care units in hospitals all over the country.2,20 The project is conducted in accordance with the Declaration of Helsinki and has been approved by the regional ethical review board (Nr. 2013/116–31/2).
N
N O
Diphenidine
Methoxphenidine (MXP)
N N
N
Lefetamine
MT-45
Fig. 1. Chemical structures of the dissociative NPS diphenidine (1-(1,2-diphenylethyl) piperidine) and its 2-methoxylated derivative MXP (2-MeO-diphenidine). Two structurally similar but pharmacologically rather distinct substances, the stimulant analgesic lefetamine and the opioid-like MT-45, are also shown.
Clinical data related to the intoxications are collected in a standardized way when medical staff consult the Poisons Information Centre (a national 24/7 service to clinicians and the public) by telephone and later retrieved from medical records. The cases were graded retrospectively using the Poisoning Severity Score (PSS).21 The level of consciousness was documented using the Glasgow Coma Scale (GCS) or the Reaction Level Scale (RLS).22 Blood and urine samples are collected as soon as possible after admission and forwarded to the Karolinska University Laboratory for analysis of NPS and classical drugs of abuse, as detailed elsewhere.2,20 Identification and quantification of NPS in urine and serum samples are performed by flexible multi-component liquid chromatography–tandem mass spectrometry (LC–MS/MS) and LC–high-resolution MS (LC–HRMS) methods that are updated with new substances as they appear and reference material becomes available.23,24 For diphenidine and MXP (parent drugs), retrospective reanalysis of samples was sometimes necessary. Reference material of diphenidine was obtained from LGC Standards (Teddington, UK) and of MXP from Cayman Chemical (Ann Arbor, MI, USA). The measuring range of both compounds was 1–10000 ng/mL in urine and 1–500 ng/mL in serum, with detection limits 0.2 ng/mL.
Results Poisons information statistics on diphenidine and MXP During the 12-month study period from January to December 2014, 1580 consultations regarding suspected intoxications by NPS were registered at the Swedish Poisons Information Centre. The first inquiry related to a suspected MXP intoxication occurred in January 8, 2014, and for diphenidine in February 14, 2014. In total, there were 4 cases related to MXP as the suspected intoxication substance during the study period, compared with 23 on diphenidine. In 17 of the 27 (63%) inquiries related to cases of suspected diphenidine or MXP exposure, samples were collected for analytical confirmation within the STRIDA project. Laboratory data on diphenidine and MXP During the 12-month study period, 750 cases of suspected NPS intoxication originating from all over the country were enrolled in the project (i.e., both biological samples and clinical data were available), of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) for MXP (Table 1). However, they were never seen in combination. In most cases (71%), the analytical findings of diphenidine or MXP were consistent with information from self-report or clinical suspicion (Table 1). The 17 diphenidine- or MXP-positive patients were aged 20–48 (mean: 31.8, median: 32) years and 13 (76%) were men. The diphenidine concentration in serum ranged between 2 and 262 (mean: 88.4, median: 69.5) ng/mL and in urine between 8 and 19000 (mean: 2213, median: 621) ng/mL. When the urine concentration was normalized to the creatinine concentration, to compensate for urine dilution, the Clinical Toxicology Early Online 2015
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Intoxications by diphenidine and MXP 3 diphenidine-to-creatinine ratio ranged between 1.2 and 1158 (mean: 247, median: 125) µg/mmol (Table 1). The corresponding results for the three MXP-positive cases were 187 and 409 ng/mL (case no. 17 tested negative) in serum, and 3–8367 (median: 610) ng/mL in urine (0.3–346 µg/mmol of creatinine, median: 59.2), respectively. Sampling was typically done within a few hours of admission to the emergency department (Table 1). However, in one case (no. 2 in Table 1) that was not sampled until 24 h after admission, diphenidine was still detectable in both serum and urine. Examples of the analytical results by LC–HRMS are shown in Fig. 2. Co-exposure to other NPS and/or classical drugs of abuse was common and confirmed in all but two of the diphenidine- and in all MXP-positive patients (i.e., in 88% of all cases). Except for usual drugs given during intensive hospital care treatment (e.g., benzodiazepines), 34 other psychoactive substances or metabolites were identified in blood and/or urine, also other dissociatives (i.e., 3-/4-MeOPCP) (Table 2). The most common other substances were ethanol (including conjugated ethanol metabolites), 3,4dichloromethylphenidate (3,4-CTMP), diclazepam/lorazepam (lorazepam is available as a drug at its own but is also a metabolite of diclazepam), 3-MeO-PCP, and pregabalin, which were each found in 18–35% of the cases (Table 2). Four patients (cases no. 3, 7, 13, and 14 in Table 1) brought zip-locked transparent plastic bags containing an off-white powder (3 were labeled “diphenidine”) to the hospital and handed it over to the medical staff. The products were demonstrated by LC–MS/MS and nuclear magnetic resonance (NMR) analysis (results not shown) to contain diphenidine, with no other psychoactive substance identified (personal communication, K-H. Jönsson, Swedish Medical Products Agency). Clinical features in diphenidine- or MXP-positive cases The patients testing positive for diphenidine or MXP, albeit in most cases also for other NPS and/or classical drugs (Table 1), commonly presented with adverse symptoms such as hypertension (systolic blood pressure 140 mmHg; 76%), tachycardia ( 100/min; 47%), anxiety (65%), and agitation (47%), and less frequently ( 35%) with nystagmus, dilated pupils, and muscle rigidity (Table 3). In 65% of cases, an altered mental status was also registered, which included signs such as an altered level of consciousness (graded by the GCS or RLS), hallucinations, confusion, disorientation, and dissociation. Three patients (20%; cases no. 11, 14, and 15 in Table 1) were deeply unconscious (GCS 3 or RLS 8) during transport or on admission to hospital. They all tested positive for several drugs besides diphenidine or MXP (Table 1). One responded to flumazenil, in accordance to a self-reported intake of the novel benzodiazepine diclazepam, while the other two woke up spontaneously. Upon awakening, two patients became agitated, one with elements of hallucinations and the other with painful muscle spasms, whereas the third patient had signs of confusion, disorientation, and horizontal and/or vertical nystagmus. Two patients showed Copyright © Informa Healthcare USA, Inc. 2015
a prolonged activated partial thromboplastin time (APTT; 180 s, reference interval: 30–45 s), but there were no signs of bleeding and their APTT decreased spontaneously. Besides observation and standard supportive therapy, pharmacological sedative treatment was used in 7 cases; benzodiazepines (diazepam and/or midazolam) were administered in 6 cases, and in 5 cases there was also a need for propofol treatment. Haloperidol was given in one case. The time in hospital treatment ranged between 1 and 3 (mean: 1.6, median: 2.0) days (Table 1), and there was an overall good agreement between the hospital care days and PSS (P 0.004; rank correlation). In half of the 12 intoxications involving diphenidine, it was the only suspected drug mentioned during consultations with the Poisons Information Centre. However, based on the results of blood and urine drug testing, only two cases (no. 4 and 12 in Table 1) were indicated to be pure diphenidine intoxications, one graded as a mild (PSS 1) and one, which was a suicide attempt, as a severe (PSS 3) intoxication. Of the 6 cases of diphenidine or MXP intoxication for which the clinical features were graded as severe (PSS 3), all but one were polyintoxications with other NPS and/or classical drugs (Table 1). According to self-reported routes of drug administration, oral, nasal, rectal, and intravenous exposures were used (Table 1).
Discussion The huge growth in type and number of NPS made available through online-based drug sale over the past 6 years represents a new health threat to society. When new substances are introduced for use as recreational drugs, there is usually only limited information on their metabolism, clinical signs and symptoms, and acute and chronic toxicity. Despite close structural similarities to well-known drugs of abuse or prescribed drugs, the pharmacological actions of seemingly related substances might diverge. Examples of this are the diarylethylamine dissociative substances diphenidine and MXP, which showed comparable activity to arylcyclohexylamine dissociative anesthetic substances such as PCP, ketamine, and MXE,9 albeit being structurally more similar to lefetamine, a stimulant with analgesic effect,25 and to the opioid-like MT-45 (Fig. 1).4 Another common phenomenon that was noted in this and previous studies is that NPS users frequently combine different types of drugs.2,4,23,26 This may result in unpredicted, serious interactions, and often makes it difficult to relate clinical signs and symptoms to a specific substance and hence assessing its unique toxicity. The interest in diphenidine and MXP as recreational drugs started soon after a UK arylcyclohexylamine ban covering, for example, 3- and 4-MeO-PCP that came into effect at the end of February 2013.9 Already in March 2013, diphenidine and MXP were introduced by NPS sale through the Internet as legal replacements of the classified dissociatives. At the same time, online drug discussion forums started threads on diphenidine,27,28 and later (November 2013) also on MXP.29,30 Threads on diphenidine and MXP on a Swedish drug chat
Reported or suspected NPS
F/27
M/32
M/37
M/36
M/25
M/47
M/39
M/27
3
4
5
6
7
8
9
10
F/33
M/29
2
11
M/20
1
a-PVP, a-PVT
bk-2C-B, 4-BMC, 2C-P, 3,4-CTMP, EFLEA, meclonazepam, 5-MeONiPT, THJ-018
Diphenidine
Diphenidine
Diphenidine
Diphenidine, benzofurans, PCP analog, Psilocybe mushrooms
Diphenidine, PCP analog, Psilocybe mushrooms
Diphenidine, diclazepam Diphenidine
Diphenidine
Diphenidine
Diphenidine-positive cases
Case no Sex/Years
–
–
–
–
50 mg
100 mg
–
– “Powder”
200–250 mg 450 mg
–
Reported dose
rec and/or iv
–
nas
nas
po
–
–
po
po
iv
po
ROA
3.5 h
30 min
30 min
2.5 h
45 min
1h
1h
1h
“Promptly”
24 h
1h
81
6
52
233
51
18
105
134
2
9
119
538
0.5
108
125
28.0
196
436
41.2
1.2
1.6
26.7
Sampling Diphenidine/ Diphenidine/ time MXP in MXP in urine (after admis- serum (ng/ (ng/mmol sion) mL) creatinine)
Ketamine, dexmedetomidine, midazolam, propofol, remifentanil, diazepam
Diazepam
Diazepam
Observation
Observation
Diazepam, propofol
Diazepam, propofol
Observation
Observation
Observation
Observation
Treatment
Initially unconsciousness (RLS 8), dissociation, frothing from mouth, followed by increased level of consciousness, agitation, occasional painful muscle spasms
Disorientation, tachycardia, hypertension, dilated pupils (GCS 14) Hypertension, anxiety (RLS 1) Visual hallucinations, nystagmus, diaphoresis
Agitated delirium, muscle rigidity, followed by myoclonus, hyperreflexia. Horizontal nystagmus, tachycardia, hypertension, urinary retention Tachycardia, hypertension (RLS 1)
Anxiety, reduced level of mental receptiveness (RLS 1) Agitated delirium, muscle rigidity, tachycardia, hypertension, urinary retention (RLS 2–4)
Dilated pupils, hypertension (RLS 1) Tachycardia, hypertension (RLS 1) Tachycardia
3
1
1
1*
1
2
2
1
1
2
1*
5-MeO-NiPT, a-PVP, a-PVT (ketamine, 4-hydroxymidazolam)
3
2
1
a-PVT 4-BMC, cannabis, 2C-P, 3,4-CTMP, 5-MeONiPT, 3-MeO-PCP, methiopropamine, 2-MMC, pregabalin (desmethyldiazepam)
2
1
3
3
1
1
2
1
Diclazepam, ethanol, ethanol metabolites, lorazepam Pregabalin
5-APB/6-APB, buprenorphine, butylone, ethanol metabolites, 3-MeO-PCP (oxazepam, temazepam) 5-APB/6-APB, butylone, ethanol metabolites, 3-MeOPCP
Ethanol metabolites, flubromazepam, Methylphenidate/ ritalinic acid Lorazepam, pyrazolam
Other substances Hospital detected in urine and/ Main clinical features (RLS care or blood (intensive care or GCS) days related) PSS
Table 1. Laboratory and clinical data of 17 analytically confirmed cases of diphenidine or MXP intoxication in the STRIDA project.
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4 A. Helander et al.
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M/22
M/27
13
14
Synthetic cannabinoids
3,4-CTMP
Diphenidine
Reported or suspected NPS
_
_
–
Reported dose
_
_
iv
ROA
F/48
17
PCP
MXP, diclazepam, 3,4-CTMP
–
–
–
–
“Promptly”
1h
1.5 h
2h
1.5 h
2 h (serum)/ ”Promptly” (urine)
ND
409
187
262
108
58
0.3
343
59.2
1158
386
621
Observation
Naloxone, flumazenil, propofol
Observation
Midazolam, propofol
Oxygen supply diazepam, propofol
Diazepam, propofol, haloperidol
Sampling Diphenidine/ Diphenidine/ time MXP in MXP in urine (after admis- serum (ng/ (ng/mmol sion) mL) creatinine) Treatment
Unconsciousness (GCS 8), dilated pupils on arrival. Flumazenil iv resulted in agitation and hallucinations Unconsciousness (GCS 3), muscle rigidity, jaw clenching, hypertension on arrival followed by increasing level of consciousness, confusion, disorientation, horizontal and vertical nystagmus
Hypertension, anxiety (RLS 1)
Agitation (GCS 7), dilated pupils, hyperthermia (39°C), diaphoresis, aspiration, tachycardia, hypertension
Agitation, dissociation, frothing from mouth, hypertension, tachycardia, anxiety Muscle rigidity, disorientation, anxiety, dilated pupils, tachycardia, hypertension
2
2
2
2
1
3
3-MeO-PCP, 4-MeOPCP, MT-45, oxazepam, temazepam
7-Aminonitrazepam, cannabis, lorazepam, methiopropamine, a-PBP, pentylone, pregabalin 3,4-CTMP, lorazepam, methiopropamine, thiothinone
4-BMC, 4-CMC, MDPHP, ethylone, MDPV, pregabalin, fentanyl, ethanol metabolites
3,4-CTMP, pentedrone, 4F-a-PVP, ethanol
(Desmethyldiazepam)
3
3
1
3
3
3
Other substances Hospital detected in urine and/ Main clinical features (RLS care or blood (intensive care or GCS) days related) PSS
nas, nasal (snorted); po, peroral; rec, rectal; ethanol metabolites, ethyl glucuronide and ethyl sulfate; –, information or sample missing; ND, not detected ( detection limit). *Patient absconded from hospital.
Data are consecutive STRIDA cases collected from January to December 2014. ROA, route of administration; RLS, Reaction Level Scale; GCS, Glasgow Coma Scale; PSS, Poisoning Severity Score; iv, intravenous;
M/33
16
Methoxphenidine (MXP)-positive cases 15 M/25 MXP, nitrazepam 3 100 nas mg 500 iv mg
F/33
12
Case no Sex/Years
Table 1. (Continued)
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Intoxications by diphenidine and MXP 5
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6 A. Helander et al.
Fig. 2. Chromatograms from the LC–HRMS analysis of non-fatal cases of NPS intoxication in the STRIDA project, one case testing positive for diphenidine (case no. 12 in Table 1) in serum (A; 58 ng/mL) and urine (B; 610 ng/mL), and one for MXP (case no. 14 in Table 1) in serum (C; 409 ng/mL) and urine (D; 8367 ng/mL). Results were obtained using a Thermo Fisher Scientific Q Exactive MS equipped with a Dionex 200 LC system. The theoretical exact mass is 266.19033 for the diphenidine ion and 296.20089 for the MXP ion. The instrument was operated at 70000 resolution (m/z 200) and mass chromatograms were extracted with a 5-ppm tolerance. The retention time difference to reference was 0.00–0.02 min and the mass difference was 0.03–1.26 ppm.
forum both appeared in November 2013.31,32 Diphenidine and MXP are presently subject to classification investigation by the Public Health Agency of Sweden. However, it should be noted that because 3- and 4-MeO-PCP were not classified in Sweden until January 2015, they could be continuously used during the study period, as was demonstrated in some of the STRIDA cases. According to user experiences posted on the drug forums,27–32 diphenidine and MXP are typically taken orally (“bombed”) in ∼50–150 mg doses, although occasional intake of up to 600 mg totally in successive doses was also reported. Nasal (∼15–300 mg), rectal (20 mg), and intravenous routes of administration, and more lately, smoking and inhalation of vaporized diphenidine at lower dosage, have also been used. This information is consistent with the self-report data obtained in the STRIDA cases, both regarding drug dosage (i.e., up to several hundred milligrams in single or consecutive doses) and routes of administration, with oral, nasal, and intravenous administration being about as usual. In the drug forums, the psychoactive and clinical effects of diphenidine and MXP were reported to be mild-to-moderate for oral doses of up to ∼100 mg, but with an apparent steep dose–response curve at higher doses sometimes causing strong dissociative and even adverse effects.27–32 Furthermore, the onset of full effects was usually reported to be delayed ( 1 h), implying risk for overdosing, and the duration of action was ∼3–7 h. Diphenidine and MXP have been reported to act similar to the arylcyclohexylamine dissociative drugs ketamine, MXE, and 3-MeO-PCP,7,9,10,33 both regarding desired psychoactive and undesired adverse effects,27–32 as well as NMDA recep-
tor antagonism.8,19 The undesired clinical features noted in the STRIDA case series of non-fatal acute intoxications by diphenidine or MXP, including hypertension, nystagmus, and urinary retention, were consistent with previously published information and self-reported experiences mentioned in online drug user reports.7–10,27–33 The signs and symptoms usually resolved with symptomatic treatment, but benzodiazepines were sometimes administered for treatment of tachycardia and hypertension and for sedation. In cases of NPS intoxications, a prolonged APTT is occasionally noted in the medical records and mentioned during consultation with the Poisons Information Centre. In this case series, a prolonged APTT was noted twice, but whether APTT was also measured in the other cases is not known. A possible association between NPS products and APTT prolongation should be further investigated. Most patients were discharged from hospital after 1–2 days, despite variable and sometimes high substance concentrations in blood and urine. For comparison, in a published fatal case where diphenidine was judged to have played a major role,34 although synthetic cannabinoids were also involved, the diphenidine concentration in blood was ∼3fold higher than the highest concentration found among the present non-fatal cases. Likewise, in three fatalities involving MXP,35 the blood concentrations were 3–60-fold higher than those observed in the STRIDA cases. To conclude, information on newly introduced psychoactive drugs, such as the dissociative substances diphenidine and MXP, is often rare and data may originate from a variety of sources such as the Internet, the analysis of seized or Clinical Toxicology Early Online 2015
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Intoxications by diphenidine and MXP 7 Table 2. Psychoactive substances detected along with the new dissociative substances diphenidine or MXP in 17 non-fatal intoxication cases in the STRIDA project. Drugs reported to have been administered during hospital care treatment are not included.
Table 3. Clinical features in 17 analytically confirmed intoxications in the STRIDA project involving diphenidine or MXP, and mostly other drugs also, as documented in medical records or during telephone consultations with the Swedish Poisons Information Centre.
Other psychoactive substance
N
%
Clinical features noted at any time during admission
N
%
5-APB/6-APB (5- or 6-(2-aminopropyl)benzofuran) 4-BMC (4-bromomethcathinone) Butylone Buprenorphine Cannabis 4-CMC (clephedrone, 4-chloromethcathinone) 2C-P (2,5-dimethoxy-4-propylphenethylamine) 3,4-CTMP (3,4-dichloromethylphenidate) Diazepam and/or oxazepam Diclazepam and/or lorazepam Ethylone Ethanol and/or ethanol metabolites Fentanyl Flubromazepam 4F-a-PVP (4-fluoro-a-pyrrolidinopentiophenone) MDPHP (methylenedioxyphentermine) MDPV (methylenedioxypyrovalerone) 5-MeO-NiPT (5-methoxy-N-isopropyltryptamine) 3-MeO-PCP (3-methoxyphencyclidine) 4-MeO-PCP (4-methoxyphencyclidine) Methylphenidate Methiopropamine 2-MMC (2-methylmethcathinone) MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) Nitrazepam a-PBP (a-pyrrolidinobutiophenone) Pentedrone Pentylone Pregabalin a-PVP (a-pyrrolidinopentiophenone) a-PVT (a-pyrrolidinopentiothiophenone) Pyrazolam Temazepam Thiothinone
2 2 2 1 2 1 1 3 1 4 1 6 1 1 1 1 1 2 4 1 1 3 1 1 1 1 1 1 4 1 2 1 1 1
12 12 12 6 12 6 6 18 6 24 6 35 6 6 6 6 6 12 24 6 6 18 6 6 6 6 6 6 24 6 12 6 6 6
Hypertension (systolic blood pressure 140 mmHg) Anxiety Altered mental status (e.g., confusion, disorientation, dissociation, and hallucinations) Agitation Tachycardia ( 100/min) Dilated pupils Nystagmus/abnormal eye movements Muscle rigidity Deep unconsciousness
13 11 11
76 65 65
8 8 6 4 4 3
47 47 35 24 24 18
purchased drug materials,36–38 and single case reports.34 The comprehensive analytical and clinical data from case series of NPS intoxications in the STRIDA project therefore represent valuable added and timely information on the recreational use and health hazards of selected substances, but not on overall prevalence.2,20 For example, the first cases of diphenidine or MXP intoxication in the project appeared in January–February 2014, while diphenidine was first seized in Sweden on April 4, 2014 and MXP on May 12, 2014 (personal communication, J. Rosengren-Holmberg, the Swedish Police). It should be noted that the STRIDA project covers mainly the most severe cases of NPS intoxication, as only patients requiring intensive treatment in an emergency room and hospitalization are included. It is therefore probable that some cases of diphenidine or MXP exposure have been missed, because medical staff do not report minor intoxications to the Poisons Information Centre. In addition, the high proportion of polydrug use made it difficult to identify a unique toxidrome related to diphenidine or MXP, but the majority of patients displayed clinical signs of hypertension, tachycardia, and altered mental status, including hallucinations, confusion, disorientation, and dissociation, features which are consistent with other dissociative substances. Copyright © Informa Healthcare USA, Inc. 2015
Likewise, treatment of intoxications involving diphenidine or MXP included standard supportive therapy and benzodiazepines as the first-line pharmaceutical treatment of clinical features including tachycardia and hypertension.
Declaration of interest The authors report no declarations of interest. This work was supported in part by grants from The Public Health Agency of Sweden (1189/2014).
References 1. Hill SL, Thomas SH. Clinical toxicology of newer recreational drugs. Clin Toxicol (Phila) 2011; 49:705–719. 2. Helander A, Bäckberg M, Hultén P, Al-Saffar Y, Beck O. Detection of new psychoactive substance use among emergency room patients: results from the Swedish STRIDA project. Forensic Sci Int 2014; 243:23–29. 3. EMCDDA. Risk assessments of various psychoactive substances 1999–2014. 2014. http://www.emcdda.europa.eu/publications/searchr esults?action list&type PUBLICATIONS&SERIES_PUB w12 (Accessed on March 2015). 4. Helander A, Bäckberg M, Beck O. MT-45, a new psychoactive substance associated with hearing loss and unconsciousness. Clin Toxicol (Phila) 2014; 52:901–904. 5. Kronstrand R, Thelander G, Lindstedt D, Roman M, Kugelberg FC. Fatal intoxications associated with the designer opioid AH-7921. J Anal Toxicol 2014; 38:599–604. 6. Vorce SP, Knittel JL, Holler JM, Magluilo J Jr., Levine B, Berran P, Bosy TZ. A fatality involving AH-7921. J Anal Toxicol 2014; 38:226–230. 7. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate. Br J Pharmacol 1983; 79:565–575. 8. Berger ML, Schweifer A, Rebernik P, Hammerschmidt F. NMDA receptor affinities of 1,2-diphenylethylamine and 1-(1,2-diphenylethyl)piperidine enantiomers and of related compounds. Bioorg Med Chem 2009; 17:3456–3462. 9. Morris H, Wallach J. From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal 2014; 6:614–632. 10. Wallach J, De Paoli G, Adejare A, Brandt SD. Preparation and analytical characterization of 1-(1-phenylcyclohexyl)piperidine (PCP) and 1-(1-phenylcyclohexyl)pyrrolidine (PCPy) analogues. Drug Test Anal 2014; 6:633–650. 11. Dargan PI, Wood DM. Recreational drug use in the Asia Pacific region: Improvement in our understanding of the problem through the UNODC programmes. J Med Toxicol 2012; 8:295–299.
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8 A. Helander et al. 12. Li G, Baker SP, Zhao Q, Brady JE, Lang BH, Rebok GW, DiMaggio C. Drug violations and aviation accidents: findings from the US mandatory drug testing programs. Addiction 2011; 106:1287–1292. 13. Platteborze PL, Kippenberger DJ, Martin TM. Drug positive rates for the Army, Army Reserve, and Army National Guard from fiscal year 2001 through 2011. Mil Med 2013; 178:1078–1084. 14. Bokor G, Anderson PD. Ketamine: an update on its abuse. J Pharm Pract 2014; 27:582–586. 15. deRoux SJ, Sgarlato A, Marker E. Phencyclidine: a 5-year retrospective review from the New York City Medical Examiner’s Office. J Forensic Sci 2011; 56:656–659. 16. Xu J, Lei H. Ketamine - an update on its clinical uses and abuses. CNS Neurosci Ther 2014; 20:1015–1020. 17. Misselbrook GP, Hamilton EJ. Out with the old, in with the new? Case reports of the clinical features and acute management of two novel designer drugs. Acute Med 2012; 11:157–160. 18. Hofer KE, Degrandi C, Muller DM, Zurrer-Hardi U, Wahl S, Rauber-Luthy C, Ceschi A. Acute toxicity associated with the recreational use of the novel dissociative psychoactive substance methoxphenidine. Clin Toxicol (Phila) 2014; 52:1288–1291. 19. Wallach J, Kavanagh PV, McLaughlin G, Morris N, Power JD, Elliott SP, et al. Preparation and characterization of the ‘research chemical’ diphenidine, its pyrrolidine analogue, and their 2,2-diphenylethyl isomers. Drug Test Anal 2014. doi: 10.1002/dta.1689. 20. Helander A, Beck O, Hägerkvist R, Hultén P. Identification of novel psychoactive drug use in Sweden based on laboratory analysis - initial experiences from the STRIDA project. Scand J Clin Lab Invest 2013; 73:400–406. 21. Persson HE, Sjöberg GK, Haines JA, Pronczuk de Garbino J. Poisoning severity score. Grading of acute poisoning. J Toxicol Clin Toxicol 1998; 36:205–213. 22. Starmark JE, Stålhammar D, Holmgren E, Rosander B. A comparison of the Glasgow Coma Scale and the Reaction Level Scale (RLS85). J Neurosurg 1988; 69:699–706. 23. Bäckberg M, Beck O, Hultén P, Rosengren-Holmberg J, Helander A. Intoxications of the new psychoactive substance 5-(2-aminopropyl) indole (5-IT): a case series from the Swedish STRIDA project. Clin Toxicol (Phila) 2014; 52:618–624. 24. Al-Saffar Y, Stephanson NN, Beck O. Multicomponent LC-MS/MS screening method for detection of new psychoactive drugs, legal highs, in urine-experience from the Swedish population. J Chromatogr B Analyt Technol Biomed Life Sci 2013; 930:112–120. 25. Mannelli P, Janiri L, De Marinis M, Tempesta E. Lefetamine: new abuse of an old drug - clinical evaluation of opioid activity. Drug Alcohol Depend 1989; 24:95–101.
26. Bäckberg M, Lindeman E, Beck O, Helander A. Characteristics of analytically confirmed 3-MMC-related intoxications from the Swedish STRIDA project. Clin Toxicol (Phila) 2015; 53:46–53. 27. Bluelight.org. The Big & Dandy Diphenidine Thread. http://www. bluelight.org/vb/threads/668291-The-Big-amp-Dandy-DiphenidineThread. (Accessed on December 2014). 28. Drugs-Forum.com. Diphenidine (1,2-diphenylethylpiperidine) drug info. https://www.drugs-forum.com/forum/showthread.php?t210615. (Accessed on December 2014). 29. Bluelight.org. The Big & Dandy Methoxphenidine/MXP/2-MeO-Diphenidine Thread. http://www.bluelight.org/vb/threads/700834-TheBig-amp-Dandy-Methoxphenidine-(MXP-2-MeO-Diphenidine)Thread. (Accessed on December 2014). 30. Drugs-Forum.com. Methoxphenidine (2-MeO-diphenidine) Drug Info. https://www.drugs-forum.com/forum/showthread.php?t231278. (Accessed on December 2014). 31. Flashback.org. Diphenidine. https://www.flashback.org/t2254547. (Accessed on December 2014). 32. Flashback.org. Methoxphenidine/MXP/2-MeO-Diphenidine. https:// www.flashback.org/t2266154. (Accessed on December 2014). 33. Wood DM, Davies S, Puchnarewicz M, Johnston A, Dargan PI. Acute toxicity associated with the recreational use of the ketamine derivative methoxetamine. Eur J Clin Pharmacol 2012; 68:853–856. 34. Hasegawa K, Wurita A, Minakata K, Gonmori K, Nozawa H, Yamagishi I, et al. Postmortem distribution of AB-CHMINACA, 5-fluoro-AMB, and diphenidine in body fluids and solid tissues in a fatal poisoning case: usefulness of adipose tissue for detection of the drugs in unchanged forms. Forensic Toxicol 2014. doi: 10.1007/ s11419-014-0245-6. 35. Elliott S, Brandt SD, Wallach J, Morris H, Kavanagh PV. First reported fatalities associated with the ‘research chemical’ 2-methoxydiphenidine. J Anal Toxicol 2015. doi: 10.1093/jat/bkv006. 36. Uchiyama N, Shimokawa Y, Kawamura M, Kikura-Hanajiri R, Hakamatsuka T. Chemical analysis of a benzofuran derivative, 2-(2ethylaminopropyl)benzofuran (2-EAPB), eight synthetic cannabinoids, five cathinone derivatives, and five other designer drugs newly detected in illegal products. Forensic Toxicol 2014; 32:266–281. 37. Wurita A, Hasegawa K, Minakata K, Watanabe K, Suzuki O. A large amount of new designer drug diphenidine coexisting with a synthetic cannabinoid 5-fluoro-AB-PINACA found in a dubious herbal product. Forensic Toxicol 2014; 32:331–337. 38. Strano Rossi S, Odoardi S, Gregori A, Peluso G, Ripani L, Ortar G, et al. An analytical approach to the forensic identification of different classes of new psychoactive substances (NPSs) in seized materials. Rapid Commun Mass Spectrom 2014; 28:1904–1916.
Clinical Toxicology Early Online 2015
ORIGINAL ARTICLE
Intoxications by the dissociative new psychoactive substances diphenidine and methoxphenidine Anders Helander,1,2 Olof Beck,1,2 and Matilda Bäckberg3 1Department
of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden of Clinical Pharmacology, Karolinska University Laboratory, Stockholm, Sweden 3Swedish Poisons Information Centre, Stockholm, Sweden
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2Department
Background. Diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) are substances with dissociative effects that were recently introduced for “recreational” purpose through the online-based sale of new psychoactive substances (NPS). A number of analytically confirmed non-fatal intoxications associated with diphenidine or MXP have occurred in Sweden and were included in the STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS and requiring intensive treatment in an emergency room and hospitalization in Sweden. Patients and methods. Blood and urine samples were collected from intoxicated patients presenting at emergency departments all over the country. NPS analysis was performed by multi-component liquid chromatography–mass spectrometry methods. Data on clinical features were collected during telephone consultations with the Poisons Information Centre and retrieved from medical records. Information was also obtained from online drug discussion forums. Case series. Over a 12-month period from January to December 2014, 750 cases of suspected NPS intoxication originating from emergency departments were enrolled in the STRIDA project of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) tested positive for MXP. Co-exposure to several other NPS (e.g., 5-/6-(2-aminopropyl)benzofuran, 2-4-bromomethcathinone, butylone, 3,4-dichloromethylphenidate, 5-methoxy-N-isopropyltryptamine, methiopropamine, and a-pyrrolidinopentiothiophenone), also including other dissociative substances (3-/4-methoxyphencyclidine), and classical drugs of abuse (e.g., cannabis and ethanol) was documented in 87% of these cases. The 17 patients were aged 20–48 (median: 32) years, and 13 (76%) were men. They commonly presented with hypertension (76%), tachycardia (47%), anxiety (65%), and altered mental status (65%) including confusion, disorientation, dissociation, and/or hallucinations. Eight patients (47%) displayed severe intoxication (Poisoning Severity Score 3). The diphenidine- or MXP-positive patients required hospitalization for 1–3 (median: 2) days. In addition to standard supportive therapy, half of the cases were treated with benzodiazepines and/or propofol. Conclusion. The adverse effects noted in analytically confirmed cases of NPS intoxication involving diphenidine or MXP were similar to those reported for other dissociative substances such as ketamine and methoxetamine. However, the high proportion of polysubstance use might have played a role in the intoxication and clinical features in some cases. Keywords Diphenidine; Dissociative drugs; LC–MS; Legal highs; Methoxphenidine; New psychoactive substance; NMDA receptor antagonist; Research chemicals; Severe adverse events; STRIDA project
NPS detected in Europe, according to notifications from the EU Early Warning System operated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and Europol, remained at a relatively stable level of around 10 novel substances per year. Since then, partly in response to legal actions undertaken to regulate individual NPS,2 there has been a steady increase from 24 new substances in 2009 to 101 in 2014.3 Accordingly, each week on average 2 new substances are currently introduced in the European recreational drugs market. In addition to the structurally modified NPS variants (“designer drugs”) that replace the banned ones, there is also an increasing diversity of new and potentially hazardous substances, as other classes of psychoactive substances such as designer benzodiazepines and opioids have started to appear. For example, the NPS opioids MT-45 and AH-7921 have recently been associated with severe adverse responses
Background In the past decade, there has been a dramatic increase in the panel of psychoactive substances used for “recreational” purpose. Besides the classical set of stimulant, sedative, and hallucinogenic drugs of abuse, such as amphetamines, cannabis, cocaine, opiates, and lysergic acid diethylamide, a large number of new psychoactive substances (NPS) mainly of synthetic origin are openly sold by online-based vendors as unregulated drug alternatives (e.g., “legal highs” and “research chemicals”).1,2 Until 2008, the official number of Received 13 January 2015; accepted 20 March 2015. Address correspondence to Prof. Anders Helander, C1:74, Clinical Chemistry, Karolinska University Laboratory Huddinge, SE-141 86 Stockholm, Sweden. Tel: 46 70 4841888. E-mail: anders.helander@ ki.se
1
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2 A. Helander et al. and fatalities.4–6 In addition, designed dissociative anesthetic substances with comparable activity to phencyclidine (PCP), ketamine, methoxetamine (MXE), and dextromethorphan, acting by N-methyl-D-aspartate (NMDA) receptor antagonism, have emerged on the recreational drugs market and are used for their mind-altering effects.7–10 The interest among drug users for this type of compounds has been documented for PCP and ketamine, albeit at a relatively low prevalence,11–13 and also many cases of serious toxicity.14–16 The substituted PCP analogs 3- and 4-methoxyphencyclidine (3- and 4-MeO-PCP) were among the first designer dissociatives introduced as NPS.10,17 More recently, two structurally different dissociative substances, the diarylethylamines diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) (Fig. 1), have been introduced.18,19 Diphenidine and MXP are known from the scientific and patent literature, diphenidine since 1924 and MXP since 1989.9 However, despite documented central nervous system (CNS) effects and resemblance with already controlled substances, neither diphenidine nor MXP are classified drugs in Sweden and both were still available on several websites in February 2015. This report presents laboratory results and clinical characteristics in a case series of analytically confirmed non-fatal intoxications involving diphenidine or MXP in the Swedish STRIDA project.
Methods STRIDA is a collaborative project between the Karolinska University Laboratory, the Karolinska Institutet, and the Swedish Poisons Information Centre that monitors the occurrence and health hazards of newly emerging drugs of abuse in Sweden. Results of blood and urine drug testing are compared with the associated clinical features, among cases of acute NPS intoxication presenting at emergency departments or intensive care units in hospitals all over the country.2,20 The project is conducted in accordance with the Declaration of Helsinki and has been approved by the regional ethical review board (Nr. 2013/116–31/2).
N
N O
Diphenidine
Methoxphenidine (MXP)
N N
N
Lefetamine
MT-45
Fig. 1. Chemical structures of the dissociative NPS diphenidine (1-(1,2-diphenylethyl) piperidine) and its 2-methoxylated derivative MXP (2-MeO-diphenidine). Two structurally similar but pharmacologically rather distinct substances, the stimulant analgesic lefetamine and the opioid-like MT-45, are also shown.
Clinical data related to the intoxications are collected in a standardized way when medical staff consult the Poisons Information Centre (a national 24/7 service to clinicians and the public) by telephone and later retrieved from medical records. The cases were graded retrospectively using the Poisoning Severity Score (PSS).21 The level of consciousness was documented using the Glasgow Coma Scale (GCS) or the Reaction Level Scale (RLS).22 Blood and urine samples are collected as soon as possible after admission and forwarded to the Karolinska University Laboratory for analysis of NPS and classical drugs of abuse, as detailed elsewhere.2,20 Identification and quantification of NPS in urine and serum samples are performed by flexible multi-component liquid chromatography–tandem mass spectrometry (LC–MS/MS) and LC–high-resolution MS (LC–HRMS) methods that are updated with new substances as they appear and reference material becomes available.23,24 For diphenidine and MXP (parent drugs), retrospective reanalysis of samples was sometimes necessary. Reference material of diphenidine was obtained from LGC Standards (Teddington, UK) and of MXP from Cayman Chemical (Ann Arbor, MI, USA). The measuring range of both compounds was 1–10000 ng/mL in urine and 1–500 ng/mL in serum, with detection limits 0.2 ng/mL.
Results Poisons information statistics on diphenidine and MXP During the 12-month study period from January to December 2014, 1580 consultations regarding suspected intoxications by NPS were registered at the Swedish Poisons Information Centre. The first inquiry related to a suspected MXP intoxication occurred in January 8, 2014, and for diphenidine in February 14, 2014. In total, there were 4 cases related to MXP as the suspected intoxication substance during the study period, compared with 23 on diphenidine. In 17 of the 27 (63%) inquiries related to cases of suspected diphenidine or MXP exposure, samples were collected for analytical confirmation within the STRIDA project. Laboratory data on diphenidine and MXP During the 12-month study period, 750 cases of suspected NPS intoxication originating from all over the country were enrolled in the project (i.e., both biological samples and clinical data were available), of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) for MXP (Table 1). However, they were never seen in combination. In most cases (71%), the analytical findings of diphenidine or MXP were consistent with information from self-report or clinical suspicion (Table 1). The 17 diphenidine- or MXP-positive patients were aged 20–48 (mean: 31.8, median: 32) years and 13 (76%) were men. The diphenidine concentration in serum ranged between 2 and 262 (mean: 88.4, median: 69.5) ng/mL and in urine between 8 and 19000 (mean: 2213, median: 621) ng/mL. When the urine concentration was normalized to the creatinine concentration, to compensate for urine dilution, the Clinical Toxicology Early Online 2015
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Intoxications by diphenidine and MXP 3 diphenidine-to-creatinine ratio ranged between 1.2 and 1158 (mean: 247, median: 125) µg/mmol (Table 1). The corresponding results for the three MXP-positive cases were 187 and 409 ng/mL (case no. 17 tested negative) in serum, and 3–8367 (median: 610) ng/mL in urine (0.3–346 µg/mmol of creatinine, median: 59.2), respectively. Sampling was typically done within a few hours of admission to the emergency department (Table 1). However, in one case (no. 2 in Table 1) that was not sampled until 24 h after admission, diphenidine was still detectable in both serum and urine. Examples of the analytical results by LC–HRMS are shown in Fig. 2. Co-exposure to other NPS and/or classical drugs of abuse was common and confirmed in all but two of the diphenidine- and in all MXP-positive patients (i.e., in 88% of all cases). Except for usual drugs given during intensive hospital care treatment (e.g., benzodiazepines), 34 other psychoactive substances or metabolites were identified in blood and/or urine, also other dissociatives (i.e., 3-/4-MeOPCP) (Table 2). The most common other substances were ethanol (including conjugated ethanol metabolites), 3,4dichloromethylphenidate (3,4-CTMP), diclazepam/lorazepam (lorazepam is available as a drug at its own but is also a metabolite of diclazepam), 3-MeO-PCP, and pregabalin, which were each found in 18–35% of the cases (Table 2). Four patients (cases no. 3, 7, 13, and 14 in Table 1) brought zip-locked transparent plastic bags containing an off-white powder (3 were labeled “diphenidine”) to the hospital and handed it over to the medical staff. The products were demonstrated by LC–MS/MS and nuclear magnetic resonance (NMR) analysis (results not shown) to contain diphenidine, with no other psychoactive substance identified (personal communication, K-H. Jönsson, Swedish Medical Products Agency). Clinical features in diphenidine- or MXP-positive cases The patients testing positive for diphenidine or MXP, albeit in most cases also for other NPS and/or classical drugs (Table 1), commonly presented with adverse symptoms such as hypertension (systolic blood pressure 140 mmHg; 76%), tachycardia ( 100/min; 47%), anxiety (65%), and agitation (47%), and less frequently ( 35%) with nystagmus, dilated pupils, and muscle rigidity (Table 3). In 65% of cases, an altered mental status was also registered, which included signs such as an altered level of consciousness (graded by the GCS or RLS), hallucinations, confusion, disorientation, and dissociation. Three patients (20%; cases no. 11, 14, and 15 in Table 1) were deeply unconscious (GCS 3 or RLS 8) during transport or on admission to hospital. They all tested positive for several drugs besides diphenidine or MXP (Table 1). One responded to flumazenil, in accordance to a self-reported intake of the novel benzodiazepine diclazepam, while the other two woke up spontaneously. Upon awakening, two patients became agitated, one with elements of hallucinations and the other with painful muscle spasms, whereas the third patient had signs of confusion, disorientation, and horizontal and/or vertical nystagmus. Two patients showed Copyright © Informa Healthcare USA, Inc. 2015
a prolonged activated partial thromboplastin time (APTT; 180 s, reference interval: 30–45 s), but there were no signs of bleeding and their APTT decreased spontaneously. Besides observation and standard supportive therapy, pharmacological sedative treatment was used in 7 cases; benzodiazepines (diazepam and/or midazolam) were administered in 6 cases, and in 5 cases there was also a need for propofol treatment. Haloperidol was given in one case. The time in hospital treatment ranged between 1 and 3 (mean: 1.6, median: 2.0) days (Table 1), and there was an overall good agreement between the hospital care days and PSS (P 0.004; rank correlation). In half of the 12 intoxications involving diphenidine, it was the only suspected drug mentioned during consultations with the Poisons Information Centre. However, based on the results of blood and urine drug testing, only two cases (no. 4 and 12 in Table 1) were indicated to be pure diphenidine intoxications, one graded as a mild (PSS 1) and one, which was a suicide attempt, as a severe (PSS 3) intoxication. Of the 6 cases of diphenidine or MXP intoxication for which the clinical features were graded as severe (PSS 3), all but one were polyintoxications with other NPS and/or classical drugs (Table 1). According to self-reported routes of drug administration, oral, nasal, rectal, and intravenous exposures were used (Table 1).
Discussion The huge growth in type and number of NPS made available through online-based drug sale over the past 6 years represents a new health threat to society. When new substances are introduced for use as recreational drugs, there is usually only limited information on their metabolism, clinical signs and symptoms, and acute and chronic toxicity. Despite close structural similarities to well-known drugs of abuse or prescribed drugs, the pharmacological actions of seemingly related substances might diverge. Examples of this are the diarylethylamine dissociative substances diphenidine and MXP, which showed comparable activity to arylcyclohexylamine dissociative anesthetic substances such as PCP, ketamine, and MXE,9 albeit being structurally more similar to lefetamine, a stimulant with analgesic effect,25 and to the opioid-like MT-45 (Fig. 1).4 Another common phenomenon that was noted in this and previous studies is that NPS users frequently combine different types of drugs.2,4,23,26 This may result in unpredicted, serious interactions, and often makes it difficult to relate clinical signs and symptoms to a specific substance and hence assessing its unique toxicity. The interest in diphenidine and MXP as recreational drugs started soon after a UK arylcyclohexylamine ban covering, for example, 3- and 4-MeO-PCP that came into effect at the end of February 2013.9 Already in March 2013, diphenidine and MXP were introduced by NPS sale through the Internet as legal replacements of the classified dissociatives. At the same time, online drug discussion forums started threads on diphenidine,27,28 and later (November 2013) also on MXP.29,30 Threads on diphenidine and MXP on a Swedish drug chat
Reported or suspected NPS
F/27
M/32
M/37
M/36
M/25
M/47
M/39
M/27
3
4
5
6
7
8
9
10
F/33
M/29
2
11
M/20
1
a-PVP, a-PVT
bk-2C-B, 4-BMC, 2C-P, 3,4-CTMP, EFLEA, meclonazepam, 5-MeONiPT, THJ-018
Diphenidine
Diphenidine
Diphenidine
Diphenidine, benzofurans, PCP analog, Psilocybe mushrooms
Diphenidine, PCP analog, Psilocybe mushrooms
Diphenidine, diclazepam Diphenidine
Diphenidine
Diphenidine
Diphenidine-positive cases
Case no Sex/Years
–
–
–
–
50 mg
100 mg
–
– “Powder”
200–250 mg 450 mg
–
Reported dose
rec and/or iv
–
nas
nas
po
–
–
po
po
iv
po
ROA
3.5 h
30 min
30 min
2.5 h
45 min
1h
1h
1h
“Promptly”
24 h
1h
81
6
52
233
51
18
105
134
2
9
119
538
0.5
108
125
28.0
196
436
41.2
1.2
1.6
26.7
Sampling Diphenidine/ Diphenidine/ time MXP in MXP in urine (after admis- serum (ng/ (ng/mmol sion) mL) creatinine)
Ketamine, dexmedetomidine, midazolam, propofol, remifentanil, diazepam
Diazepam
Diazepam
Observation
Observation
Diazepam, propofol
Diazepam, propofol
Observation
Observation
Observation
Observation
Treatment
Initially unconsciousness (RLS 8), dissociation, frothing from mouth, followed by increased level of consciousness, agitation, occasional painful muscle spasms
Disorientation, tachycardia, hypertension, dilated pupils (GCS 14) Hypertension, anxiety (RLS 1) Visual hallucinations, nystagmus, diaphoresis
Agitated delirium, muscle rigidity, followed by myoclonus, hyperreflexia. Horizontal nystagmus, tachycardia, hypertension, urinary retention Tachycardia, hypertension (RLS 1)
Anxiety, reduced level of mental receptiveness (RLS 1) Agitated delirium, muscle rigidity, tachycardia, hypertension, urinary retention (RLS 2–4)
Dilated pupils, hypertension (RLS 1) Tachycardia, hypertension (RLS 1) Tachycardia
3
1
1
1*
1
2
2
1
1
2
1*
5-MeO-NiPT, a-PVP, a-PVT (ketamine, 4-hydroxymidazolam)
3
2
1
a-PVT 4-BMC, cannabis, 2C-P, 3,4-CTMP, 5-MeONiPT, 3-MeO-PCP, methiopropamine, 2-MMC, pregabalin (desmethyldiazepam)
2
1
3
3
1
1
2
1
Diclazepam, ethanol, ethanol metabolites, lorazepam Pregabalin
5-APB/6-APB, buprenorphine, butylone, ethanol metabolites, 3-MeO-PCP (oxazepam, temazepam) 5-APB/6-APB, butylone, ethanol metabolites, 3-MeOPCP
Ethanol metabolites, flubromazepam, Methylphenidate/ ritalinic acid Lorazepam, pyrazolam
Other substances Hospital detected in urine and/ Main clinical features (RLS care or blood (intensive care or GCS) days related) PSS
Table 1. Laboratory and clinical data of 17 analytically confirmed cases of diphenidine or MXP intoxication in the STRIDA project.
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4 A. Helander et al.
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Copyright © Informa Healthcare USA, Inc. 2015
M/22
M/27
13
14
Synthetic cannabinoids
3,4-CTMP
Diphenidine
Reported or suspected NPS
_
_
–
Reported dose
_
_
iv
ROA
F/48
17
PCP
MXP, diclazepam, 3,4-CTMP
–
–
–
–
“Promptly”
1h
1.5 h
2h
1.5 h
2 h (serum)/ ”Promptly” (urine)
ND
409
187
262
108
58
0.3
343
59.2
1158
386
621
Observation
Naloxone, flumazenil, propofol
Observation
Midazolam, propofol
Oxygen supply diazepam, propofol
Diazepam, propofol, haloperidol
Sampling Diphenidine/ Diphenidine/ time MXP in MXP in urine (after admis- serum (ng/ (ng/mmol sion) mL) creatinine) Treatment
Unconsciousness (GCS 8), dilated pupils on arrival. Flumazenil iv resulted in agitation and hallucinations Unconsciousness (GCS 3), muscle rigidity, jaw clenching, hypertension on arrival followed by increasing level of consciousness, confusion, disorientation, horizontal and vertical nystagmus
Hypertension, anxiety (RLS 1)
Agitation (GCS 7), dilated pupils, hyperthermia (39°C), diaphoresis, aspiration, tachycardia, hypertension
Agitation, dissociation, frothing from mouth, hypertension, tachycardia, anxiety Muscle rigidity, disorientation, anxiety, dilated pupils, tachycardia, hypertension
2
2
2
2
1
3
3-MeO-PCP, 4-MeOPCP, MT-45, oxazepam, temazepam
7-Aminonitrazepam, cannabis, lorazepam, methiopropamine, a-PBP, pentylone, pregabalin 3,4-CTMP, lorazepam, methiopropamine, thiothinone
4-BMC, 4-CMC, MDPHP, ethylone, MDPV, pregabalin, fentanyl, ethanol metabolites
3,4-CTMP, pentedrone, 4F-a-PVP, ethanol
(Desmethyldiazepam)
3
3
1
3
3
3
Other substances Hospital detected in urine and/ Main clinical features (RLS care or blood (intensive care or GCS) days related) PSS
nas, nasal (snorted); po, peroral; rec, rectal; ethanol metabolites, ethyl glucuronide and ethyl sulfate; –, information or sample missing; ND, not detected ( detection limit). *Patient absconded from hospital.
Data are consecutive STRIDA cases collected from January to December 2014. ROA, route of administration; RLS, Reaction Level Scale; GCS, Glasgow Coma Scale; PSS, Poisoning Severity Score; iv, intravenous;
M/33
16
Methoxphenidine (MXP)-positive cases 15 M/25 MXP, nitrazepam 3 100 nas mg 500 iv mg
F/33
12
Case no Sex/Years
Table 1. (Continued)
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Intoxications by diphenidine and MXP 5
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6 A. Helander et al.
Fig. 2. Chromatograms from the LC–HRMS analysis of non-fatal cases of NPS intoxication in the STRIDA project, one case testing positive for diphenidine (case no. 12 in Table 1) in serum (A; 58 ng/mL) and urine (B; 610 ng/mL), and one for MXP (case no. 14 in Table 1) in serum (C; 409 ng/mL) and urine (D; 8367 ng/mL). Results were obtained using a Thermo Fisher Scientific Q Exactive MS equipped with a Dionex 200 LC system. The theoretical exact mass is 266.19033 for the diphenidine ion and 296.20089 for the MXP ion. The instrument was operated at 70000 resolution (m/z 200) and mass chromatograms were extracted with a 5-ppm tolerance. The retention time difference to reference was 0.00–0.02 min and the mass difference was 0.03–1.26 ppm.
forum both appeared in November 2013.31,32 Diphenidine and MXP are presently subject to classification investigation by the Public Health Agency of Sweden. However, it should be noted that because 3- and 4-MeO-PCP were not classified in Sweden until January 2015, they could be continuously used during the study period, as was demonstrated in some of the STRIDA cases. According to user experiences posted on the drug forums,27–32 diphenidine and MXP are typically taken orally (“bombed”) in ∼50–150 mg doses, although occasional intake of up to 600 mg totally in successive doses was also reported. Nasal (∼15–300 mg), rectal (20 mg), and intravenous routes of administration, and more lately, smoking and inhalation of vaporized diphenidine at lower dosage, have also been used. This information is consistent with the self-report data obtained in the STRIDA cases, both regarding drug dosage (i.e., up to several hundred milligrams in single or consecutive doses) and routes of administration, with oral, nasal, and intravenous administration being about as usual. In the drug forums, the psychoactive and clinical effects of diphenidine and MXP were reported to be mild-to-moderate for oral doses of up to ∼100 mg, but with an apparent steep dose–response curve at higher doses sometimes causing strong dissociative and even adverse effects.27–32 Furthermore, the onset of full effects was usually reported to be delayed ( 1 h), implying risk for overdosing, and the duration of action was ∼3–7 h. Diphenidine and MXP have been reported to act similar to the arylcyclohexylamine dissociative drugs ketamine, MXE, and 3-MeO-PCP,7,9,10,33 both regarding desired psychoactive and undesired adverse effects,27–32 as well as NMDA recep-
tor antagonism.8,19 The undesired clinical features noted in the STRIDA case series of non-fatal acute intoxications by diphenidine or MXP, including hypertension, nystagmus, and urinary retention, were consistent with previously published information and self-reported experiences mentioned in online drug user reports.7–10,27–33 The signs and symptoms usually resolved with symptomatic treatment, but benzodiazepines were sometimes administered for treatment of tachycardia and hypertension and for sedation. In cases of NPS intoxications, a prolonged APTT is occasionally noted in the medical records and mentioned during consultation with the Poisons Information Centre. In this case series, a prolonged APTT was noted twice, but whether APTT was also measured in the other cases is not known. A possible association between NPS products and APTT prolongation should be further investigated. Most patients were discharged from hospital after 1–2 days, despite variable and sometimes high substance concentrations in blood and urine. For comparison, in a published fatal case where diphenidine was judged to have played a major role,34 although synthetic cannabinoids were also involved, the diphenidine concentration in blood was ∼3fold higher than the highest concentration found among the present non-fatal cases. Likewise, in three fatalities involving MXP,35 the blood concentrations were 3–60-fold higher than those observed in the STRIDA cases. To conclude, information on newly introduced psychoactive drugs, such as the dissociative substances diphenidine and MXP, is often rare and data may originate from a variety of sources such as the Internet, the analysis of seized or Clinical Toxicology Early Online 2015
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Intoxications by diphenidine and MXP 7 Table 2. Psychoactive substances detected along with the new dissociative substances diphenidine or MXP in 17 non-fatal intoxication cases in the STRIDA project. Drugs reported to have been administered during hospital care treatment are not included.
Table 3. Clinical features in 17 analytically confirmed intoxications in the STRIDA project involving diphenidine or MXP, and mostly other drugs also, as documented in medical records or during telephone consultations with the Swedish Poisons Information Centre.
Other psychoactive substance
N
%
Clinical features noted at any time during admission
N
%
5-APB/6-APB (5- or 6-(2-aminopropyl)benzofuran) 4-BMC (4-bromomethcathinone) Butylone Buprenorphine Cannabis 4-CMC (clephedrone, 4-chloromethcathinone) 2C-P (2,5-dimethoxy-4-propylphenethylamine) 3,4-CTMP (3,4-dichloromethylphenidate) Diazepam and/or oxazepam Diclazepam and/or lorazepam Ethylone Ethanol and/or ethanol metabolites Fentanyl Flubromazepam 4F-a-PVP (4-fluoro-a-pyrrolidinopentiophenone) MDPHP (methylenedioxyphentermine) MDPV (methylenedioxypyrovalerone) 5-MeO-NiPT (5-methoxy-N-isopropyltryptamine) 3-MeO-PCP (3-methoxyphencyclidine) 4-MeO-PCP (4-methoxyphencyclidine) Methylphenidate Methiopropamine 2-MMC (2-methylmethcathinone) MT-45 (1-cyclohexyl-4-(1,2-diphenylethyl)piperazine) Nitrazepam a-PBP (a-pyrrolidinobutiophenone) Pentedrone Pentylone Pregabalin a-PVP (a-pyrrolidinopentiophenone) a-PVT (a-pyrrolidinopentiothiophenone) Pyrazolam Temazepam Thiothinone
2 2 2 1 2 1 1 3 1 4 1 6 1 1 1 1 1 2 4 1 1 3 1 1 1 1 1 1 4 1 2 1 1 1
12 12 12 6 12 6 6 18 6 24 6 35 6 6 6 6 6 12 24 6 6 18 6 6 6 6 6 6 24 6 12 6 6 6
Hypertension (systolic blood pressure 140 mmHg) Anxiety Altered mental status (e.g., confusion, disorientation, dissociation, and hallucinations) Agitation Tachycardia ( 100/min) Dilated pupils Nystagmus/abnormal eye movements Muscle rigidity Deep unconsciousness
13 11 11
76 65 65
8 8 6 4 4 3
47 47 35 24 24 18
purchased drug materials,36–38 and single case reports.34 The comprehensive analytical and clinical data from case series of NPS intoxications in the STRIDA project therefore represent valuable added and timely information on the recreational use and health hazards of selected substances, but not on overall prevalence.2,20 For example, the first cases of diphenidine or MXP intoxication in the project appeared in January–February 2014, while diphenidine was first seized in Sweden on April 4, 2014 and MXP on May 12, 2014 (personal communication, J. Rosengren-Holmberg, the Swedish Police). It should be noted that the STRIDA project covers mainly the most severe cases of NPS intoxication, as only patients requiring intensive treatment in an emergency room and hospitalization are included. It is therefore probable that some cases of diphenidine or MXP exposure have been missed, because medical staff do not report minor intoxications to the Poisons Information Centre. In addition, the high proportion of polydrug use made it difficult to identify a unique toxidrome related to diphenidine or MXP, but the majority of patients displayed clinical signs of hypertension, tachycardia, and altered mental status, including hallucinations, confusion, disorientation, and dissociation, features which are consistent with other dissociative substances. Copyright © Informa Healthcare USA, Inc. 2015
Likewise, treatment of intoxications involving diphenidine or MXP included standard supportive therapy and benzodiazepines as the first-line pharmaceutical treatment of clinical features including tachycardia and hypertension.
Declaration of interest The authors report no declarations of interest. This work was supported in part by grants from The Public Health Agency of Sweden (1189/2014).
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