Eur J Clin Pharmacol

DOI 10.1007/s00228-011-1142-0

PHARMACODYNAMICS

A case series of individuals with analytically confirmed acute

diphenyl-2-pyrrolidinemethanol (D2PM) toxicity
David M. Wood & Malgorzata Puchnarewicz &
Atholl Johnston & Paul I. Dargan

Received: 23 August 2011 / Accepted: 5 October 2011

# Springer-Verlag 2011

Abstract
Purpose There is increasing interest in the use of pipradrol
and pipradrol derivatives, such as diphenylproplinol
[diphenyl-2-pyrrolidinemethanol (D2PM)] and desoxypipradrol [2-diphenylmethylpiperidine (2-DPMP)], as recreational drugs. There is limited information on the acute
toxicity related to both D2PM and 2-DPMP. We report here
a case series of five individuals with acute toxicity related
to the use of D2PM.
Case series Five patients aged between 21 and 33 years old
presented to the Emergency Department (ED) on unrelated
occasions having used a range of different novel psychoactive substances; none had actually purchased D2PM.
D. M. Wood : P. I. Dargan
Clinical Toxicology, Guys and St Thomas NHS Foundation
Trust and Kings Health Partners,
London, UK
D. M. Wood : P. I. Dargan
Kings College London,
London, UK
M. Puchnarewicz
Analytical Services International Ltd,
St Georges University of London,
London, UK
A. Johnston
Barts and The London School of Medicine and DentistryQueen
Mary University of London,
London, UK
D. M. Wood (*)
Medical Toxicology Office, Guys Hospital, 2nd Floor,
Bermondsey Wing,
Great Maze Pond,
London SE1 9RT, UK
e-mail: David.Wood@gstt.nhs.uk

They presented with ongoing prolonged neuropsychiatric

symptoms of agitation, anxiety and insomnia lasting 2496 h
post-ingestion. None had evidence of sympathomimetic
toxicity on presentation to the ED. All were reassured and
discharged home after review.
Toxicological screening Urine collection at the time of
presentation to the ED was subsequently analysed by
gas chromatographymass spectrometry (GC-MS). All
of the urine samples tested positive for D2PM and
benzophenone. Additional screening by liquid chromatography tandem massspectrometry (LC-MS-MS) demonstrated that the benzophenone detected was an
analytical artefact due to the high-injection temperature
of the GC-MS analysis.
Conclusions This descriptive case series provides more
detailed information on the acute toxicity related to the
use of D2PM. This information is useful for clinical
pharmacologists and clinicians managing these individuals to be able to provide more appropriate advice on
the acute toxicity associated with the use of D2PM,
particularly in relation to the prolonged neuropsychiatric
symptoms seen.
Keywords Diphenylprolinol . Diphenyl-2pyrrolidinemethanol . Recreational drugs . Toxicological
screening . Acute toxicity

Introduction
Compounds known as novel psychoactive substances or
legal highs are increasingly being used as recreational
drugs across Europe [1]. Typically these compounds are
structurally very similar to classical controlled recreational
drugs [2]. The pattern of acute toxicity associated with

Eur J Clin Pharmacol

these drugs is often similar to that seen with classical

recreational drugs [3]. For example, the novel psychoactive
substance 4-methylmethcathinone (mephedrone), which
was increasingly used during 2009/2010, has a pattern of
acute harm similar to that of amphetamines and other
sympathomimetic recreational drugs [4, 5].
These novel psychoactive substances can be purchased from a variety of Internet-based suppliers for
shipment to countries within Europe. They are often
being supplied from an area or country where they are
not controlled and shipped to a European country where
they are controlled [6, 7]. A number of studies analysing
the contents of novel psychoactive substances purchased
from different Internet sites have shown that the stated
content(s) of novel psychoactive substances on the
packaging/Internet site is often not as described, and there
is variation in contents over time [68]. There have been
numerous reports of individuals presenting to the Emergency Department (ED) with acute toxicity following use
of one or more classical recreational drugs [such as 3,4methylenedioxymethamphetamine (MDMA) or amphetamine], but where subsequent toxicological screening of
biological samples has demonstrated that the individual
has been sold a novel psychoactive substance instead of
the classical recreational drug that they intended to use [3,
5, 911]. Therefore, before ascribing the toxicity seen in a
patient presenting with acute recreational drug toxicity to
a particular drug based on the self-reported agent ingested,
it is importantfrom a research and epidemiological
perspectivethat analytical screening of biological samples
is undertaken to determine the actual drug(s) responsible for
the toxicity.
When there is evidence of use and acute and/or
chronic toxicity associated with the use of a novel
psychoactive substance, the legal classification of the
compound/class of compounds may be considered on a
national or international level [1216]. However, this
requires that there to be sufficient evidence to confirm
which drug(s) was being used and that there are significant
adverse consequences related to its use. There is a one
reported case of acute harm associated with the use of the
pipradrol drug diphenylproplinol [diphenyl-2-pyrrolidinemethanol (D2PM)] in an individual who presented with
acute onset of agitation and chest pain [9]. However, there
has been no further published information regarding the
acute toxicity related to the use of D2PM, and only limited
information is available on the toxicity of the structurally
related compound desoxypipradrol [2-diphenylmethylpiperidine (2-DPMP)] [17, 18]. We describe here five
additional cases of acute toxicity related to the recreational
use of D2PM, which helps to provide more evidence of
the significant acute toxicity related to the use of this
compound.

Case series
Case one
A 33-year-old male with underlying human immunodeficiency virus (HIV) and hepatitis B infection reported taking
eight capsules of Benzofury over a 6-h period. Initially he
developed a rush which lasted less than 1 h. He described
this as being similar to that which he had experienced using
mephedrone (4-methylmethcathinone). He had no chest
pain, palpitations, fever, headache or seizures. He did,
however, develop anxiety and paranoia, and presented to
the ED 48 h after use due to ongoing feelings of paranoia.
On examination at the time of presentation he had dilated
pupils but no other clinical features of sympathomimetic
toxicity [heart rate 63 bpm, blood pressure (BP) 154/90
mmHg, temperature 36.0C, neurological examination
normal). There was no indication for any specific treatment
on review, and therefore he was reassured that his
symptoms would settle and he was discharged home.
Case two
A 21-year-old male with no significant past medical history
took one capsule of an unknown stimulant. Initially he
developed a high, which was associated with a racing
heart, nausea and vomiting. The latter symptoms settled,
but he developed insomnia and anxiety and presented to the
ED approximately 48 h post-ingestion with ongoing
insomnia and anxiety. On examination at the time of
presentation, he had dilated pupils but no other clinical
features of sympathomimetic toxicity (heart rate 92 bpm,
BP 128/87 mmHg, temperature 36.9C, neurological
examination normal). He was treated with 5 mg of
diazepam orally; after a short period of observation he
was reassured and discharged home.
Case three
A 29-year-old male with no significant past medical history
snorted a total of 1 g of NRG3 and a swallowed a small
amount of what he believed to be MDMA powder;
approximately 34 h after use he developed a heaviness
in his limbs, but no features of acute sympathomimetic
toxicity. He presented to the ED approximately 60 h postuse, with prolonged and ongoing insomnia. He had selfmedicated 24 h previously with an over-the-counter
diphenhydramine-based sleeping medication (Nytol;
GlaxoSmithKline, London, UK), which he felt was of no
benefit. On examination at the time of presentation, he had
dilated pupils but no other clinical features of sympathomimetic toxicity (heart rate 80 bpm, BP 138/82 mmHg,
temperature 36.5C, neurological examination normal). There

Eur J Clin Pharmacol

was no indication for any specific treatment on review and,

therefore, he was reassured that his symptoms would settle
and he was discharged home.
Case four
A 25-year-old male with no significant past medical history
admitted to ingesting an unknown liquid whilst out
clubbing. He collapsed whilst out, which was thought to
be secondary ingestion of gamma-hydroxybutyrate (GHB)
or gamma-butyrolactone (GBL) in the liquid, which was
managed in the pre-hospital setting. However, he developed
anxiety and insomnia, which persisted for over 96 h,
leading to his presentation to the ED. He had selfmedicated with an over-the-counter diphenhydraminebased sleeping medication (Nytol). On examination at the
time of presentation he had dilated pupils but no other
clinical features of sympathomimetic toxicity (heart rate 98
bpm, BP 134/98 mmHg, temperature 36.4C, neurological
examination normal). He was treated with a total of 5 mg of
lorazepam; he had ongoing agitation and neuropsychiatric
symptoms and therefore on the advice of the psychiatrists
he was treated with 5 mg olanzapine and transferred to a
local psychiatric hospital for ongoing management.
Case five
A 17-year-old male with no significant past medical history
admitted to nasal insufflation of 1 g of a powder that he
believed to be MDMA. Following use, he developed a
feeling of his heart racing, paranoia and visual hallucinations.
He had ongoing features of insomnia, paranoia and visual
hallucinations when he presented to the ED approximately
24 h after use. On examination at the time of presentation, he
had dilated pupils, a mild sinus tachycardia (120 bpm) and
mild systolic hypertension (156/91 mmHg), but had a normal
temperature (36.5C) and neurological examination. He was
treated with 5 mg of diazepam orally; after a short period of
observation he was reassured and discharged home.

Toxicological screening
Informed consent was obtained from all five patients for
toxicological screening of urine samples collected at the
time they were reviewed by one of the clinical toxicologists. Initial screening of the urine samples was performed
using full scan electron impact gas chromatographymass
spectrometry (GC-MS) following alkaline liquidliquid
extraction. This was an extended toxicological screen that
included classical recreational drugs, novel psychoactive
substances and other pharmacologically active compounds.
The results are shown in Table 1 and indicate all of the
substances that were detected on the extended toxicological
screen. Screening of a serum sample by GC-MS obtained
from Case 1 confirmed the presence of D2PM at a
concentration of 0.22 mg/L.
Due to the typical high temperature of the GC-MS
injection port, it was suspected that the detection of
benzophenone could be the result of the temperaturerelated degradation of D2PM. Further investigation was
undertaken by analysing the urine samples by liquid
chromatography tandem massspectrometry (LC-MS/MS).
The results confirmed the presence of D2PM whilst
benzophenone was not detected. This procedure confirmed
that the detection of benzophenone by GC-MS was an
analytical artefact.

Discussion
We have reported here five individuals who presented to the
ED with acute and prolonged recreational drug toxicity and
in whom the presence of diphenylproplinol (D2PM) was
confirmed by toxicological screening. In three of these
patients D2PM was the only drug found; in one case
MDMA and amfetamine were also found, and in another
case mephedrone had been taken in addition to D2PM.
It should be noted that none of the individuals thought or
knew that they had purchased D2PM. In each case

Table 1 Urine toxicological screening results for the five cases

Case

Age (years), Sex

Self-reported drugs ingested

Urine results by GC-MS

1
2
3

33, Male
21, Male
29, Male

Benzofury
Unknown stimulant
NRG-3, MDMA and Nytol

D2PM, benzophenone
D2PM, benzophenone
D2PM, benzophenone, amfetamine, MDMA,
diphenhydramine and 4-methylmethcathinone

4
5

25, Male
17, Male

Unknown liquid and Nytol

MDMA powder

D2PM, benzophenone and diphenydramine

D2PM, benzophenone and normephedrone

GC-MS, Gas chromatographymass spectrometry; NRG-3, naphyrone; MDMA, 3,4-methylenedioxymethamphetamine; D2PM, diphenylproplinol (diphenyl-2-pyrrolidinemethanol)
Nytol is the trade name for a product containing diphenhydramine

Eur J Clin Pharmacol

described here, the individual had been sold D2PM instead

of the drug(s) that they had been intending to purchase.
There is limited published information on the acute
toxicity related to the use of D2PM. In a previously
published case report, a 21-year-old male presented to the
ED with agitation and ischaemic sounding chest pain after
using a legal high product purchased under the name
Head Candy [9]. Analytical screening of the individual
demonstrated that he had in fact used both D2PM and
glaucine; the authors concluded that the D2PM was the
likely agent responsible for ischaemic chest pain as the
acute toxicity of glaucine is more likely to be hallucinogenic
in nature [10, 19, 20].
There have been reports of acute toxicity related to
the use of the structurally similar desoxypipradrol (2DPMP) from both Scotland and Ireland [17, 18]. The
description of the acute toxicity seen in these cases was
included neuropsychiatric symptoms (hallucinations, insomnia, agitation, paranoia, anxiety, restlessness and
aggression) and stimulant features (tachycardia, palpitations and chest pain). The individuals in the cases from
Scotland reported that they had used a legal high with
the name of Ivory Wave [17]. Ivory Wave has
previously been reported to have contained methylenedioxypyrovalerone (MDPV) [21]; however, toxicological
analysis of the patients in the Scottish series confirmed the
presence of 2-DPMP in a minority of these cases, although
the data have only been published in abstract form to date
[17]. With respect to the patients from Ireland, who
reported using a substance known as Whack, toxicological
screening confirmed the use of both 2-DPMP and flourotropacocaine, and therefore it was not possible to determine
whether the symptoms in these cases were due to the 2-DPMP
or the flourotropacocaine [18].
Both D2PM and 2-DPMP are structurally related to
pipradrol, a drug which was initially developed to treat
obesity. 2-DPMP is the desoxy form of pipradrols, and
D2PM is a pyrrolidine analogue. These drugs differ only by
the size of the nitrogen containing ring; 2-DPMP, like
pipradrols, has a six-membered piperidine ring, whilst
D2PM has a five-membered pyrrolidine ring. Although
pipradrol was controlled under relevant drugs legislation in
the 1970s, both D2PM and 2-DPMP are not controlled in
the UK. However, following the reports from Scotland of
potential acute toxicity related to the use of 2-DPMP, in an
attempt to try and control the availability of 2-DPMP, this
compound has required an open general import licence in
the UK since October 2010.
Whilst there is evidence in the original patent application
for D2PM that both the R(+) and S() isomers of D2PM
show activity at the cocaine binding site on the dopamine
transporter protein, this has not been confirmed in any
animal or human pharmacodynamic or pharmacokinetic

study carried out to date [22]. However, based on the five

cases we have reported here and the previously reported
case [9], we feel that there is sufficient information to
describe the pattern of acute toxicity as being related to the
recreational use of D2PM. The initial pattern of acute
toxicity seen after use is similar to that seen with other
sympathomimetic drugs, with users describing a high/
rush. However, the consistent pattern seen in the five
patients in this series was prolonged neuropsychiatric
symptoms lasting for up to and longer than 2472 h
following the use of the D2PM. This descriptive case series
will allow clinicians and clinical pharmacologists to
provide more appropriate advice on the acute toxicity seen
following the use of D2PM and reassure individuals
regarding the prolonged neuropsychiatric symptoms. Additionally, the information reported here will allow legislative
authorities to consider the appropriate measures to control
the supply and use of D2PM and other structurally related
pipradrol derivatives.

Competing interests DW and PD have acted as scientific advisors

to the UK Advisory Council on the Misuse of Drugs (ACMD) and the
European Monitoring Centre for Drugs and Drug Addiction
(EMCDDA).

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