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Review article: Medical intelligence | Published 14 January 2015, doi:10.4414/smw.2015.14043
Cite this as: Swiss Med Wkly. 2015;145:w14043
Novel psychoactive substances (designer drugs):
overview and pharmacology of modulators of
monoamine signalling
Matthias E. Liechti
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital and University of
Basel, Switzerland
Summary
Novel psychoactive substances are newly used designer
drugs (“internet drugs”, “research chemicals”, “legal
highs”) potentially posing similar health risks to classic
illicit substances. Chemically, many novel psychoactive
substances can be classified as phenethylamines, amphet-
amines, synthetic cathinones, piperazines, pipradrols/
List of abbreviations
AMT alpha-methyltryptamine;
5-APB 5-(2-aminopropyl)benzofuran;
6-APB 6-(2-aminopropyl)benzofuran;
BZP benzylpiperazine;
CB cannabinoid;
2C-B 2,5-dimethoxy-4-bromophenethylamine;
2C-I 2,5-dimethoxy-4-iodophenethylamine;
m-CPP meta-chlorophenylpiperazine;
DAT dopamine transporter;
DMT dimethyltryptamine;
DOB 2,5-dimethoxy-4-bromoamphetamine;
DOI 2,5-dimethoxy-4-iodoamphetamine;
DOM 2,5-dimethoxy-4-methylamphetamine;
2-DPMP 2-diphenylmethylpiperidine;
D2PM diphenyl-2-pyrrolidinemethanol;
EMCDDA European Monitoring Centre for Drugs and Drug
Addiction;
Euro-DEN European Drug Emergency Network;
3-FMC 3–fluoromethcathinone;
4-HO-MET 4-hydroxy-N-methyl-N-ethyltryptamine;
5-IAI 5-iodoaminoindane;
MDAI 5,6-methylenedioxy-2-aminoindane;
MDMA 3,4-methylenedioxymethamphetamine;
MDPV 3,4-methylenedioxypyrovalerone;
4-MEC 4-methylethylcathinone;
4-MTA 4-methylthioamphetamine;
25I-NBOMe 4-Iodo-2,5-dimethoxy-N-
(2-methoxybenzyl)phenethylamine;
NET noradrenaline (norepinephrine) transporter;
PMA paramethoxyamphetamine;
PMMA paramethoxymethamphetamine;
α-PVP α-pyrrolidinopentiophenone;
SERT serotonin transporter;
TFMPP trifluoromethylphenylpiperazine;
THC tetrahydrocannabinol
piperidines, aminoindanes benzofurans, and tryptamines.
Pharmacologically, these substances interact with various
monoaminergic targets. Typically, stimulants inhibit the
transport of dopamine and noradrenaline (pipradrols, pyro-
valerone cathinones) or induce the release of these
monoamines (amphetamines and methamphetamine-like
cathinones), entactogens predominantly enhance serotonin
release (phenylpiperazines, aminoindanes, para-substituted
amphetamines, and MDMA-like cathinones) similar to
MDMA (ecstasy), and hallucinogens (tryptamines, hallu-
cinogenic phenethylamines) are direct agonists at sero-
tonergic 5-HT2A receptors. Synthetic cannabinoids are an-
other group of novel substances which all act as agonists at
the cannabinoid CB1receptor similar to THC but are chem-
ically diverse. In particular, the relative serotonergic vs
dopaminergic activity (determined by the dopamine/sero-
tonin transporter inhibition ratio in vitro) can be helpful to
predict the desired psychotropic but also the toxic effects
of novel substances as well as their potential for addiction.
Although the use of novel psychoactive substances mostly
produces minor or moderate poisonings, serious complica-
tions occur. Serotonergic drugs (entactogens and hallucino-
gens) are associated with acute serotonin syndrome, hyper-
thermia, seizures, and hyponatremia. Dopaminergic drugs
are highly addictive and acute toxicity includes prolonged
stimulation, insomnia, agitation, and psychosis. Agitation,
anxiety, paranoia, hypertension, and rarely myocardial in-
farction and renal failure are seen with synthetic cannabin-
oids. Treatment is supportive.
Key words: novel psychoactive substances; designer
drugs; amphetamines; research chemicals; pharmacology;
toxicology; serotonin; dopamine
Introduction
The term “novel psychoactive substances” refers to newly-
misused narcotic or psychotropic drugs that may pose a
threat to public health comparable to classic previously
listed psychotropic substances. Typically, the novel sub-
stances or “designer drugs” are analogues or chemical de-
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rivatives of controlled substances designed to produce ef-
fects similar to the controlled substances they mimic. In
contrast to classic illicit drugs (“street drugs”), novel psy-
choactive substances are typically sold through the Internet
(“internet drugs”). The substances are misbranded as “re-
search chemicals”, “bath salts”, “plant food”, and labelled
as “not for human consumption”. The substances are typ-
ically chemically slightly different from already scheduled
drugs to circumvent regulations and are therefore also
termed “legal highs”. The fully synthetic drugs are mostly
produced in China and South East Asia and sold world-
wide by numerous Internet retail vendors often as less ex-
pensive replacements of classic stimulants or narcotics [1].
In the last years we have seen an unprecedented growth in
the number of new psychoactive substances on the illicit
drug market. In the European Union (EU), 41 novel psy-
choactive substances were identified for the first time in
2010, 49 in 2011, 73 in 2012, 81 in 2013, and 37 by April
2014 within the European Early Warning System [2]. By
2014, more than 300 novel substances have been detec-
ted since 2005. Currently, more than one new substance
is identified in one of the EU countries every week. The
European Monitoring Centre for Drugs and Drug Addic-
tion (EMCDDA) collects information on these substances
from various national sources including police, customs,
forensic laboratory networks, health care systems, event or-
ganisers, drug checks, and Internet test purchase samples.
Internet snapshots are also an important method to describe
trends in new substances available for online sale [3]. The
EMCDDA also regularly publishes reports on the risk as-
sessments of novel psychoactive substances (ht-
tp://www.emcdda.europa.eu/activities/action-on-new-
drugs). Furthermore, the European Drug Emergency Net-
work (Euro-DEN) collects health emergency data from
hospitals to look at trends in the acute harms associated
with the use of novel psychoactive drugs [4]. The
University Hospital of Basel participates in the Euro-DEN
and we characterised several intoxications with novel drugs
[5,6] and in particular their pharmacological properties
[7–9]. Data on the clinical characteristics of intoxications
with novel psychoactive substances are also typically col-
lected and reported by poison centres [10–13].
In this review I will describe the in vitro pharmacodynam-
ics of novel psychoactive substances acting on monoamine
signalling and how it relates to the clinical effects of these
compounds. Several excellent publications have more
comprehensively reviewed the pharmacology and toxico-
logy of novel psychoactive substances [14,15].
Classification of novel psychoactive
substances
The new psychoactive substances can be classified based
on their psychotropic effects as stimulants, empathogens/
entactogens (3,4-methylenedioxymethamphetamine
[MDMA, ecstasy]-like substance) or hallucinogens or ac-
cording to their chemical family as phenethylamines,
amphetamines, cathinones, piperazines, pipradrols/
piperidines, aminoindanes, benzofurans, and tryptamines
[15]. The synthetic cannabinoids include a large number of
chemically diverse substances which act on the cannabin-
oid CB1receptor and have mostly hallucinogenic but also
some stimulant properties. Currently, the compounds are
classified based on their common pharmacological action
rather than similar chemical structures.
The substances exhibit a rather broad spectrum of dopam-
inergic, noradrenergic, or serotonergic pharmacological ef-
fects even within their chemical family [7–9,16]. Accord-
ingly, the psychotropic and clinical toxicological effects are
also quite diverse and vary considerable from drug to drug.
Synthetic cannabinoids
Herbal mixtures (“spices”) have emerged as legal altern-
atives to cannabis [17]. It was initially assumed that the
psychotropic effects were derived from the plants them-
selves. However, synthetic compounds added to the herbal
blends and with action at the CB1receptor were found
to be responsible for the psychopharmacological activity
[18]. “Spice” drugs have become popular alternatives to
marijuana among teenagers and constitute an exceptionally
large class of novel psychoactive substances [2]. Synthetic
cannabinoids vary considerably in chemical structure while
they uniformly act as agonists at the CB1receptor [17].
Many of the substance names (abbreviations) typically start
with the initials of the chemists (JWH or AM) followed
by numbers. Most synthetic cannabinoids produce overall
similar effects and toxicity to tetrahydrocannabinol (THC)
[6,17]. However, synthetic cannabinoids are thought to be
associated with more severe psychosis and agitation and
more sympathomimetic effects because they are more po-
tent full receptor agonists and also lack cannabidiol, which
is contained in natural THC-containing products and has
anxiolytic and antipsychotic properties. In fact, agitation,
aggression, paranoid thinking and anxiety are common
symptoms after consumptions of synthetic cannabinoids
[19,20]. However, more recently a second generation of
synthetic cannabinoids has emerged both in the US and in
Europe and lead to epidemics associated with more severe
toxicity including collapses, seizures, and cardiac toxicity
[11]. Cases with acute kidney injury have also been de-
scribed [21]. The effect of the synthetic cannabinoids is
typically short-lasting compared with amphetamine-type
substances [5,20]. Short-time monitoring and supportive
care is sufficient to treat most cases with intoxications.
Synthetic cannabinoids are not detected by drug screening
tests for THC, and highly specialised mass spectrometry
techniques and time are required to document the presence
of these novel compounds in biological samples [6,22].
Phenethylamines and amphetamines
Phenethylamine is the core structure of many novel psy-
choactive substances (fig. 1). Amphetamines (alpha-
methyl-phenyl-ethyl-amine, fig. 1) are formed by the ad-
dition of an alpha methyl group which protects against
metabolism by monoamine oxidase [23]. Methylation of
the terminal amine results in methamphetamine and greater
CNS activity. Amphetamine and methamphetamine (fig. 1)
are both classic psychostimulants which have been used
clinically, recreationally and by military services since the
1930s [23]. The amphetamine-derivative MDMA (fig. 1) is
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not a designer drug or novel psychoactive substance as it
has been used for decades. However, MDMA is still one
of the most widely used recreational drugs and many novel
psychoactive substances were designed to mimic its effects
or as substitutes for MDMA in ecstasy pills. MDMA is the
prototypical empathogen or entactogen meaning that it pro-
duces feelings of empathy or “being touched”. The drug is
mostly used to enhance sociability [24]. In controlled stud-
ies, MDMA increases emotional empathy, trust, extrover-
sion, and sociality relatively more than stimulants which
mainly produce arousal and stimulation [25,26].
Role of dopamine, serotonin and
noradrenaline in the pharmacology
and toxicology of novel psychoactive
substances
Many novel psychoactive substances interact with biogenic
amine neurotransmitter transporters. Amphetamines in-
cluding methamphetamine and MDMA inhibit the dopam-
ine, serotonin and noradrenaline (norepinephrine) trans-
porter (DAT, SERT, NET, respectively) and also release
these monoamines through the respective transporter.
Methamphetamine predominantly increases dopamine and
noradrenaline. MDMA mostly increases serotonin and
noradrenaline. The entactogenic effects of MDMA are gen-
erally considered to depend on its serotonergic effects [27].
MDMA also increases oxytocin [25,28] which may me-
diate its prosocial effects [29]. Consequently, substances
which predominantly release serotonin, similar to MDMA,
can be expected to produce MDMA-like entactogenic ef-
fects. MDMA and similar serotonergic substances are also
associated with serotonergic toxicity including serotonin
syndrome, hyponatremia, hyperthermia, and seizures
[30–32]. In contrast, psychostimulants such as
methamphetamine or methylphenidate are mostly enhan-
cing dopaminergic neurotransmission [7,33]. Dopamine
mediates the reinforcing and addictive properties of drugs
of abuse. In contrast, an increase in the serotonergic proper-
Figure 1
Structures of representative novel psychoactive substances
(stimulants and empathogens). Chemically, the substances shown
include amphetamines (amphetamine, methamphetamine, MDMA,
PMA), cathinones (β-keto-amphetamines such as methedrone,
mephedrone, methylone, pentylone, buphedrone, methcathinone,
naphyrone, MDPV or α-PVP), an aminoindane (MDAI), piperazines
(mCPP and BZP) and pipradrols (2-DPMP and methylphenidate).
Pharmacologically, these substances are psychostimulants or
empathogens and primarily interact with monoamine transporters.
ties of a substance is associated with a reduced potential for
addiction [34]. Consequently the relative dopaminergic to
serotonergic properties in vitro (dopamine/serotonin trans-
porter inhibition ratio) of a novel substance can be determ-
ined as a useful marker for its potential clinical psycho-
tropic and acute toxic effects [7] (fig. 2). Serotonin release
[27] and a DAT/SERT inhibition ratio of typically 0.01–0.1
are expected to result in subjective drug effects similar to
those of MDMA or other empathogens [7,8] (fig. 2). Co-
caine has a DAT/SERT inhibition ratio close to unity, and
methamphetamine is more selective for the DAT, with a
DAT/SERT inhibition ratio >10 and mostly exerting psy-
chostimulant effects in humans [7] (fig. 2). Compounds
with a DAT/SERT inhibition ratio >1 are also associated
with a high abuse potential [7]. Furthermore, all classic
amphetamines and novel psychoactive substances increase
the activity of the noradrenergic system [7–9], which res-
ults in the sympathomimetic cardiostimulant effects associ-
ated with all these substances. The potency of a substance
to activate the noradrenergic system inversely correlates
with the doses typically used recreationally [7,35]. The
profiles of novel psychoactive substances can be determ-
ined in vitro and compared with those of the classic sub-
stances where the clinical effects are known. Substances
which selectively activate the catecholamine systems such
as methamphetamine, or 3,4-methylenedioxypyrovalerone
(MDPV) or α-pyrrolidinopentiophenone (α-PVP) [7,36]
are considered highly addictive and their acute toxicity typ-
ically includes prolonged insomnia, agitation, and psychot-
ic symptoms [37].
Figure 2
Relative dopamine/serotonin inhibition potencies of selected novel
psychoactive substances. Dopamine to serotonin transporter (DAT/
SERT) inhibition ratios (mean ± 95% confidence intervals) for novel
substances are shown in comparison with those of classic
empathogens/entactogens (MDMA, ecstasy) and stimulants
(cocaine, amphetamine, and methamphetamine). The ratios
derived from in vitro studies help to predict the typically unknown
clinical toxicity of novel substances. A low DAT/SERT inhibition
ratio (<0.1) indicates tenfold greater relative serotonergic vs
dopaminergic activity similar to MDMA. A high DAT/SERT inhibition
ratio (>10) indicates greater relative dopaminergic vs serotonergic
activity similar to methamphetamine. A high DAT/SERT inhibition
ratio is a pharmacological characteristic associated with more
stimulant effects and with higher potential for addiction.
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Para-(4)-phenyl-substituted
(serotonergic) amphetamines
Paramethoxyamphetamine (PMA) and paramethoxy-
methamphetamine (PMMA) are typically sold as ecstasy
[38]. This substitution for MDMA is unwanted because
PMA and PMMA are associated with higher morbidity and
mortality particularly attributable to hyperthermia [38,39].
The para-substituted amphetamines are potent noradren-
aline and serotonin transporter inhibitors and releasers of
these monoamines [8]. Their hyperthermic properties are
stronger than those of MDMA [40] and have been asso-
ciated with serotonergic and adrenergic receptor activation
[41]. Therefore, hyperthermic complications are of particu-
lar concern when these amphetamines or novel psychoact-
ive substances with a comparable pharmacological profile
are used [8]. Novel substances with a predominantly sero-
tonergic action [8] and associated with high serotonergic
toxicity are 4-methylthioamphetamine (4-MTA) [42] and
methedrone (β-keto-PMMA) [43]. 4-MTA is the methyl-
thio analog of PMA. 4-MTA produces MDMA-like effects
in animals and humans and is typically used by ecstasy
users [44]. Methedrone is the β-keto-substituted analog of
PMMA. Methedrone is a serotonergic cathinone found in
“bath salt” products.
Synthetic cathinones
Cathinones contain a ketone group at the β-position of
the amphetamine (β-keto-amphetamines, fig. 1). The most
commonly found synthetic cathinones are mephedrone
(4-methylmethcathinone), methylone (β-keto-MDMA),
4-methylethylcathinone (4-MEC), and MDPV [45,46].
Other abused cathinones include ethylone, methedrone,
naphyrone, flephedrone, 3–fluoromethcathinone (3–FMC),
pentylone, buphedrone, α-PVP, and others [7,8,15,45].
The pharmacology of the various cathinones has recently
been determined [7,8,16,47,48]. Cathinones can be clas-
sified based on their pharmacological profiles (mostly the
DAT/SERT inhibition ratio) with relevance to their clinic-
al toxicity [7]. The serotonergic cathinone methedrone pre-
dominantly acts on the serotonin system similar to MDMA
or PMA and PMMA as noted above [8]. The cocaine-
MDMA-mixed cathinons group includes substances which
are roughly equipotent inhibitors of DAT and SERT similar
to cocaine and release serotonin similar to MDMA. The
group includes mephedrone, 4-MEC, methylone, ethylone,
and butylone [7,8]. For example, the subjective effects of
mephedrone have been reported to be similar to those of
cocaine [49] but also MDMA [50]. Typically, these drugs
produce psychotropic effects similar to MDMA when ad-
ministered orally but with enhanced psychostimulation
similar to cocaine when administered intranasally. All cath-
inones exhibit higher dopaminergic activity when com-
pared with their non-β-keto amphetamine analogs. This in-
creased dopaminergic property of the cathinones suggests
higher stimulant-type effects and greater risk for depend-
ence. For example, mephedrone, which is readily self-ad-
ministered by rats [51], has been reported to produce strong
craving in humans and is said by users to be more addictive
than cocaine [49]. In addition, substances with fast brain
access have a higher risk of dependence. Naphyrone is
very similar to cocaine. Both inhibit all monoamine trans-
porters with equal potency but do not release monoamines
[7]. The methamphetamine-like cathinones including cath-
inone, methcathinone, ethcathinone, flephedrone, and
3–FMC exhibit a DAT/SERT inhibition ratio similar to
methamphetamine, with high inhibitory potencies at the
DAT and low potencies at the SERT [7,8]. These cath-
inones also release dopamine and noradrenaline similar
to methamphetamine. Clinically, these cathinones produce
similar toxicity to amphetamine, including hypertension,
hyperthermia, euphoria, locomotor activation, and hallu-
cinations following higher or repeated doses. The pyro-
valerone cathinones include pyrovalerone, MDPV, α-PVP,
and others. These substances are very potent and selective
inhibitors of the DAT and NET, at least 10–fold more po-
tent than cocaine or methamphetamine. The drugs are no
substrates of the transporter and therefore do not release
monoamines. The pyrovalerone derivatives also readily
cross the blood-brain barrier because of their high lipo-
philicity [7]. Consistent with its high potency as a dopam-
ine transporter inhibitor, MDPV is a potent reinforcer in
rats, similar to methamphetamine [52]. Taken together
these pharmacological properties predict high risks of sym-
pathomimetic toxicity and of addiction in humans. Acute
toxic effects of MDPV and α-PVP mainly include acute
psychotic symptoms with agitation and hallucinations [12,
37]. Of note, the pharmacology of MDPV is strikingly dif-
ferent from that of MDMA, although MDPV and MDMA
both share the characteristic 3,4-methylenedioxy-phenyl
group. In fact, caution is needed when making predictions
about the pharmacological activity of new phenetylamine-
type psychoactive substances based only on the chemical
structures. Pharmacological data are needed for each novel
designer drug [53].
Ring substituted phenethylamines and
amphetamines (2-C and 2-D series)
Addition of methoxy-groups at the 2- and 5-positions with
any hydrophobic substitution at the 4-position of the phen-
ethylamine confers hallucinogenic activity (2C-series or
Figure 3
Structures of representative novel psychoactive substances
(hallucinogenic phenethylamines, furans and difurans, and
hallucinogenic tryptamines). Chemically, the shown substances
include phenethylamines of the 2-C series (2C-B, 2C-I, and 25I-
NBOMe) and of the 2-D series (DOM and DOI), a bezofuran
(6-APB), a benzodifuran (2C-B-fly), and tryptamines (DMT, AMT,
and 4-OH-MET). Pharmacologically, all presented substances are
hallucinogens and potent serotonin 5-HT2A receptor agonists
except for 6-APB which is an empathogen and indirect serotonin
agonist similar to MDMA.
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ring substituted phenethylamines). Example drugs of the
large 2-C series are
2,5-dimethoxy-4-bromophenethylamine (2C-B) and
2,5-dimethoxy-4-iodophenethylamine (2C-I) (fig. 3). The
hallucinogenic properties of these drugs are further en-
hanced by a methyl-group at the α-carbon (D-Series or
ring substituted amphetamines or hallucinogenic amphet-
amines). Example drugs included in this group are
2,5-dimethoxy-4-methylamphetamine (DOM),
2,5-dimethoxy-4-bromoamphetamine (DOB), and
2,5-dimethoxy-4-iodoamphetamine (DOI) (fig. 3). Nausea
and tachycardia but also long-lasting hallucinogenic ef-
fects, agitation, and ergotism (vasospasms) have been re-
ported in intoxications with these hallucinogenic amphet-
amines. The hallucinogenic activity of the 2-C and D series
drugs is mediated by an interaction with the serotonergic
5-HT2A receptor [54].
Various N-methoxybenzyl-substituted phenethylamines
have emerged on the EU drug market since 2012 [2]. These
drugs such as 4-Iodo-2,5-dimethoxy-N-
(2-methoxybenzyl)phenethylamine (25I-NBOMe, fig. 3)
exert an even higher potency at the 5-HT2A receptor and
possibly also at other receptors compared with the already
very potent classic hallucinogens [55]. Severe and fatal
intoxications including agitation, hallucinations, seizures,
and hyperthermia have been reported with 25I-NBOMe
[56,57] consistent with serotonergic but also sympathomi-
metic toxicity. Importantly these novel hallucinogens are
extremely potent and psychoactive at microgram doses.
This is likely to result in overdosing.
Benzofurans and benzodifurans
Benzofurans and benzodifurans are also groups of ring sub-
stituted amphetamines. Benzofurans containing one furan
ring are 6-(2-aminopropyl)benzofuran (6-APB, fig. 3) and
5-(2-aminopropyl)benzofuran (5-APB) and several others.
These drugs are structurally related to MDMA and simil-
arly inhibit monoamine transporters [16] and release sero-
tonin and noradrenaline (unpublished data by the author).
Users report the effects of 5-APB and 6-APB to be com-
parable to MDMA but more intense [58]. Adverse effects
include nausea, sympathomimetic stimulation, and agita-
tion [58]. Benzodifurans are a group also known as the
“fly” drugs (bromo-dragon fly, 2C-B-fly [fig. 3], etc.) and
are hallucinogen. These drugs may produce paranoia, agit-
ation, tachycardia, and hyperthermia and have been implic-
ated in several fatalities [58].
Piperazines
Piperazines are commonly found in ecstasy pills as sub-
stitutes for MDMA [59]. The phenylpiperazines
meta-chlorophenylpiperazine (m-CPP, fig. 1) and trifluoro-
methylphenylpiperazine (TFMPP) are indirect and direct
serotonergic agonists without dopaminergic activity. Con-
sistently these drugs are not reinforcing [60]. m-CPP and
TFMPP have less desirable psychotropic effects and more
adverse effects, including dysphoria, anxiety, and nausea,
compared with MDMA [61–63]. Benzylpiperazine (BZP,
fig. 1) is an indirect dopamine and noradrenaline agonist
without serotonergic properties [9] and exerts stimulant ef-
fects in humans [64]. The clinical toxicity of BZP mainly
includes hallucinations, agitation, seizures, and hyperther-
mia [65]. Drug users report more unpleasant effects and
hallucinations with BZP than with MDMA [61]. BZP is
sometimes combined with m-CPP or TFMPP and sold as
ecstasy [59] mimicking the mixed dopaminergic-serotoner-
gic profile of MDMA. However, the BZP-TFMPP com-
bination is not well tolerated at higher doses and produces
agitation, anxiety, hallucinations, and vomiting [66].
Aminoindanes
Aminoindanes such as 5,6-methylenedioxy-2-aminoindane
(MDAI, fig. 1) and 5-iodoaminoindane (5-IAI) are al-
legedly less-neurotoxic alternatives to MDMA. MDAI and
5-IAI release serotonin and noradrenaline comparable with
MDMA [9]. Consistently the subjective effects of MDAI
are also reported to be very similar to those of MDMA [67].
Complications include serotonin syndrome and hyperther-
mia [67], also similar to MDMA.
Pipradrols/piperidines
Intoxications with “ivory wave”, which contains the pi-
pradrol derivative desoxypipradrol (2-diphenyl-methyl-
piperidine [2-DPMP, fig. 1]) or diphenylprolinol (diphen-
yl-2-pyrrolidinemethanol [D2PM]) have been reported
starting in 2010 [68,69]. D2PM and 2-DPMP are selective
and very potent catecholamine transporter inhibitors
without transporter-mediated substrate-releasing proper-
ties, similar to methylphenidate [9]. This pharmacological
profile is also very similar to MDPV, α-PVP, and other
pyrovalerone cathinones [7,36] and likely associated with
high abuse liability and an increased risk of psychiatric
complications. The clinical toxicity of 2-DPMP and D2PM
is long-lasting (24-72 h) and involves sympathomimetic
stimulation with hypertension, agitation, hallucinations,
and insomnia [45,68,69].
Tryptamines
Tryptamines contain an indole structure joined to an ethyl-
amine group in simple tryptamines (for a classification see
[15]). Natural tryptamines include serotonin and hallucino-
gens such as psilocybin in magic mushrooms and dimethyl-
tryptamine (DMT, fig. 3) in Ayahuasca. Ergolines are more
complex tryptamines and include the prototypic hallucino-
gen LSD. Commonly misused novel synthetic tryptam-
ines (designer hallucinogens) are alpha-methyltryptamine
(AMT) [13] and 4-hydroxy-N-methyl-N-ethyltryptamine
(4-HO-MET) [45] (fig. 3). Tryptamine-induced hallucina-
tions are mostly mediated by direct interaction with sero-
tonergic 5-HT2A receptors [54]. However, many tryptam-
ines also release serotonin [70] and in some cases dopam-
ine and noradrenaline [71]. As a result serotonin syndrome
and sympathomimetic toxicity may occur and tryptamines
have stimulant as well as hallucinogenic properties [13].
Typically visual hallucinations predominate. Consistent
with their action as serotonergic agonists tryptamines are
not addictive [71].
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Prevalence of novel psychoactive
substance use
In a German survey, 9% of 15-18 year-old school students
reported having smoked spice products at least once in their
lives and 2% also within the last 30 days. Other “legal
highs” (research chemicals, bath salts) had been used by
3% at least once and in 1% within the last 30 days [72]. In
contrast, in the UK, life-time prevalence rates of mephed-
rone use of 20.3% have been reported from some areas in
2010 [73].
In Switzerland, the prevalence of novel psychoactive sub-
stances use is yet unknown. In 2009–2010, 37% of people
using classic drugs such as amphetamines or MDMA tested
positive for novel psychoactive substances in hair [74].
For example, m-CPP was found in 10.5%, mephedrone in
3%, 4-fluoroamphetamine in 4% [74]. However, many sub-
stances were possibly not yet used at the time of analysis
or were not yet detectable. Considering our ongoing sur-
veillance data collections from emergency department vis-
its, presentations of intoxications with novel psychoactive
substances are infrequent compared with those with alco-
hol, cannabis or cocaine [4,75].
Treatment of intoxications
Table 2 lists typically reported acute medical problems as-
sociated with novel substances from each class. The clin-
ical toxicity of novel psychoactive substances is generally
similar to that of other amphetamines including MDMA.
The majority of patients (85-95%) presenting at emergency
departments with acute medical problems associated with
the use of novel psychoactive substances are minor or mod-
erate poisonings [12,45,76]. Common clinical features
are hypertension, tachycardia, chest pain, agitation, and
hallucinations [12,76,77]. Severe and fatal poisonings
manifest as serotonin syndrome [67], hyperthermia [38,
78], seizures, and brain oedema due to hyponatremia [79].
These are also the severe complications of MDMA use [31,
80]. Treatment is mainly supportive. Heart rate, blood pres-
sure, and body temperature should be monitored. Depend-
ing on clinical features laboratory tests including electro-
lytes, creatine kinase, liver enzymes, and cardiac enzymes
may be indicated. Acute treatment of a sympathomimetic
toxidrome primarily includes benzodiazepines and fluid re-
placement to control agitation, cardiovascular stimulation
and hyperthermia. The use of haloperidol without benzo-
diazepines is generally not recommended because seizure
and dysrhythmia thresholds are lowered and negative drug-
induced psychological effects including anxiety may in-
crease [81]. Hypertension should be treated primarily with
nitrates. β-blockers should be avoided because of unop-
posed α-adrenergic stimulation resulting in further in-
creases in blood pressure [82]. PhentoIamine may be useful
but α-blockade increases stimulant-induced tachycardia
[83]. Combined α-β-blockade with carvedilol reduced
MDMA-induced elevations in blood pressure, heart rate
and also body temperature [84], but it is not a routine treat-
ment for stimulant-induced toxicity [85]. Physical cooling
and relaxation may be needed in cases of severe hyperther-
mia, but antipyretics are of no use.
Drug screening
Most stimulant-type novel psychoactive substances are not
detected by standard immunoassay urine drug screens.
Thus, intoxication would typically present as sympathomi-
metic or serotonergic toxidromes with a negative screening
result for amphetamines. Ideally, urine and blood should
Table 1: Monoamine transporter inhibition.
NET DAT SERT DAT/SERT
Substance Chemical class Pharmacological class IC50 [µM] IC50 [µM] IC50 [µM] Ratio
PMA Amphetamine Empathogen 0.8 71 2.4 0.03
m-CPP Piperazine Empathogen 1.7 31 1.2 0.04
MDMA Amphetamine Empathogen 0.45 17 1.4 0.08
Methedrone Cathinone Empathogen 2.2 35 4.7 0.14
MDAI Aminoindane Empathogen 0.65 31 8.3 0.21
Mephedrone Cathinone Empathogen-stimulant 0.25 3.3 4.6 1.4
Naphyrone Cathinone Empathogen-stimulant 0.25 0.47 0.96 2.0
Cocaine Cocaine Stimulant 0.45 0.8 2.4 3.1
Methylone Cathinone Empathogen-stimulant 0.54 4.8 16 3.3
BZP Piperazine Stimulant 0.41 17 57 3.4
Pentylone Cathinone Stimulant 0.99 1.3 8.4 6.2
Methamphetamine Amphetamine Stimulant 0.06 1.1 24 22
Buphedrone Cathinone Stimulant 0.65 4.2 104 25
Methcathinone Cathinone Stimulant 0.09 1.1 33 30
Amphetamine Amphetamine Stimulant 0.09 1.3 52 40
MDPV Pyrovalerone-cathinone Stimulant 0.04 0.03 9.3 300
2-DPMP Pipradrol Stimulant 0.14 0.07 93 1328
PVP Pyrovalerone Stimulant 0.02 0.05 301 6020
Methylphenidate Pipradrol Stimulant 0.13 0.12 807 6725
NET = noradrenaline transporter; DAT = dopamine transporter; SERT = serotonin transporter. Values are concentrations at which the transporter is inhibited by 50%. A low
value indicates greater potency.
DAT/SERT ratio = 1/DAT IC50: 1/SERT IC50. A low DAT/SERT ratio (<0.1) indicates tenfold greater relative serotonergic vs dopaminergic activity similar to MDMA. A high
DAT/SERT ratio (>10) indicates greater relative dopaminergic vs serotonergic activity similar to methamphetamine.
Data are from Simmler et al. 2013 and 2014 and unpublished by the author (PVP)
Review article: Medical intelligence Swiss Med Wkly. 2015;145:w14043
Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 6 of 12
be sampled and analysed by liquid chromatography-mass
spectrometry by a specialised laboratory. Typically the
identity of the novel psychoactive substances will not be
readily available for the management of the acute intox-
ication. Nevertheless, the novel psychoactive substances
should be identified to better document the substances and
their associated toxicity.
Conclusion
Stimulants inhibit the transport of dopamine and norad-
renaline (pipradrols, pyrovalerone cathinones) or induce
the release of these monoamines (amphetamines and
methamphetamine-like cathinones), entactogens predomin-
antly enhance serotonin release (phenylpiperazines, amin-
oindanes, para-substituted amphetamines, and MDMA-like
cathinones) similar to MDMA, and hallucinogens (trypt-
amines, hallucinogenic phenethylamines) are direct agon-
ists at serotonergic 5-HT2A receptors. Synthetic cannabin-
oids act as agonists at the cannabinoid CB1receptor similar
to THC. In particular, the dopamine/serotonin transporter
inhibition ratio in vitro can be helpful to predict the ex-
pected psychotropic but also the toxic effects of novel sub-
stances.
Acknowledgement: The author thanks Anna Rickli for
designing Figure 1 and 3 and Anna Rickli, Yasmin Schmid, and
Linda D. Simmler for comments on the manuscript. Anna Rickli,
Linda Simmler, and Marius Hoener contributed to the original
research reviewed in this paper.
Funding / potential competing interests: The described
research was supported by the Swiss National Science
Foundation (no. 320030_149493/1), the Federal Office of Public
Health (no. 13.006497), the Translational Medicine Hub
Innovation Fund of F. Hoffmann-La Roche and the University of
Basel, and the Swiss Centre for Applied Human Toxicology.
Correspondence: Professor Matthias E. Liechti, MD, Division
of Clinical Pharmacology, University Hospital Basel,
Hebelstrasse 2, CH-4031 Basel, Switzerland,
matthias.liechti[at]usb.ch
Table 2: Acute clinical toxicity associated with novel psychoactive substances.
Substances Classification Leading acute toxicity
PMA (Para-substituted) amphetamine, empathogen Serotonergic toxidrome, hyperthermia, nausea,
seizures, fatalities
MDMA Amphetamine, empathogen Serotonergic and sympathomimetic toxidrome,
hyperthermia, hyponatraemia, renal and liver
failure
MDAI Aminoindane, empathogen Serotonergic and sympathomimetic toxidrome,
hyperthermia
Mephedrone, methylone (Cocaine-MDMA-mixed) cathinone,
empathogen/stimulant
Sympathomimetic toxidrome, agitation,
vomiting, psychosis, chest pain, seizures,
insomnia
3-FMC, flephedrone, methcathinone (Methamphetamine-like) cathinone, stimulant Sympathomimetic toxidrome, psychosis,
agitation, chest pain, insomnia
MDPV, α-PVP (Pyrovalerone-)cathinone, stimulant, high
potency drug
Psychosis, agitation, combative behaviour,
sympathomimetic toxidrome, chest pain,
prolonged insomnia
m-CPP, TFMPP (Phenyl)piperazine, entactogen Serotonergic toxicity, nausea, vomiting, anxiety,
headache, dizziness, dysphoria, confusion,
hallucinations, tachycardia
BZP (Benzyl)piperazine, stimulant Mostly sympathomimetic toxicity, agitation,
anxiety
2-DPMP, methylphenidate Pipradrol, stimulant Sympathomimetic toxidrome, insomnia,
agitation, hallucination, anxiety, insomia
6-APB Benzofuran, empathogen Serotonergic and sympathomimetic toxidrome,
nausea, agitation, anxiety, dizziness,
hyperthermia
“fly” drugs Benzodifurans, hallucinogens Psychosis, agitation, hyperthermia,
sympathomimetic toxicity, vasospasm, limb
pain/ischaemia, seizures, fatalities
2C-B (Ring-substituted) phenethylamine, hallucinogen Psychosis, agitation,vomiting, vasospasms
25-I-NBOMe "NBOM"-phenethylamine, hallucinogen, very
high potency drug
Serotonergic and sympathomimetic toxidrome,
psychosis, agitation, seizures, hyperthermia
AMT Tryptamine, hallucinogen Serotonergic and sympathomimetic toxidrome,
psychosis, agitation, hyperthermia, nausea
Synthetic cannabinoids Cannabinoid, hallucinogen Psychosis, agitation, anxiety, sympathomimetic
toxidrome, chest pain, myocardial infarction,
renal injury, seizure, vomiting
Sympathomimetic toxidrome typically includes hypertension, tachycardia, mydriasis, agitation, and sweating
Serotonergic toxidrome typically includes tremor, clonus, hyperreflexia, sweating, hyperthermia, mydriasis, agitation, and confusion
Psychosis includes hallucinations and paranoia
AMT = alpha-methyltryptamine; α-PVP = alpha-pyrrolidinopentiopenone; 6-APB = 6-(2-aminopropyl)benzofuran; BZP = benzylpiparazine; 2C-B =
2,5-dimethoxy-4-bromophenethylamine; m-CPP = meta-chlorophenylpiperazine; 2-DPMP = 2-diphenylmethlpiperidine; 3-FMC =
3-fluoromethcathinone; MDAI = 5,6-methylenedioxy-2-aminoindane; MDMA = 3,4-methlylenedioxymethamphetamine; MDPV =
3,4-methlyenedioxypyrovalerone; 25I-NBOMe = 4-iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine; PMA = paramethoxyamphetamine;
TFMPP = trifluoromethylphenylpiperazine.
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Swiss Medical Weekly · PDF of the online version · www.smw.ch Page 7 of 12
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Figures (large format)
Figure 1
Structures of representative novel psychoactive substances (stimulants and empathogens). Chemically, the substances shown include
amphetamines (amphetamine, methamphetamine, MDMA, PMA), cathinones (β-keto-amphetamines such as methedrone, mephedrone,
methylone, pentylone, buphedrone, methcathinone, naphyrone, MDPV or α-PVP), an aminoindane (MDAI), piperazines (mCPP and BZP) and
pipradrols (2–DPMP and methylphenidate). Pharmacologically, these substances are psychostimulants or empathogens and primarily interact
with monoamine transporters.
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Figure 2
Relative dopamine/serotonin inhibition potencies of selected novel psychoactive substances. Dopamine to serotonin transporter (DAT/SERT)
inhibition ratios (mean ± 95% confidence intervals) for novel substances are shown in comparison with those of classic empathogens/
entactogens (MDMA, ecstasy) and stimulants (cocaine, amphetamine, and methamphetamine). The ratios derived from in vitro studies help to
predict the typically unknown clinical toxicity of novel substances. A low DAT/SERT inhibition ratio (<0.1) indicates tenfold greater relative
serotonergic vs dopaminergic activity similar to MDMA. A high DAT/SERT inhibition ratio (>10) indicates greater relative dopaminergic vs
serotonergic activity similar to methamphetamine. A high DAT/SERT inhibition ratio is a pharmacological characteristic associated with more
stimulant effects and with higher potential for addiction.
Figure 3
Structures of representative novel psychoactive substances (hallucinogenic phenethylamines, furans and difurans, and hallucinogenic
tryptamines). Chemically, the shown substances include phenethylamines of the 2–C series (2C-B, 2C-I, and 25I-NBOMe) and of the 2–D series
(DOM and DOI), a bezofuran (6–APB), a benzodifuran (2C-B-fly), and tryptamines (DMT, AMT, and 4–OH-MET). Pharmacologically, all
presented substances are hallucinogens and potent serotonin 5–HT2A receptor agonists except for 6–APB which is an empathogen and indirect
serotonin agonist similar to MDMA.
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