Toxicological risk assessment of various
emerging drugs
Nathan Bijl
National Dutch Information Centre for Poisoning, University Medical Center Utrecht, The
Netherlands
Writing assignment Toxicology and Environmental Health
Supervisor: Laura Hondebrink1, Annette Nugteren- van Lonkhuyzen2
1. Toxicologist (ERT) / Postdoctoral Researcher, University Medical Centre Utrecht, National
Poisons Information Centre
2. Junior Researcher, University Medical Centre Utrecht, National Poisons Information Center
May 21, 2014
Utrecht
Abstract
0.6 per cent of the global adult population is a problem drug of abuse user. Yearly, there are more
than a million of emergency department visits worldwide due drug-induced toxicity and 1 per cent of
the deaths among adults are attributed to illicit drug use. There are many types of drugs available on
the Dutch market which are prohibited but also new legal drugs appears on the market which are
manufactured to circumvent the law: designer drugs.
Several emerging (designer) drugs are entering the Dutch market but information about the drugs is
lacking: mephedrone, 4-fluoroamphetamine (4-FA), 4-methylethcathinone (4-MEC), para-methoxyN-methylamphetamine (PMMA), methoxetamine, 4-bromo-2,5-dimethoxyphenethylamine (2C-B)
and 25I-NBOMe. These drugs of abuse belong to the group of hallucinogenic drugs or stimulant
drugs. We gathered information about these emerging drugs which is necessary to perform a
toxicological risk assessment.
Each drug has a specific profile of desired and adverse effects, although both stimulant and
hallucinogenic drugs also have many similarities. The effect of the drugs depends on various factors:
appearances of the drug, route of administration, dosage, multiple drug use and sensitivity
(tolerance). For each drug these factors differ per person which can lead to different
desired/adverse effects.
For some drugs it was difficult to gather sufficient information but we can conclude that not all drugs
are equally toxic and lethal. The designer drugs are labeled as not for human consumption but the
drugs are taken in recreational settings and intoxications occur when taken in excess. Especially for
mephedrone, PMMA and 25I-NBOMe which has a high potency to induce toxicity, especially in the
presence of other psychoactive drug. The adverse side effects have been associated with many
hospitalizations and fatalities worldwide, compared with other emerging drugs. In the Netherlands
mephedrone, 2C-B and PMMA are illegal but 25I-NBOMe, 4-MEC, 4-FA and methoxetamine have a
legal status. However, no guidelines are available after purchasing the drug so there is no data
available about the appropriate dose.
2
Table of contents
1
Introduction…………………………………………………………………………………………..….……………………4
2
Stimulants
2.1.1
Mephedrone...……………………………………………………………………………………………….........6
2.1.2
4-Fluoroamphetamine.…………………………………………………………...........………………………12
2.1.3
4-Methylethcathinone……………….……..........................................................................14
2.1.4
Para-methoxy-N-methylamphetamine.…………..……………………………………………………....16
2.2
3
Discussion………………………...……………………………………………………..…..…....…………..................19
Psychedelics
3.1.1
Methoxetamine………………………………………………………………………..…..……………………......20
3.1.2
4-bromo-2,5-dimethoxyphenethylamine…………………………………………………………………23
3.1.3
2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine.…………..26
3.2
Discussion………………………………………………………………………..…..………………………..……………….29
4
General discussion………………………………………………………………………………………….…….…………30
5
References………………………………………………………………………..…..………………………………………..32
3
Introduction
Humans have been using drugs of all kinds and sorts for more than thousands of years. At first,
newly discovered substances were unregulated and drugs were freely prescribed by doctors and
physicians. Sometimes the drugs were used as medicine but the drugs were often taken for
nonmedical reasons. When drugs are taken for nonmedical reasons it is called a drug of abuse. They
include legal drugs/medicines as well as illicit drugs5. Until the 19th century, drugs originated from
two sources: plants and animals1. In the 20th century, a third source became available via chemical
development and the number of drugs increased2. As a result, more people started using drugs and
the problems of addiction were quickly noticed. When abuse of these compounds reached
concerning levels, their distribution, production and use were more controlled1.
The United Nations Office on Drugs and Crime (UNODC) estimated that around 230 million people, 1
in every 20 adult people, took an illicit drug at least once in 201064. About 27 million people in the
global adult population, 1 in every 200 adult people, are problem drug users which is 0.6 per cent of
the total adult population64. Approximately 1 in every 100 deaths among adults is attributed to illicit
drug use64 of which 80% is male3. However, in the Netherlands the number of fatalities due to a drug
overdose of psychoactive drugs is relative low compared to other countries (fig. 1)4.
Psychoactive drugs are substances that acts upon the central nervous system resulting in temporary
change of mood, behavior, consciousness and thoughts5. There are many types of psychoactive
drugs but the most used worldwide are alcohol, caffeine tobacco, cannabis, cocaine, MDMA,
amphetamine, heroin (opiates) and gamma-hydroxybutyrate (GHB)4. In 2009 the life-time
prevalence in Dutch adults was 84% for alcohol, 28% for tobacco, 26% for cannabis, 6% for ecstasy,
5% for cocaine, 3% for amphetamine, 1% for GHB and 0.5% for heroin4. Although there is no exact
data: caffeine is the most widely used drug. In the Dutch adult population the use of GHB, cannabis,
cocaine, amphetamines and MDMA has increased in popularity in the recent years. In addition, the
use of opium has declined and the percentage of people using tobacco or alcohol is stable in the last
few years4.
Figure 1. Deaths by overdose of drugs in the Netherlands, from 19964
4
Illicit drugs are regulated by law on a global level. The same applies in the Netherlands, where
regulations on drugs are laid down in the Opium Act: a law that prohibits production, possession,
sale, trade, transport, export and import of drugs listed in it. The Opium Act distinguishes category I
and category II drugs. List I drugs are classified as hard drugs which can seriously cause health effects
of the user (e.g. cocaine, MDMA, amphetamine, heroin) and list II are classified as soft drugs which
cause fewer health problems (e.g. cannabis, GHB)82. However, prevention of drug use by listing them
on the Opium Act is counteracted by new legal derivatives that appear on the market when existing
drugs are prohibited. This occurs especially with ‘designer drugs’, which are manufactured in order
to circumvent the law3.
Designer drugs were created in the 1960s and refer to chemicals that are created for recreational
use. This is commonly done by modification of the molecular structures of existing illegal drugs with
the objective to produce similar effects from recreational drugs7. Creating new substances, which
are not regulated yet, hampers control on the sale and possession of these drugs. Mostly, when the
popularity of the drug increase, the drug becomes regulated14. Because most designer drugs are
relatively new, little or no information on the effects they can induce, are available. Therefore many
designer drugs of abuse are being labeled as "not for human consumption" to avoid regulation8.
Drugs are divided into several groups based on their effect: cannabinoids, stimulants, hallucinogens,
opioids, club drugs and dissociative drugs6. In this study, we have focused on stimulants and
psychedelics.
Stimulants enhance the activity of the peripheral and central nervous systems inducing temporary
improvement of physical or mental functions, e.g., enhanced wakefulness, alertness and
locomotion28. However, the use of stimulants can also result in adverse effects e.g., feelings of
paranoia, depression, feelings of paranoia, panic attacks, sleep and appetite disturbances29. Cocaine,
MDMA and amphetamine are the most widely used stimulants. These drugs are closely associated
with nightlife but also have a history of being used to enhance performance in the working area64.
Psychedelics are hallucinogens that are mainly used in closed groups but also as party drug65.
Psychedelics primarily alter thought processes in the brain causing primarily illusions and
hallucinations3, although mechanisms of action are not known. Psychedelics have a long history of
use in medicine, religion or recreational purposes. Psychedelics tend to affect the mind in different
ways such as a trance, spirituality, meditation and even near-death experiences65.
We aimed to gather information about various stimulant and psychedelic emerging drug that is
necessary to perform a toxicological risk assessment. Included drugs are relative new on the Dutch
market so limited data is available about these substances. The following stimulant drugs are
included: mephedrone, 4-fluoroamphetamine, 4-methylethcathinone and para-methoxy-Nmethylamphetamine. The following psychedelic drugs are included: methoxetamine, 4-bromo-2,5dimethoxyphenethylamine and 25I-NBOMe.
5
Mephedrone
- Chemical name: 2-methylamino-1-(4-methylphenyl)propan-1-one
- Street names: 4‐methylmethcathinone, 4-methylephedrone, MMCat, Drone, 4-MMC, meow meow,
Miaow, Ronzio, MMC hammer, Meph, Fiskrens, Bubbles, Ronzio, Tornado Spice E, Krabba, top cat,
Charge, Diablo XXX, Crab, Rush and Blow
- Molecular formula: C11H15NO
- Molecular weight: 177.24
Cathinone is an active alkaloid that can be found in the leaves of the Catha edulis (khat plant).
Synthetic derivatives of cathinone are entering the recreational drug market, including mephedrone
(4-MMC) which is a synthetic stimulant with entactogenic effects: it increases the feelings of
empathy. Despite its first synthesis in 1929, it has a short history of consumption14. Until 2010, it was
one of the most popular drug in European countries but reports indicate that the popularity of
mephedrone is declining12. This is mainly because mephedrone has become illegal, increased pricing,
some users have a negative experiences and the availability of a good quality cocaine and MDMA12.
The increase in popularity and its toxicity resulted in taking it under control as a class II drug and
prohibit its use in most European countries, including the Netherlands14.
Mephedrone (fig. 2) is also known as bath salts, plant
food or plant feeders. In the United States the name
bath salts is mainly used but in Europe the term plant
feeders and plant food are more common13.
Mephedrone can be taken as part of polydrug
combinations (e.g. alcohol, cannabis, ketamine)66 but it
is also sold as a substitute for ecstasy or cocaine14. In
Europe the prices range between €18 and €25 for one
gram12.
Figure 2. Molecular structure of
mephedrone12
Appearance
Mephedrone is usually sold as an odorless, white crystalline powder with a light yellow hue and less
frequently as capsules or tablets10. It is often sold in small plastic sealed bags with the labels
‘research chemical’, ‘not for human consumption’ or ‘not tested for hazards or toxicity’14. The
quantity of mephedrone in tablets sold to users in the Netherlands was found to be between 96 and
155 mg per tablet15.
Route of administration
Common modalities of intake are through snorting (nasal insufflation), by ingestion through
swallowing capsules/tablets or wrapping mephedrone powder in cigarette papers and swallowing it
(bombing)14. Nasal insufflation can lead to significant nasal irritation, so some users switch to
ingestion14. Less common methods include rectal administration (plugging or dissolved in an enema),
smoking or intravenous use67. Mephedrone powder is readily soluble in water and can be dissolved
for rectal/oral use or for injection67.
Pharmacokinetics
Absorption
Onset of the desired effects is typically seen within 15 to 45 minutes after ingestion. For nasal
insufflation or intravenous injection the desired effects occur within a few minutes14. Users
6
recommend to take mephedrone on an empty stomach because a delay of the onset of effects can
occur after ingestion on a full stomach14.
Metabolism
Mephedrone is metabolized by cytochrome P450 2D6 in the liver with the contribution from other
NAPDH-dependent enzymes and has five phase I active metabolites12. The following metabolites can
be detected in urine after usage: hydroxytolyl mephedrone, nor-hydroxyl mephedrone,
normephedrone, nor-dihydro mephedrone and 4-carboxy-dihydro mephedrone11. Mephedrone is
metabolized by three phase I pathways. The metabolic pathway of mephedrone starts with the Ndemethylation to the primary amine (nor-mephedrone, nor-dihyro mephedrone and norhydroxytolyl mephedrone metabolites), the reduction of the keto moiety to the respective alcohols
(nor-dihydromephedrone and 4-carboxy-dihydro mephedrone metabolites) and oxidation of the
tolyl moiety to the corresponding alcohols (hydroxytolyl mephedrone and nor-hydroxytolyl
mephedrone metabolites)10. The nor-hydroxytolyl mephedrone and hydroxytolyl mephedrone
metabolites are partly excreted in the urine as sulfate and glucuronide conjugates14.
In rats the maximum concentration (Cmax) was achieved rapidly after oral dosing. The time that
Cmax was reached (Tmax) was 25 minutes to 1 hour and plasma concentrations declined to
undetectable levels after 9 hours18.
Duration of effect
Ingested mephedrone effects last for 2 to 5 hours10 but according to different users a typical session
can also last for 10 hours12. Several consumers first snort and then ingest the drug in order to
achieve both fast and long lasting effects13.
Half-life
Human elimination half-life (t1/2) of mephedrone is not known, but t1/2 in rats after oral
administration of 30 mg/kg and 60 mg/kg is 30 minutes18.
Mechanism of action
In vitro studies of mephedrone confirm that the mechanism of action is similar to that of
amphetamine. It is being characterized by a predominant action on plasma membrane
catecholamine transporters. Mephedrone display potency as non-selective substrates for
noradrenalin, serotonin and dopamine transporters, differing from each other by its relative binding
potency. Mephedrone evoke transporter mediated release of monoamines through reversal of
normal transporter flux83. Repeated mephedrone injections in rats showed an IC50 to inhibit
dopamine uptake of 467 nM, whereas the IC50 value for serotonin uptake was 558 nM. There is no
data for the IC50 value of norepinephrine72.
In rats, researcher found that mephedrone produce elevations in extracellular dopamine and
serotonin with preferential effects on serotonin. A 950% increase in serotonin concentration and a
500% increase in dopamine concentration was observed in nucleus accumbens68.
Due the presence of the beta group in mephedrone, they show a reduced ability to cross the blood
brain barrier when compared with amphetamine analogs. The beta group is responsible for
increased solubility and it hinders crossing the blood-brain barrier. Because of these properties a
higher doses is required to achieve similar effects12.
Dose
Mephedrone is used in single use doses between 15 and 250 mg when ingested and between 5 and
7
125 mg for nasal insufflation. Use by other routes is less common: there is no data available about
these routes of administration14.
Mephedrone users commonly start with low amounts for nasal insufflation (50-75 mg), although due
to short-lived effects the total doses used per session rapidly increase to hundreds of milligrams per
dose14. To achieve an effect of 10 hours an average amount of 0.91 gram was used, divided into
several doses66.
Clinical effects
Mephedrone shares psychoactive properties of MDMA, amphetamines and cocaine. Users suggest
that the acute toxicity associated with mephedrone use is similar to that of MDMA, amphetamines
and cocaine9.
Desired effects14,10:
Short increases in locomotion
Increased energy and motivation,
Increased alertness and awareness
Euphoria
Improved mood
Excitement
Mild empathogenic effects
Reduced hostility
Intensification of sensory experiences
Sociability and talkativeness
Music sensitivity
Reduced appetite
Moderate sexual arousal
Perceptual distortions
Unwanted effects (per system) 12,13,18,10
1) Central nervous system:
Tremors
Trismus
Bruxism
Tense jaws
Mild muscle clenching
Headache
Stiff neck/shoulders
Dizziness
Rhabdomyolysis
Insomnia
Seizures
Tinnitus
Nystagmus blurred vision
Pupil dilation
Numbness of tactile sensitivity
2) Gastrointestinal system:
Loss of appetite
Nausea
Dry mouth
8
-
Vomiting
Stomach ache
3) Cardiovascular system:
Tachycardia
Respiratory difficulties
Elevated blood pressure
Peripheral vasoconstriction
Chest pain
Cold/blue fingers
4) Central nervous system/psychiatric:
Anxiety
Confusion
Agitation
Dysphoria
Aggression
Irritability
Depression
Anhedonia; time distortions
Lack of motivation
Long-lasting hallucinations
Short-term psychosis
Paranoid
Short-term mania; insomnia and nightmares
Poor concentration
Impaired short-term memory
Mental fatigue
Suicidal thoughts/actions
Developing psychological dependency
5) Miscellaneous:
Changes in body temperature regulation
Hyperthermia
‘Mephedrone sweat’ with a strong body odour
Nose and throat bleeds with burns and ulcerations
Painful nasal drip
Immunological toxicity
6) Renal/urinary excretory system:
Kidney failure
Difficulties in urination
Anorgasmia
Nephrotoxicity
7) Others:
Decrease in locomotion
Binging
Hyponatremia
Hyperuricemia
Hyperkalemia
9
-
Increased serum levels of creatinine kinase and creatinine
Weight loss after prolonged use
Metabolic acidosis
Toxicity (concentration)
Overdose: Wood et al. describe 15 patients who arrived at the emergency department after selfreported mephedrone use (mean exposure 2.1-2.3 grams). Several symptoms were reported; most
commonly were agitation, tachycardia (>100 bpm), seizures and hypertension (>160 mmHg)(table
1). 20% of the patients required treatment predominantly for management of agitation. The patients
were discharged without lasting damage70.
Recreational use of mephedrone usually results in blood levels ~0.3 mg/L. However, levels of 0.74
mg/L were also reported and did not result in fatalities16.
Table 1. Percentage of patients with clinical effects that are presented in the hospital after an overdose of
mephedrone70
Fatalities
In 2010, 45 mephedrone-related deaths were reported in England, 12 in Scotland, 1 in Northern
Ireland, 1 in Wales, and 1 in Guernsey13. However, generally there are no toxicological findings
available at the time of death to conclude if mephedrone use was responsible for the death.
Notably, even if mephedrone is detected, that does not necessarily mean that mephedrone was the
cause of or has contributed to the death14.
The first mephedrone-related death was an 18 year old female in Sweden in 2008. Despite a
successful resuscitation, she was brain dead 36 hours after arrival in the hospital. Initial
investigations showed hyponatraemia (120 mmol/L), cerebral oedema and a metabolic acidosis.
Toxicological screening of blood and urine revealed that no other drugs, apart from mephedrone,
were used. However, the mephedrone concentration was not reported26.
A few cases are reported in which plasma or blood concentrations of mephedrone are defined. A 22
year old male in the USA who was found collapsed, not responsive and was unsuccessfully
resuscitated. Urine toxicological screening was positive for different drugs and mephedrone (198
mg/L). Mephedrone was detected at a concentration of 0.5 mg/L in a postmortem blood sample.
The cause of death was due accidental multiple drug toxicity and there is no data available about the
amount of mephedrone that is consumed84.
10
Maskell et al. describe a 49-year-old female who insufflated 0.5 gram of mephedrone. After 2 to 4
hours she had a sore chest and vomited, shortly afterward she collapsed and died. Autopsy revealed
myocardial fibrosis within the anterior left ventricular wall (15 mm) and an old atherosclerotic
occlusion of the anterior descending coronary artery. Her death was to the adverse effects of
mephedrone with myocardial fibrosis and atherosclerotic coronary artery disease being contributing
factors. The mephedrone concentration was 0.98 mg/L in femoral venous blood.9 However,
generally in fatal cases concentrations of mephedrone are between 1 to 6 mg/L17.
11
4-Fluoroamphetamine
- Chemical name: 1-(4-Fluorophenyl)propan-2-amine
- Street names: PFA, 4-FA, 4-FMP, PAL-303, 4-flava, 4floor, 4-fluor, P-FMP, Flux (-cd cleaner),
benzeneethanamine, 1-(4-fluorfenyl)propaan-2-amine, para-fluoroamphetamine, 4-Fluoro-αmethylamphetamine and RDJ
- Molecular formula: C9H12FN
- Molecular weight: 153.20
4-Fluoroamphetamine (4-FA) is a designer drug and belongs to
the group of stimulants and has entactogenic effects. 4Fluroamphetamine is an amphetamine-like substance sharing
the same psychoactive properties to that of amphetamine
(fig. 3)21. In the Netherlands 4-FA is not listed in the Opium
Act. Although scientific studies have been conducted with this
drug already in 1975, it entered the market in 200721. The
drug exists for some years but limited data is available about
4-FA.
Figure 3. Molecular structure of 4fluoroamphetamine21
Appearance
4-FA is usually sold as crystal or powder. It may also occur that 4-FA is dissolved in a liquid or sold as
a tablet21.
Route of administration
The powder form is usually snorted (nasal) and liquids or tablets are usually ingested. When 4-FA is
swallowed, the powder is often placed in a capsule or wrapped into a cigarette paper. The drug can
also be smoked but this is less common22.
Pharmacokinetics
Absorption
After nasal insufflation onset of the desired effects occurs after a few minutes. After ingestion the
effects occur within 15 to 45 minutes22.
Metabolism
4-FA is probably entirely unchanged excreted from the body. Likely, 4-FA is not metabolized in the
liver by cytochrome P450 oxidase because the C-F bond at the 4-position on the phenyl ring resists
deactivation20.
Duration of effect
Users report that desired effects are seen within an hour of ingestion and the effects last for 5 to 8
hours. When insufflated, the duration of the effects will be shorter22. There are no published data
about the duration of the effects of other routes of administration.
Mechanism of action
4-FA strongly inhibits the re-uptake and is a releasing agent of dopamine, serotonin, and
norepinephrine.19 The IC50 values for inhibiting the re-uptake of dopamine, serotonin and
norepinephrine were 0.77, 6.8 and 0.42 µM, respectively. The EC50 values for stimulating the release
12
of dopamine, serotonin, and norepinephrine from synaptosome were 0.2, 0.73, and 0.037 µM,
respectively69.
Dose
4-FA is reported to be used in doses of between 75–150 mg for oral administration and 50-75 mg for
nasal insufflation22. Data about the doses for other routes of administration is not available.
Clinical effects
The effects are broadly similar to that of amphetamine and MDMA. Therefore, 4-FA produce mainly
sympathomimetic effects and also exhibit entactogenic properties19. Users reported that it is slightly
more hallucinogenic21.
Desired effects21:
Euphoria
Increased energy
Excessive talking
Mood elevation
Increased alertness and awareness
Reduced appetite
Unwanted effects22:
Tachycardia
Headache/dizziness
Anxiety or paranoia
Agitation
Clenching of the jaw
Difficulty concentrating
Hyperthermia
Insomnia
Harmful/painful to the nose (when snorted)
Nausea
Vomiting
Toxicity (concentration)
There is data available were serum samples were positive for 4-FA. Röchrich et al. describe two
individuals that were suspected for driving under the influence and seemed to have been impaired
by psychostimulant drugs. First, both individuals had been diagnosed as not having used drugs but
further toxicological screening revealed 4-FA serum concentrations of 0.35 mg/L and 0.475 mg/L. 4FA psychoactive effects are expected at these serum concentrations19.
There are no reports of fatalities or overdoses directly related to 4-FA use.
13
4-Methylethcathinone
- Chemical name: 2-Ethylamino-1-(4-methylphenyl)propan-1-one
- Street name: 4-MEC, 4-methyl-N-ethylcathinone
- Molecular formula: C12H17NO
- Molecular weight: 191.27
4-Methylethcathinone (4-MEC) is a synthetic stimulant
with entactogenic effects derived from cathinone (fig.
4). Its structure is similar to mephedrone and it has
been sold as replacement for mephedrone. After the
ban of mephedrone, 4-MEC has become available
online in 2010 as a legal alternative product. It can be
found in different bath salts including NRG-1 and NRG2. However, 4-MEC has an extremely short history of
human use23.
Figure 4. Molecular structure of 4Methylethcathinone23
Appearance
4-MEC is commonly sold in the form of a white powder or white/yellow crystals but is also available
as capsules or tablets. It is usually sold as a research chemical in quantities that vary from 1 gram to
1 kilogram with the labels not for human consumption. Sometimes 4-MEC is sold in mixtures with
other psychoactive substances, especially other cathinones. In that case it is mainly mixed with 3,4methylenedioxypyrrolidin-1-ynvalerone
(MDPV)
and
3,4-methylenedioxypyrrolidin-1ynbutiophenone (MDPBP)23.
Dose/route of administration
Users report that common starting doses are between 50-100 mg when ingested, although average
doses are between 100 to 200 mg and higher doses between 150 to 300 mg or more. Some users
consume multiple doses during a session to prolong the duration of the effect (1 to 1.5 gram). When
snorted, a lower dosage is used (with a common dose between 40 to 100 mg)23,25.
Pharmacokinetics
Absorption
Since pharmacokinetic data on 4-MEC is absent and 4-MEC is structurally similar to mephedrone23,
we assume that 4-MEC kinetics resembles mephedrone kinetics.
Onset of desired effects of mephedrone occurs within a few minutes after nasal exposure. When
mephedrone is ingested, effects are typically seen within 15 to 45 minutes14. We assume that the
absorption rate of mephedrone is equally to 4-MEC
Duration of effect
The strongest effects are observed after 30 to 40 minutes and the effects ends after approximately 2
to 4 hours when ingested. Effects of 4-MEC are similar to mephedrone but shorter, much weaker
and without intense euphoric effects23.
Mechanism of action
4-MEC is a re-uptake inhibitor: it inhibits the dopamine, norepinephrine and serotonin transporter.
The IC50 values for transporter inhibition dopamine, norepinephrine and serotonin are 4.28, 2.23 and
14
7.93 µM, respectively. 4-MEC is also a monoamine releaser: it induce transporter-mediated release
of serotonin but not dopamine and norepinephrine24.
Clinical effects
Desired effects23:
Excitation
Euphoria
Mood elevation
Increased energy
Relaxation
Empathy
Feeling of bliss
Increased tactile and musical appreciation
Unwanted effects23:
Lethargy confusion
Disappointing and weak effects
Anxiety
Nasal pain
Tremor
Tachycardia
Nystagmus
Sweating
Nausea
Vomiting
Some users reported that 4-MEC, compared with mephedrone, does not cause unpleasant
afterwards effects
Toxicity (concentration)
Overdose/fatalities: Gil et al. reported three cases were 4-MEC was found in blood samples with
concentrations of 0.046, 0.056 and 0.152 mg/L. In the first case, a man was found dead in his car.
The man was driving his car after using 4-MEC and alcohol. The blood concentration of 4-MEC was
0.152 mg/L but the alcohol concentration was also high (0.12 g/dL). In a second case, a man was
found unconscious after using multiple drugs. Despite resuscitation attempts, the man died in the
hospital following brain damage. Blood levels of 4-MEC amounted up to 0.056 mg/L. However, this
was not the main substance present in his blood. In both cases there was not a lethal concentration
of 4-MEC. In the last case, a 4-MEC blood concentration of 0.046 mg/L was found in a 27-year old
arrested man. The concentration of 4-MEC of the deceased (0.056 mg/L) was not much higher than
in the case of the arrested man23.
Fatalities
One case of fatal poisoning has been reported where an overdose of 4-MEC is clearly the cause of
death. However, limited data is available about this case. The only available information is the
concentration: 1.27 mg/L85.
15
para-Methoxy-N-methylamphetamine
- Chemical name: 1-(4-methoxyphenyl)-N-methyl-propan-2-amine
- Street names: PMMA, death, 4-MMA, Methyl-MA, 4-methoxy-N-methylamphetamine
- Molecular formula: C11H17NO
- Molecular weight: 179.26
para-Methoxy-N-methylamphetamine (PMMA) is a stimulant with entactogenic effects and a
psychedelic drug. It is the 4-methoxy analogue of methamphetamine (fig. 5). Its first synthesis was in
1938 but in the 1990s PMMA appeared on the market.
Generally, it is found in combination with MDMA59. In most
cases the users are unaware that the ecstasy pills are
contaminated with PMMA.54 However, PMMA it is used as
a substitute for ecstasy causing that it is mistakenly
ingested as ecstasy.58 PMMA is cheaper to produce and
has, in small amounts, similar effects to amphetamines or
ecstasy, although the toxicity of PMMA is substantially
higher. Because many intoxications and deaths were
reported, PMMA is known as “death”. In the Netherlands
Figure 5. Molecular structure of
PMMA is scheduled as a controlled drug57.
PMMA56
Appearance
PMMA is mostly sold in tablets but also in capsules.60 Common logos that are found on tablets
containing PMMA are Jumbo, Mitsubishi, or E58.
Route of administration
Data about the routes of administration is not available. Generally, just like ecstasy, ingestion will be
the most common route of intake.
Pharmacokinetics
Absorption
Kinetics regarding time of onset of effects of PMMA is not known but PMMA has, compared to
MDMA, a delayed onset of effects54; MDMA starts to work after 20 to 60 minutes61.
Metabolism
PMMA is metabolized by CYP2D6 on cytochrome P450 in the liver of rats mainly by O-demethylation
of the methoxy moiety to 4-hydroxy methamphetamine. Then catechol-O-methyl transferase
(COMT) catalyses methylation to 4'-hydroxy-3'-methoxy methamphetamine occurred. 3'-hydroxy-4'methoxy methamphetamine was formed to a small extent either by direct hydroxylation of PMMA
or COMT methylation of the 4'-position. A second metabolic pathway was the alteration of the side
chain. The metabolite 4-hydroxy amphetamine was formed via PMMA N-demethylation to PMA
followed by O-demethylation. PMA is an active metabolite of PMMA56.
Duration of effect
There is no exact data available about the duration of the desired effects. However, when desired
effects arise, the duration of effects are short62.
16
Half-life
The elimination half-life value in rats was approximately 1.0 hour with a plasma clearance of 4.4
L/h59.
Mechanism of action
PMMAs mechanism of action seems to be similar to that of MDMA: It is a potent releaser of
serotonin (EC50=41 nM), norepinephrine (EC50=147 nM) and reduced activity as a releaser of
dopamine (EC50=1.0 nM) from synaptic terminals86. PMMA is also a strong inhibitor of
monoaminoxidase (MAO) type A54.
PMMA produces long-term effects on brain serotonin neurons: it produces reductions in the
concentration of 5-HT and its metabolite (5-HIAA) in the brain. In addition, it produces a loss of
cortical 5-HT uptake sites55.
Dose
PMMA tablets contain between 20 and 97 mg58. PMMA has stimulant and hallucinogenic effects
with doses of less than 50 mg. Doses over 60 to 80 mg are potentially lethal, especially in the
presence of other psychoactive drug like alcohol63.
Clinical effects
Due the poor MDMA-like effects of PMMA, this can be perceived as a failure or weakness of the pill.
This may lead to re-dosing of more pills and eventually an overdose. In other, rare cases, users take
PMMA together with ecstasy to enhance the effects54.
Desired effects54:
Euphoria
Psychedelic effects.
Increased energy
Unwanted effects54:
Extreme hyperthermia
Agitation
Rhabdomyolysis
Cardiomyolysis
Hallucinations
Arrhythmias due to hyperkalemia
Dry mouth
Convulsions
Severe coagulopathy
Teeth grinding
Sweating
Nausea
Headache
Weakness
Difficulty speaking
Coma
Death (serotonin syndrome)
Toxicity (concentration)
Overdose: Detailed data is available on 22 cases of acute toxicity associated with recreational PMMA
use in Norway during a 6 month period which resulted in hospitalizations but no fatalities. The mean
17
PMMA blood concentration was 0.10 mg/L with a range of 0.01–0.65mg/L. However, one person
had a PMMA concentration of 0.65 mg/L, which is above the reported toxic range and can lead to
the death57. Also in Israel there were cases of recreational use of PMMA without fatalities. The
clinical manifestations reported several symptoms: coma, seizures, headache, tremor, dilated pupils,
diaphoresis, acute respiratory failure, cardiac arrhythmias, hyperthermia and organ failure76.
Fatalities
Worldwide many PMMA-related deaths are reported58. Vevelstad et al. indicate that until 2003
more than 90 fatal poisonings are attributed to the ingestion of PMMA in Canada, USA, Australia and
Europe57. Also after 2003 PMMA-related deaths were reported (table 2)57,75,76.
In Norway there was during a 6 month period 12 fatal intoxications related to PMMA use. 12 victims
were found dead. Initial investigations showed symptoms of hyperthermia, hyperactivity, acute
respiratory distress, cardiac arrest, sudden collapse, convulsions and/or multiple organ failure. The
mean PMMA concentration in peripheral blood was 2.02 mg/L. In 11 of these fatalities, the PMMA
concentrations were above 0.5 mg/L, and in most cases greater than 1.24 mg/L. PMMA blood
concentrations above 0.5 mg/L are reported to be associated with toxic and possibly lethal effects57.
In Israel the presence of PMMA in the blood is confirmed in 24 fatal cases. The mean age of these
cases was 27 years and 19 were males. 17 patients were pronounced dead at the scene, three died
on the route to the hospital while being resuscitated and four died in the hospital. The mean post
mortem blood PMMA concentration was 2.72 mg/L. Multiple drugs were taken in 17 fatal cases76.
In Taiwan there were 8 fatalities related to PMMA use75. The post mortem PMMA blood
concentrations in these cases are similar to those found in Israel.
Table 2. Number of PMMA-related deaths worldwide. Reported since 201188
Date
January 2011
March 2011
April 2011
2011
January 2012
September 2012
September 2012
December 2012 - January 2013
June 2013
August 2013
No. of cases
12
4
1
4
Ecstasy related deaths which
occurred that year were in fact
the result of a PMMA overdose
(N=?)
2
1
Several deaths (N=?)
1
1
Place
Norway
Netherlands (Limburg)
Iceland
Scotland
Canada
Ireland (County Cork)
Australia (Queensland)
United Kingdom
Netherlands (s-Hertogenbosch)
Netherlands (Sliedrecht)
18
Discussion
Mephedrone,
4-Fluoroamphetamine,
4-Methylethcathinone
and
para-Methoxy-Nmethylamphetamine are synthetic stimulants which affect the dopaminergic, serotonergic and
norepinephrine systems: they increase the neurotransmitter levels of these monoamines. Only
PMMA has a reduced effect on the dopaminergic system (EC50=1.0 nM) and there is no data of the
effect of mephedrone on the norepinephrine system.
4-MEC entered the market in 2010 as a legal alternative product for mephedrone. 4-MEC and
mephedrone (4-MMC) share many similarities and have similar sounding (street) names. Similarity in
action and structure of 4-MEC and mephedrone can predict some of its toxicity and properties.
However, often 4-MEC doses are used that are 40–100% higher than in the case of mephedrone.
Therefore, the similarities may cause confusion amongst users which can have consequences with
respect to their use.
In some countries mephedrone can be sold as either cocaine or ecstasy. The same applies for PMMA
which is sold as a substitute for ecstasy. This is also the case with 4-MEC, although this is mixed with
other psychoactive substances such as MDPV and MDPBP. Because the drug can be mixed with
other substances, drug users are unaware what substance is being consumed. This suggests that the
effects that occur after the drug is used can be falsely assigned to the use of mephedrone, 4-MEC or
PMMA. This is likely more of an issue with drugs that is purchased from dealers rather than from the
internet.
Most short-term clinical effects of these stimulants have much in common in which there is an entire
spectrum of adverse effects. For mephedrone and PMMA there is detailed information available on
the acute health and clinical effects but for 4-FA and 4-MEC there is limited data about overdoses or
deaths directly related to their use. However, PMMA is closely associated with toxic and possibly
lethal effects; many PMMA-related deaths are reported because PMMA is mistakenly ingested as
ecstasy. The toxicity of PMMA is substantially higher compared to ecstasy. Dosages over 60 to 80 mg
are potentially lethal for PMMA. In other stimulants this is a common dose to induce desired effects.
Mephedrone is also associated with fatalities and hospitalizations. However, generally in fatal cases
of mephedrone, higher doses are consumed.
19
Methoxetamine
- Chemical name: 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone
- Street names: MXE, skang, K-max, Bladder friendly ketamine, METH-O, Roflcoptr, m-ket, mexxy,
minx, jipper, and special K
- Molecular formula: C15H21NO2
- Molecular weight: 247.33
Methoxetamine belongs to the group of psychedelics and is an N-ethyl ketamine derivative 2-(3methoxyphenyl)-2-(ethylamine)cyclo-hexanone (fig. 6)30. It is one of a number of novel designer
drugs that is available for purchase over the internet. It is synthesized as a close structural analogue
of ketamine specifically to avoid regulations but to retain the psychoactive properties of ketamine.
Unlike ketamine, methoxetamine is marketed as a legal “bladder safe” drug32. In comparison with
ketamine the 2-chlore group on the phenyl ring of ketamine molecule is replaced with a 3-methoxy
group and the N-methyl group on the amine ring is replaced with an N-ethyl group36.
Figure 6. Molecular structure of ketamine (1) and methoxetamine (2)31
Appearance
Methoxetamine is sold through the Internet as a research chemical in the form of a white, odorless
powder31 with a price of 7 dollars for 50 mg33.
Routes of administration
Insufflation, ingestion, intramuscular, sub-lingual, intravenous and rectal are potential routes of
methoxetamine administration33. The most common route of administration is by insufflating73.
Pharmacokinetics
Absorption
When snorted, effects begin commonly after 10 to 20 minutes31. Data about the kinetics regarding
time of onset of effects is not available for other routes.
Metabolism
Methoxetamine is metabolized in the liver mainly by CYP450 enzymes. Three main metabolic steps
are observed: Odemethylation (catalyzed by CYP2C19 and CYP2B6), N-demethylation to the primary
amine (catalyzed by CYP3A4 and CYP2B6) and/or hydroxylation at the aryl part (catalyzed by
CYP2B6). The following phase I metabolites could be identified but it is currently not known whether
these metabolites are active: N-deethyl-, O-demethyl-, N,Obis-dealkyl-, O-demethyl-hydroxy-,
hydroxy-aryl- and N,O-bis-dealkyl-hydroxy-MXE.
20
Also the following phase II metabolites could be identified: O-demethyl-MXE sulfate, O-demethylMXE glucuronide, N-deethyl-MXE glucuronide, N,O-bis-dealkyl-MXE sulfate, N,O-bisdealkyl-MXE
glucuronide, O-demethyl-hydroxy-MXE glucuronide, hydroxy-MXE glucuronide, O-demethylhydroxy-MXE sulfate, and N,Obis-dealkyl-hydroxy-MXE sulfate35.
The main excretion product in urine is the N-deethyl metabolite. Hydroxy-metabolites are also
present but are probably of minor relevance35.
Duration of effect
Methoxetamine has been marketed as having longer lasting effects than ketamine based on the new
N-ethyl group and replacement of 2-chlorine by 3-methoxy moiety35. Users report that the average
duration of effect is 2.5 to 4 hours when insufflated, 3 to 5 hours when ingested and 2 to 3 hours
when intramuscular73.
Half-life
Kinetics regarding half-life time of methoxetamine are not known34. However, methoxetamine has,
compared with ketamine-induced effects, longer lasting effects. Therefore, it is likely that the
elimination half-life of methoxetamine last longer than ketamine (which is 2.5 hours)31.
Mechanism of action
It is believed that methoxetamine affect the dopaminergic system (it is a dopamine D2 receptor
agonists) and is an N-methyl D-aspartate (NMDA) antagonist32. NMDA receptors are glycine and
glutamate gated ionotropic receptors expressed in the central nervous system. NMDA receptors are
activated when glycine and glutamate are bound to it. Methoxetamine primarily acting at the NMDA
receptor pore as open channel blockers and deactivate the NMDA receptor32. Disruption of NMDA
processes is the common mechanism of anesthetic action89.
Methoxetamine also affect other neurotransmitter systems: it interact with 5-HT2 receptors, σ
receptors, μ and κ opioid receptors and muscarinic cholinergic receptors31.
Dose
Large variations in exposure doses have been reported by users. The most common way of
application is intranasal with a single dose of 20 to 50 mg. For intramuscular a single dose is between
10 and 50 mg35. A research of Kjellgren et al. collected information from public Internet forums and
the amount of methoxetamine ingested varied between 10–200 mg during a single session with an
average of 88 mg73. There is no data about the doses of other routes of administration.
Clinical effects
The effects of methoxetamine are similar to those of ketamine and are dose-dependent. At a very
high dose dissociation of the physical body (M-Hole) can occur: there is a complete loss of bodily
awareness, a total loss of time perception and profound distortions34. The side effects of ketamine,
like bladder pain and ureter obstruction, are lower. Because of the N-ethyl group, chronic use of
methoxetamine has been as a bladder safe derivative of ketamine32.
Desired effects31,32,33:
Euphoria
Anti-depressant effects
Anxiolysis
Sociability and talkativeness
Relaxation
Therapeutic self-reflection
21
-
Increase in clarity of thoughts
Unwanted effects31,32,33:
Insomnia
Depressive thoughts
Intensive hallucinations
Agitation
Disorientation
Sweating
Nausea
Numbness
Anxiety
Vomiting
Tachycardia
Aataxia
Toxicity (concentration)
Overdose: Shields et al. describe three cases of acute methoxetamine overdose. A 19 year old male
was brought to the hospital with severe truncal ataxia, incoordination, nystagmus and reduced
conscious level after nasal insufflation of methoxetamine. Adverse health effects persisted for 3-4
days before recovery. A serum sample was positive for methoxetamine at a concentration of 0.24
mg/L. Two other patients with the age of 17 and 18 years (with serum methoxetamine
concentrations of 0.45 mg/L and 0.16 mg/L, respectively) were presented in the hospital after nasal
insufflation of methoxetamine with several symptoms: severe cerebellar ataxia, incoordination,
difficulty with speech, imbalance and reduced conscious level. Within 24 hours spontaneous
recovery occurred. In the three cases an unknown dose of methoxetamine is insufflated and no
other drugs were used30.
Wood et al. also described three cases of acute methoxetamine overdose. The first patient was a 42year-old man who was found collapsed on the ground. After he had insufflated 0.5 gram of
methoxetamine, he was hypertensive (blood pressure 187/83 mm/Hg), tachycardic (heart rate 135
beats/min) and pyrexial. His serum methoxetamine concentration was 0.12 mg/L. The second
patient was a 29-year-old man who was found confused with tremor and hallucinations after he had
ingested 0.2 gram methoxetamine. He had hypertension (201/104 mm/Hg) and tachycardia (121
beats/min). His serum methoxetamine concentration was 0.09 mg/L. The third patient was a 28year-old man who collapsed in a nightclub after he had used an unknown amount of
methoxetamine. He was significantly agitated and confused. He had hypertension (198/78 mm/Hg)
and tachycardia (113 beats/min). His serum methoxetamine concentration was 0.20 mg/L. All
recovered after treatment with low dose of benzodiazepines and the methoxetamine was purchases
from the internet and smart shop90,32.
Fatalities
There are not many methoxetamine-related deaths reported. Wikstro et al. describe a case were a
26-year-old male was found dead on his floor of his apartment. Post-mortem examination revealed
pulmonary edema. A concentration of 8.6 mg/L methoxetamine was found in his femoral blood as
were three different cannabinoids. According to the circumstances and the high femoral blood
concentration of methoxetamine it was concluded that an unintentional acute fatal intoxication with
methoxetamine had occurred. However, the presence of the synthetic cannabinoids can have
contributed to his death37.
22
4-bromo-2,5-dimethoxyphenethylamine
- Chemical name: 2-(4-bromo-2,5-dimethoxyphenyl)ethanamine
- Street names: 2C-B, Nexus, Rusko, Erox, Synergy, Performax, Cyber, Toonies, Bromo, Spectrum and
Venus
- Molecular formula: C10H14BrNO2
- Molecular weight: 260.13
4-bromo-2,5-dimethoxyphenethylamine (2C-B) is a psychoactive agent related to both the
amphetamine-like stimulants like ecstasy and the mescaline-like psychedelics like LSD (fig. 7). 2C-B is
part of the 2C family and was the firstly synthesized of the 2Cs42. 2C-B was synthesized from 2,5dimethoxybenzaldehyde by Alexander Shulgin in 1974 and was initially intended for psychotherapy
use. The drug was used in therapies and allowed patients to bring up repressed memories and
suppressed emotions. After becoming popular for medical use, it became popular recreationally38.
It was used as a replacement for MDMA after MDMA
became scheduled in 1985. In 1997, 2C-B was listed in
the Opium Act to prevent further popularity in the
Netherlands. However, after 2C-B get banned in the
Netherlands other 2C analogues (e.g. 2C-I) became
available by suppliers as legal alternatives but after a
while also these 2C analogues got banned38.
Nowadays, 2C-B is used as a rave and club drug43.
Figure 7. Molecular structure of 2C-B40
Appearance
2C-B was first sold as a white powder, although recently it is also present as tablets or capsules43. In
the Netherlands, pure 2C-B tablets are difficult to obtain and 2C-B is probably only available as
mixture with MDMA (but sold as 2C-B)39.
Routes of administration
Orally and intranasal exposure are the most common routes of administration although insufflating
is painful to the nose43.
Pharmacokinetics
Absorption
When ingested, onset of the desired effects is delayed compared when 2C-B is insufflated. When
orally consumed, effects are seen within 30 to 90 minutes and when insufflated the effects occur
within a few minutes (after 5 minutes)44.
Metabolism
2C-B is metabolized by liver hepatocytes resulting in demethylation and deamination of 2C-B that
produces several metabolites. It is unknown whether these metabolites are active. Six metabolites
are identified: BDMPAA, BDMPE, B-2 HMPAA, B-2-HMPE, BDMBA, and B-2-HMPEA41.
4-bromo-2,5-dimethoxybenzoic acid (BDMBA) is produced by oxidative deamination of 2C-B. It is
expected that this reaction is catalyzed by monoamine oxidase. Oxidative deamination also results in
4-bromo-2,5-dimethoxyphenylacetic acid (BDMPAA) and 2-(4-bromo-2,5-dimethoxyphenyl)-ethanol
(BDMPE) metabolites. B-2-HMPE and B-2-HMPAA can arise due further metabolism of BDMPE and
BDMPAA by demethylation which is catalyzed by a cytochrome P450 dependent reaction although
23
which isoforms are involved is not identified. These metabolites can also be generated by
demethylation of 2C-B to B-2-HMPEA followed by oxidative deamination41.
Duration of effect
Users report that the effects last for 4 to 8 hours when taken orally. When insufflated, the duration
of the effects will be shorter but more intense: 2 to 4 hours42.
Half-life
The elimination half-life value in rats was 1.1 hours42.
Mechanism of action
2C-B has an affinity towards various central adrenergic and serotonergic receptors. 2C-B shows
affinity at the 5-HT2 receptor. It also shows agonist and antagonist activity at specific sub-receptor
sites. 2C-B also demonstrates affinity to 5-HT1C, 5-HT1B and 5-HT1A.91 Activation of the serotonin
system by an agonist ligand has been associated with hallucinogenic effects, although activation of
5-HT2A –coupled phospholipase D pathway or functional antagonism may also play a role42.
Researchers also found that 2C-B has inhibitory effects on monoamine oxidase (MAO): it increases
dopamine levels in the brains of rats which explain its stimulatory effects. However, the underlying
mechanism remains unclear78.
Dose
Users report that the most common doses are between 4–30 mg when ingested. Doses of 2C-B
exceeding 30 mg may cause health effects (like agitation and hyperthermia). Insufflated doses are a
little lower. When consumed orally, lower doses (4–10 mg) induce entactogenic-stimulating effects
(like euphoria) while higher doses (10–20 mg) induce psychedelic effects (like an increase in
receptiveness of the visual, auditory, tactile and olfactory sensations)42.
Clinical effects
Desired effects42,43,44:
Euphoria
Increased energy
Increased receptiveness of the visual, auditory, tactile and olfactory sensations
Increased laughing
Increased access to spiritual ideation
Hallucinations
Unwanted effects42,43,44:
Frightening hallucinations
Tachycardia
Diarrhea
Hyperthermia
Hypertension
Paranoia
Insomnia
Headache
Sweating
Confusion
Difficulty concentrating
24
Toxicity (concentration)
Because of its very low cross-reactivity, it is hardly detectable in urine in immunoassays and no
human data on concentrations of 2C-B is available40.
In rats orally exposed to 50 mg/kg, the maximum 2C-B serum concentration amounted up to 23.3
mg/ml, attained within 30 minutes42.
No intoxication or deaths involving 2C-B are reported in literature. Limited data is available about its
involvement in mortality40.
25
2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine
- Chemical name: 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine
- Street names: 25I-NBOMe, 25I, INB-MeO, NBOMe-2C-I, N-bomb, Smiles, 25I-NBOMe Solaris and
Cimbi-5
- Molecular formula: C18H22INO3
- Molecular weight: 427.28
NBOMe compounds have become popular psychedelics and the best known NBOMe compound is
25I-NBOMe (fig. 8)46. 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine
(25I-NBOMe) is a derivative of the substituted phenethylamine psychedelic 2C-I. This substitution of
the structure significantly increases the effectiveness of the drug to induce hallucinogenic effects47.
In 2003 Ralf Heim synthesized 25I-NBOMe at the Free University of Berlin. It was made as a
pharmacological tool to study the 5-HT2A receptor45. It has similar effects as LSD but 25I-NBOMe is
active at a lower dose and the synthesis is relatively easy46.
Although 25I-NBOMe was discovered in 2003, it was not used as a common recreational drug until
201046. In the Netherlands this drug has a legal status and can easily be obtained over the internet45.
Figure 8. Molecular structure of (1) 2C-I and (2) 25I-NBOMe47
Appearance
25I-NBOMe was first sold as powder. After a while it became available in the form of pre-loaded
paper doses (blotter), as a spray50, as liquid and as a powder enclosed in purple capsules47.
Routes of administration
Modalities of intake are usually by holding 25I-NBOMe (in blotter form) in the mouth and not
swallowing it (buccal or sublingual administration). Some users take the drug through nasal
insufflation in liquid (spray) or powder form50. Administration by means of intravenous injection or
ingesting the capsules occurs but is rare47.
Pharmacokinetics
Absorption
According to user reports the liquid or blotter must be held in the mouth for 10 minutes for total
absorption51. Data about kinetics regarding time of onset of effects for other routes is not available.
Metabolism
There is reduced information available about the metabolism of 25I-NBOMe. However, generally
25I-NBOMe undergoes N-acetylation or O-demethylation of the aromatic ring followed by sulfation
26
or glucuronidation. Another metabolic pathway is the deamination to the corresponding aldehyde
followed by reduction to the corresponding alcohol or by oxidation to the corresponding acid. These
Phase II metabolites can be detected in the urine. It is unknown whether these metabolites are
active53.
Duration of effect
After insufflation, the duration ranging from 4 to 6 hours and to 8 to 10 hours when taken buccal or
sublingual51.
Mechanism of action
25I-NBOMe acts as a full potent 5-HT2A receptor agonists (with Ki =0.044nM): it increases serotonin
levels and stimulation of the 5-HT2A receptors appears to be essential for the hallucinogenic
effects48. Other psychedelics (like LSD) are partial 5-HT2A receptor agonists79. This difference in
receptor affinity makes 25I-NBOMe a strong psychedelic.
Dose
25I-NBOMe can be active at low doses ranging from 50 to 250 μg when the administration is buccal,
oral or sublingual. The common dose range from 500 to 800 μg. However, doses above 700 μg can
cause a strong psychedelic experience46.
Clinical effects
To improve their bioavailability some internet suppliers offer the materials with hydroxypropyl-betacyclodextrin. The inside surface of hydroxypropyl-beta-cyclodextrin is hydrophobic and the exterior
surface is hydrophilic so they form complexes with hydrophobic compounds87. This improves the
poor water solubility of 25I-NBOMe and increase buccal or sublingual absorption50.
Desired effects45,50:
Euphoria
Feelings of love/empathy
Open and closed eye visual
Mental and physical stimulation
Hallucinations
Increased awareness
A change in consciousness
Unusual body sensations
Unwanted effects45,50:
Confusion
Difficulty communicating
Hypertension
Frightening hallucinations
Chest pain
Agitation
Tachycardia
Nausea
Insomnia
Paranoia
Aggression
Unwanted feelings (depression)
27
Toxicity (concentration)
Overdose: In 2013, seven patients were presented to hospitals in England after an acute overdose.
25I-NBOMe was the main active substance in both plasma and urine samples but data about the
concentrations is not available. 25I-NBOMe was used at a house party in almost all patients. All
recovered after treatment and several days in the hospital. However, one patient recovered from his
symptoms after 43 days. The clinical manifestations reported were tachycardia (n=7), agitation
(n=6), hypertension (n=4), aggression and hallucinations (n=6), seizures (n=3), hyperpyrexia (n=3),
elevated white cell count (n=2), clonus (n=2), rhabdomyolysis with acute renal failure (n=1), elevated
creatine kinase (n=7), metabolic acidosis (n=3) and acute kidney injury (n=1)47.
In another case an 18 year old male was presented to the emergency department in the USA after
he jumped out of a moving car. The patient admitted that he used 25I-NBOMe. He had
hallucinations, was tachycardiac, hypertensive and required physical restraints and treatment. His
symptoms gradually improved and returned to normal after 48 hours. A serum sample was positive
for 25I-NBOMe at a concentration of 7.6x10-4 mg/L80.
Fatalities
It is believed that 25I-NBOMe use have been responsible for several deaths. There are many reports
in the media of people who die as a result of 25I-NBOMe intoxication. However, there is a lack of
scientific background information in these cases such as the confirmation that 25I-NBOMe was used
or the 25I-NBOMe concentration. An example of such a 25I-NBOMe-related death is an 18 year old
man from Scottsdale. This man died in 2013 after ingesting an unknown amount of 25I-NBOMe that
was sold as LSD. A toxicology screen revealed that the cause of death was due acute 25I-NBOMe
poisoning. No other drugs or alcohol were found in his blood but there is no data about the 25INBOMe concentration50.
Poklis et al. describe a fatality of a 19 year old man who had ingested blotter paper of 25I-NBOMe.
After ingestion his friends found him unresponsive on the floor near his apartment. He was
pronounced dead at the scene and the police concluded that the man had either jumped or fallen
from his apartment balcony. The peripheral blood concentration of 25I-NBOMe was 0.405 mg/L and
the urine was determined to contain 2.8 x10-3 mg/L. However, the man was suffering from
hallucinations and the fall has probably led to his death81.
28
Discussion
Methoxetamine, 2C-B and 25I-NBOMe are psychedelics which belong to the group of hallucinogens.
However, 2C-B has both psychedelic and stimulant effects. In general, lower doses of 2C-B induce
stimulating effects while higher doses induce psychedelic effects42. Most short-term clinical effects
of these hallucinogens have much in common. However, the most common routes of administration
differ for each drug: buccal or sublingual for 25I-NBOMe, ingestion for 2C-B and insufflating for
methoxetamine.
Methoxetamine and 25I-NBOMe are novel designer drugs which are legal in the Netherlands. More
designer drugs become available on the Dutch market and the designer drugs can simply be ordered
over the internet. However, most designer drugs disappear after a while. Only when the drug is
increasing in popularity and the product appears to be harmful to human health, the drug is listed in
the Opium Act. This was also the case with 2C-B, which in 1997 was included in the Opium Act to
prevent further increase in popularity. However, 2C-B is still a popular drug. An explanation could be
that despite the offer of many designer drugs, people still choose for the ‘old familiar’, illegal drugs.
Cocaine, MDMA, ampthetamines and heroin are worldwide still the most popular drugs despite the
fact that they are listed in the Opium Act. This may be because users rather choose for the drugs
which they are familiar with the effects and risks than for new substances for which the effects are
unknown. Although the availability, quality and price also play a role in what kind of drugs is
consumed.
In comparison with 2C-B and (especially) 25I-NBOMe, a large dose of methoxetamine is needed to
induce psychedelic effects. For methoxetamine the average amount used during a session is 88mg.
For 2C-B a dose of 10-20 mg is enough to induce psychedelic effects and for 25I-NBOMe a dose of
700 μg causes strong psychedelic effects. Therefore, only a small amount of 25I-NBOMe is needed
for a strong psychedelic experience. Because only a small dose is needed, intoxications occur quickly
if too high doses are consumed.
The reason why a higher dose is needed for methoxetamine is because it differs in mechanism of
action. Most psychedelic/hallucinogenic drug (2C-B and 25I-NBOMe) increase the serotonin levels
and stimulate the 5-HT2A receptors which is essential for the hallucinogenic effects. However, this is
not the case for methoxetamine: it affects the dopaminergic system and it is a NMDA antagonist
which is the common mechanism of anesthetic action. As a result, methoxetamine does not belong
to the group of hallucinogens but is it rather a dissociative drug. 2C-B also affects the dopaminergic
system which explains its stimulatory effects.
29
General discussion
Based on these risk assessments, psychedelics are potentially more lethal than stimulants. This is
partly because hallucinogens have a high potency to induce toxicity in small doses. Aside from
PMMA, hallucinogens are active at smaller doses so intoxications occur quicker when taken in
excess. Hallucinogens can also cause frightening hallucinations which frequently caused severe or
fatal accidents. PMMA is an exception: this stimulant is associated with many hospitalizations and
fatalities but this is more due the fact that PMMA is confused with ecstasy. In most toxicities the
data suggest that the user have used multiple drugs. It is likely that combined drug consumption will
increase the risk of toxicity. However, the data on potential drug-related fatalities needs to be
interpreted carefully. Detection of a drug in a sample does not necessarily mean that this drug is
responsible for, or has contributed to, death.
Stimulants and hallucinogens differ in their mechanism of action. Stimulants may affect multiple
monoamine mechanisms but for hallucinogens this is usually not the case. Mephedrone, 4-FA, 4MEC and PMMA are stimulants with entactogenic effects and exert their effects through affecting
the norepinephrine, serotonin and/or dopamine systems. The hallucinogens have mainly one
working mechanism: affecting the serotonin system. However, methoxetamine and 2C-B also affect
the dopaminergic system and methoxetamine is a NMDA antagonist.
Because most designer drugs are new on the market, limited research has been conducted to the
drug. The absence of information and research finding is a general problem for risk assessments.
Therefore, the risk assessment conclusions are based on partial knowledge and are tentative. For
some emerging drugs there is detailed information available on the acute health effects associated
with drug toxicity from clinical case series. However, data about the chronic effects related to the
consumption of designer drug remain unknown. In order to still gather information, occasionally
information is obtained from user self-reports on Internet forum (e.g. Erowid). This may have the
effect that the information is not entirely reliable, although Internet forums also have positive
aspects. It can ensure that the use of designer drugs is less risky. Users interact extensively on
Internet forums about their experiences per dose. This means that users pay attention to what they
do and take an appropriate dose. The dose that is consumed determines together with the way of
administration and with the sensitivity of the user, to what extent and duration effects occur. This
means that for each person different effects can arise.
Mephedrone, PMMA and 2C-B have a longer history of human use compared to 4-MEC, 4-FA,
methoxetamine and 25I-NBOMe. Because mephedrone, PMMA and 2C-B have increased in
popularity and are associated with adverse effects, they are listed in the Opium Act. More data is
available about the adverse effects and toxicity of drugs that are listed in the Opium Act. The legal
status of the drug makes the drug easy to obtain. Either from internet suppliers, smart shops or from
street drug dealers. Individuals are often able to purchase unlimited amount of drugs. Controlling a
drug has the potential to bring with it both positive and negative consequences. Positive
consequences may include reduced availability and use of the drug. However, control measures
could create an illegal market with criminal activity and reduced quality of the drug.
All drugs are toxic to humans but mephedrone, PMMA and 25I-NBOMe have a high potency to
induce toxicity. The adverse side effects have been associated with many hospitalizations and
fatalities. Mephedrone and PMMA are listed in the Opium Act but this does not apply for 25INBOMe. The designer drugs of abuse are labeled as not for human consumption but it is taken for
recreational use. 25I-NBOMe, 4-MEC, 4-FA and methoxetamine are designer drugs which are legal
in the Netherlands but no guidelines are available so there is no data available about the appropriate
dose or on the effects they can induce. A proper dose of the drug must be consumed and not as part
30
of a polydrug combination to avoid intoxication. Further research is needed, especially with respect
to potential toxicity.
31
References
1) Henderson, G.L. Designer drugs: past history and future prospects. J Forensic Sci. 33(2).
1988: 569-75.
2) Brown, L.S. Substance abuse and America: historical perspective on the federal response to a
social phenomenon. Journal of the National Medical Association 73(6). 1981: 497-506
3) Wills, S. Drugs of Abuse (book). Pharmaceutical Press, 1 jan. 2005. 2nd edition.
4) Van Laar, M.W., Cruts, A.A.N., Van Ooyen-Houben, M.M.J., Meijer, R.F., Croes, E.A. and
Ketelaars, A.P.M. Nationale Drug Monitor. Jaarbericht 2011. Utrecht: Trimbos-instituut
2012.
5) Armand, N.M. The nontherapeutic use of psychoactive drugs: A modern epidemic. The New
England Journal of Medicine 308(16). 1983: 925-933.
6) Hondebrink, L., Tan, S., Hermans, E., van Kleef, R.G.D.M., Meulenbelt, J. and Westerink,
R.H.S. Additive inhibition of human α(1)β(2)γ(2) GABA(A) receptors by mixtures of
commonly used drugs of abuse. Neurotoxicology 35. 2013: 23-29
7) Hill, S.L. and Thomas, S.H.L. Clinical toxicology of newer recreational drugs. Clinical
Toxicology 49. 2011: 705-719
8) Nelson, M.E., Bryant, S.M. and Aks, S.E. Emerging drugs of abuse. Emerg Med Clin North Am.
32(1). 2014: 1-28
9) Maskell, P.D., De Paoli, G., Seneviratne, C. and Pounder, D.J. Mephedrone (4Methylmethcathinone)-Related Deaths. J Anal Toxicol. 35(3). 2011: 188-191.
10) Maskell, P.D., De Paoli, G., Seneviratne, C. and Pounder, D.J. Mephedrone: Public health risk,
mechanisms of action, and behavioral effects. Eur J Pharmacol. 714(1-3). 2013: 32-40
11) Meyer, M.R., Wilhelm, J., Peters, F.T. and Maurer, H.H. Beta-keto amphetamines: studies on
the metabolism of the designer drug mephedrone and toxicological detection of
mephedrone, butylone, and methylone in urine using gas chromatography–mass
spectrometry. Anal Bioanal Chem 397. 2010: 1225–1233
12) Zawilska, J.B. and Wojcieszak, J. Designer cathinones—An emerging class of novel
recreational drugs. Forensic Science International 231(1-3). 2013: 42–53
13) Schifano, F., Albanese, A., Fergus, S. et al. Mephedrone (4-methylmethcathinone; ‘meow
meow’): chemical, pharmacological and clinical issues. Psychopharmacology 214 (3). 2011:
593-602
14) Dargan, P.I., Sedefov, R., Gallegos, A. and Wood, D.M. The pharmacology and toxicology
of the synthetic cathinonemephedrone (4-methylmethcathinone). Drug Test. Analysis 3.
2011: 454–463
15) Brunt, T.M., Poortman, A., Niesink, R.J. and van den Brink, W. Instability of the ecstasy
market and a new kid on the block: mephedrone. J. Psychopharmacol. 2011: 1543-1547
16) Cosbey, S.H., Peters, K.L., Quinn, A. and Bentley, A. Mephedrone (Methylmethcathinone) in
Toxicology Casework: A Northern Ireland Perspective. Journal of Analytical Toxicology 37(2).
2013: 74-82
17) Cao, J., Kang, J., Ying, X., Ji, J., Reynolds, W. and Rampe, D. Mephedrone, a new designer
drug of abuse, produces acute hemodynamic effects in the rat. Toxicology Letters 208(1).
2012: 62–68
32
18) Martínez-Clemente, J., López-Arnau, R., Carbó, M., Pubill, D., Camarasa, J. and Escubedo, E.
Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to
pharmacodynamics. Psychopharmacology 229. 2013: 295–306
19) Röhrich, J., Becker, J., Kaufmann, T., Zörntlein, S. and Urban, R. Detection of the synthetic
drug 4-fluoroamphetamine (4-FA) in serum and urine. Forensic Science International 215(1–
3). 2012: 3–7
20) Fisher, M.B., Henne, K.R. and Boer, J. The complexities inherent in attempts to decrease drug
clearance by blocking sites of CYP-mediated metabolism. Curr Opin Drug Discov Devel. 9(1).
2006: 101-109.
21) Europol drugs newsletter (2009) Alert 2009-001, Project SYNERGY, 4-fluoroamphetamine
(EDOCF403292) 1. July 1–9
22) Erowid Experience Vaults. 4-fluoroamphetamine.
http://www.erowid.org/experiences/subs/exp_4Fluoroamphetamine.shtml
23) Gil, D., Adamowicz, P., Skulska, A., Tokarczyk, B. and Stanaszek, R. Analysis of 4-MEC in
biological and non-biological material--three case reports. Forensic Science International
Volume 228(1–3). 2013: 11–15
24) Simmler, L.D., Rickli, A., Hoener, M.C. and Liechti, M.E. Monoamine transporter and
receptor interaction profiles of a new series of designer cathinones. Neuropharmacology
79. 2014: 152–160
25) Erowid 4-Methylethcathinone (4-MEC) dose.
http://www.erowid.org/chemicals/4_methylethcathinone/4_methylethcathinone_dose.sht
ml
26) Gustavsson, D. and Escher, C. Mephedrone-Internet drug which seems to have come and
stay. Fatal cases in Sweden have drawn attention to previously unknown substance.
Lakartidningen 106. 2009: 2769-2771
27) Ralston, N. and Davies L. Teen jumps to his death after $1.50 drug hit. Sydney Morning
Herald 2013; Jun 6. http://www.smh.com.au/nsw/teen-jumps-to-his-death-after-150-drughit-20130606-2nrpe.html
28) Rockville (MD). Treatment for Stimulant Use Disorders (book). Treatment Improvement
Protocol (TIP) Series, No. 33
29) Williamson, S., Gossop, M., Powis, B., Griffiths, P., Fountain, J. and Strang, J. Adverse effects
of stimulant drugs in a community sample of drug users. Drug Alcohol Depend. 44(2-3).
1997: 87-94.
30) Shields, J.E. Dargan, P.I., Wodd, D.M., Puchnarewicz, M., Davies, S. and Warning, W. S.
Methoxetamine associated reversible cerebellar toxicity: Three cases with analytical
confirmation. Clinical Toxicology 50. 2012: 438–440
31) Hofer, K.E., Grager, B., Muller, D.M., Rauber-Luthy, C., Kupferschmidt, H., Rentsch, K.M., et
al. Ketamine-like effects after recreational use of methoxetamine. Annals of Emergency
Medicine 60(1). 2012: 97-99
33
32) Wood, D.M., Davies, S., Puchnarewicz, M., Johnston, A. and Dargan, P.I. Acute toxicity
associated with the recreational use of the ketamine derivative methoxetamine. Eur J Clin
Pharmacol 68. 2012: 853–856
33) Ward, J., Rhyee, S., Plansky, J. and Boyer, E. Methoxetamine: a novel ketamine analog and
growing health-care concern. Clin Toxicol 49. 2011: 874–875.
34) Corazza, et al. Phenomenon of new drugs on the Internet: the case of ketamine derivative
methoxetamine. Human Psychopharmacology: Clinical and Experimental 27 (2). 2012: 145–
149
35) Markus, R., Bach, Me., Bach, Ma., Welter, J., Bovens, M., Turcant, A., Maurer, H.H. Ketaminederived designer drug methoxetamine: metabolism including isoenzyme kinetics and
toxicological detectability using GC-MS and LC-(HR-)MS. Anal Bioanal Chem 405. 2013:
6307–6321
36) Dargan, P.I. and Wood, D.M. Novel psychoactive substances. Classification, pharmacology
and toxicology (book). 1st edition. 2013
37) Wikstro, M., Thelander, G. Dahlgren, M. and Kronstrand, R. An Accidental Fatal Intoxication
with Methoxetamine. Journal of Analytical Toxicology 37. 2013: 43–46
38) Dean, B.V., Stellpflug, S.J., Burnett, A.M. and Engebretsen, K.M. 2C or not 2C:
phenethylamine designer drug review. J Med Toxicol. 9(2). 2013: 172-178
39) de Boer, D., Gijzels, M.J., Bosman, I.J. and Maes, R.A.J. More Data About the New
Psychoactive Drug 2C-B. Journal of Analytical Toxicology 23. 1999: 227-228
40) Giroud, C., Augsburger, M., Rivier, L. and Mangin, P. 2C-B: A New Psychoactive
Phenylethylamine Recently Discovered in Ecstasy Tablets Sold on the Swiss Black Market.
Journal of Analytical Toxicology, 22. 1998: 345-354
41) Carmo, H., Hengstler, J.G., De Boer, D.D. et al. Metabolic pathways of 4-bromo-2,5demiethoxphenethylamine (2C-B): Analysis of phase 1 metabolism with hepatocytes of six
species including human. Toxicology 206(1). 2005: 75-89
42) Rohanová,M., Pálenícek,T. and Balíková,M. Disposition of 4-bromo-2,5dimethoxyphenethylamine (2C-B) and its metabolite 4-bromo-2-hydroxy-5methoxyphenethylamine in rats after subcutaneous administration. Toxicol Lett178. 2008:
29–36.
43) Caudevilla-Gálligo, F., Riba, J., Ventura, M., González, D., Farré, M., Barbanoj, M.J. and
Bouso, J.B. 4-Bromo-2,5-dimethoxyphenethylamine (2C-B): presence in the recreational drug
market in Spain, pattern of use and subjective effects. Journal of Psychopharmacology 26(7).
2012: 1026-1035
44) "Erowid 2C-B Vault: Effects". Erowid. Retrieved 2013-09-25.
http://www.erowid.org/chemicals/2cb/2cb_effects.shtml
45) Poklis, J.L. Devers K.G., Arbefeville, E.F., Pearson J.M., Houston, E. and Poklis, A. Postmortem
detection of 25I-NBOMe [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(234
methoxyphenyl)methyl]ethanamine] in fluids and tissues determined by high performance
liquid chromatography with tandem mass spectrometry from a traumatic death. Forensic
Science International 234. 2014: 14–20
46) Erowid E, Erowid F. "Spotlight on NBOMes: Potent Psychedelic Issues". Erowid Extracts. July
2013:2-5.
47) Hill, S.L., Doris, T., Gurung, S., Katebe, S., Lomas, A., Dunn, M., Blain, P. and Thomas, S.H.L.
Severe clinical toxicity associated with analytically confirmed recreational use of 25I–
NBOMe: case series. Clinical Toxicology. 2013: 1–6.
48) Halberstadt, A.L. and Geyer, M.A. Effects of the hallucinogen 2,5-dimethoxy-4iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch
response. Neuropharmacology 77. 2014: 200–207
49) Poklis, J.L., Charles, J., Wolf, C.E., Poklis, A. High‐performance liquid chromatography tandem
mass spectrometry method for the determination of 2CC‐NBOMe and 25I‐NBOMe in human
serum. Biomedical Chromatography. 27(12). 2013: 1794-1800
50) Iversen, L. Temporary Class Drug Order Report on 5-6APB and NBOMe compounds. Advisory
Council on the Misuse of Drugs. Gov.Uk. Retrieved 16 June 2013.
51) Erowid Experience Vaults. 25I-NBOMe. https://www.erowid.org/chemicals/2ci_nbome/
52) Upshall, D.G. and Wailling, D.G. The determination of LSD in human plasma following oral
administration. Clin Chim Act 36. 1972: 67–73.
53) SOFT Designer Drug Committee Monographs vers. 1.1. Emerging Designer Drug Monograph.
25I-NBOMe. 2013
54) Páleníček, T., Balíková, M., Rohanová, M., Novák, T., Horáček, J., Fujáková, M. and Höschl, C.
Behavioral, hyperthermic and pharmacokinetic profile of para-methoxymethamphetamine
(PMMA) in rats. Pharmacology, Biochemistry and Behavior 98. 2011: 130–139
55) Steele, T.D, Katz, J.L. and Ricaurte, G.A. Evaluation of the neurotoxicity of N-methyl-1-(4methoxyphenyl)-2-aminopropane (para-methoxymethamphetamine, PMMA). Brain
Research 589 (2). 1992: 349–352
56) Staack, R.F. and Maurer, H.H. Metabolism of designer drugs of abuse. Curr Drug Metab. 6(3).
2005: 259-74.
57) Vevelstad,M., Leere Øiestad, E., Middelkoop, G., Hasvold, I., Lilleng, P., Delaveris, G.J.M.,
Eggen, T., Mørland, J. and Arnestad, M. The PMMA epidemic in Norway: Comparison of fatal
and non-fatal intoxications. Forensic Science International 219 (1–3) 2012: 151–157
58) E. European Monitoring Centre for Drugs and Drug Addiction. Risk Assessments, Report on
the Risk Assessment of PMMA in the Framework of the Joint Action on New Synthetic Drugs,
2003. http://www.emcdda.europa.eu/attachements.cfm/att_33350_EN_Risk5.pdf.
59) Rohanova, M. and Balikova, M. Studies on distribution and metabolism of paramethoxymethamphetamine (PMMA) in rats after subcutaneous administration. Toxicology
259. 2009: 61–68
60) Dong-tiang tin, Hsiu.Chuan Liu, and Hsin-Ling Yin. Recent paramethoxymethamphetamine
(PMMA) deaths in Taiwan. Journal of Analytical Toxicology, 31. 2007: 109-113
61) Nationaal Vergiftigingen Informatie Centrum. Stofmonografie MDMA. Universitair Medisch
Centrum Utrecht. https://vergiftigingen.info/stofmonografie_inzien.htm?execution=e1s6
62) Shulgin, A and Shulgin, A. Pihkal. A chemical love story (book). 1991
35
63) Degenhardt, L. & Hall, W. The health and psychological effects of “ecstasy” (MDMA) use.
NDARC Monograph No. 62. National Drug and Alcohol Research Centre
64) UNODC, World Drug Report 2012 (United Nations publication, Sales No. E.12.XI.1)
65) Millman, R,B., Beeder, A.B. The new psychedelic culture: LSD, ecstasy, "rave" parties and the
Grateful Dead. Psychiatric Annals, Vol 24(3). 1994: 148-150.
66) Winstock, A.R., Mitcheson, L.R., Deluca, P., Davey, Z., Corazza, O. and Schifano, F.
Mephedrone, new kid for the chop? Addiction, 106. 2011: 154–161
67) Psychonaut Web Mapping Research Group. Mephedrone Report. London, UK: Institute of
Psychiatry, King’s College London; 2009.
68) Kehr, J., Ichinose, F., Yoshitake, S., Goiny, M., Sievertsson, T., Nyberg, F. and Yoshitake, T.
Mephedrone, compared to MDMA (ecstasy) and amphetamine, rapidly increases both
dopamine and serotonin levels in nucleus accumbens of awake rats. British Journal of
Pharmacology 164 (8). 2011: 1949–1958.
69) Nagai, F., Nonaka, R. and Satoh Hisashi Kamimura, K. The effects of non-medically used
psychoactive drugs on monoamine neurotransmission in rat brain. European Journal of
Pharmacology. 559(2-3). 2007: 132-137
70) Wood, D.M., Greene, S.L. and Dargan, P.I. Clinical pattern of toxicityassociated with the
novel synthetic cathinone mephedrone. Emerg Med J 28. 2010: 280-282
71) Wood, D.M., Davies, S., Greene, S.L., Button, J. Holt, D.W., Ramsey, J. and Dargan, P.I. Case
series of individuals with analytically confirmed acute mephedrone toxicity. Clin. Tox. 48.
2010: 924-927
72) Hadlock, G.C., Webb, K.M. et al. 4-Methylmethcathinone (Mephedrone):
Neuropharmacological Effects of a Designer Stimulant of Abuse. The journal of
pharmacology and experimental therapeutics 339(2). 2011: 530-536.
73) Kjellgren, A. and Jonsson, K. Methoxetamine (MXE) – A Phenomenological Study of
Experiences Induced by a “Legal High” from the Internet. J Psychoactive Drugs. 45(3). 2013:
276–286.
74) Steele, T.D., Katz, J.L. and Ricaurte, G.A. Avaluation of the neurotoxicity of N-methyl-1-(4methoxphenyl)-2-aminopropane (para-methoxmethamphetamine, PMMA). Brain Research,
589. 1992: 349-352
75) Dong-Liang Lin, Hsiu-Chuan Liu and Hsin-Ling Yin. Recent Paramethoxymethamphetamine
(PMMA) Deaths in Taiwan. J Anal Toxicol 31(2). 2007: 109-113.
76) Lurie, Y., Gopher, A., Lavon, O., Almog, S., Sulimani, L. and Bentur, Y. Severe
paramethoxymethamphetamine (PMMA) and paramethoxyamphetamine (PMA) outbreak in
Israel. Clinical Toxicology 50. 2012: 39–43
77) Villalobos, C.A., Bull, P., Sáez, P., Cassels, B.K. and Pablo Huidobro-Toro, J.
4-Bromo-2,5-dimethoxyphenethylamine (2C-B) and structurally related phenylethylamines
are potent 5-HT2A receptor antagonists in Xenopus laevis oocytes. British Journal of
Pharmacology 141, 2004: 1167–1174
78) Páleníček, T. et al. Behavioral, neurochemical and pharmaco-EEG profiles of the psychedelic
drug 4-bromo-2,5-dimethoxyphenethylamine (2C-B) in rats. Psychopharmacology 225. 2013:
75–93
79) Marek, G.J. and Aghajanian, G.K. LSD and the phenethylamine hallucinogen DOI are potent
partial agonists at 5-HT2A receptors on interneurons in rat piriform cortex. J Pharmacol Exp
Ther. 278(3). 1996: 1373-1382.
36
80) Rutherford, R.S., Polkis, J.L. and Polkis, A. A case of 25I-NBOMe (25-I) intoxication: a new
potent 5-HT2A agonist designer drug. Clinical Toxicology 51(3). 2013: 174–177.
81) Poklis, J.L., Devers, K.G., Arbefeville, E.F., Pearson, J.M., Houston, E. and Poklis, A.
Postmortem detection of 25I-NBOMe [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2methoxyphenyl)methyl]ethanamine] in fluids and tissues determined by high performance
liquid chromatography with tandem mass spectrometry from a traumatic death. Forensic
Science International 234. 2014: 14–20.
82) van Ours, J.C. Is cannabis a stepping-stone for cocaine? Journal of Health Economics 22(4).
2003: 539-554
83) Baumann, M.H., Ayestas, M.A., Partilla, J.S., Sink, J.R., Shulgin, A.T., Daley, P.F., Brandt, S.D.,
Rothman, R.B., Ruoho, A.E. and Cozzi, N.V. The Designer Methcathinone Analogs,
Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue.
Neuropsychopharmacology 37. 2012: 1192–1203
84) Dickson, A.J., Vorce, S.P., Levine, B. and Past, M.R. Multiple-drug toxicity caused by
coadministration of 4-methylmethcathinon (mephedrone) and heroin. J. Anal. Toxicol. 34.
2010: 162-168
85) Rojek, S., Kłys, M., Maciów, M., Kula, K. and Strona, M. Two fatal cases of intoxication with 4MMC and 4-MEC – medicolegal expertise. Annual Meeting of the International Association
of Forensic Toxicologists, 4 June 2012, Hamamatsu, Japan
86) Glennon, R.A. and Young, R. Drug discrimination. Applications to medicinal chemistry and
drug studies (book). 2011
87) Rogers, T,L., Nelsen, A.C., Hua, J., Brown, J.N., Sarkari, M., Young, T.J., Johnston, K.P. and
Williams, R.O. A novel particle engineering technology to enhance dissolution of poorly
water soluble drugs: spray-freezing into liquid. European Journal of Pharmaceutics and
Biopharmaceutics 54. 2002: 271–280
88) Drugs-forum. para-Methoxy-N-methylamphetamine. http://www.drugsforum.com/forum/showwiki.php?title=para-Methoxy-N-methylamphetamine
89) Flohr, H., Glade, U. and Motzko, D. The role of the NMDA synapse in general anesthesia.
Toxicology Letters 100–101. 1998: 23–29
90) Logical. Analytical Monograph. Methoxetamine. LGC Standards. 2012
91) Barceloux, D.G. Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive
Plants (book). 2012
37