analytische chemie v

24 Pages·2016·1.17 MB·English

by  Katharina Rentsch

ANALYTICAL STRATEGIES 1. November 2016

CLINICAL ANALYTICS: TOXICOLOGICAL SCREENING /
SCREENING FOR DRUGS OF ABUSE

Katharina Rentsch
Laboratory Medicine, University Hospital Basel

The Laboratory Medicine at the University Hospital Basel provides the following services to
the hospital and many external costumers:
- > 4.0 Mio. results in 2015
- > 500 different analytes in plasma, serum, blood, urine, faeces, meconium, saliva
- Working hours: 365 days/year, 24 hours/day
- Very fast turn-around times for a selected panel of analytes
- Special diagnostics fields of toxicology, drug monitoring, protein and cerebrospinal fluid
analytics.

The analytical techniques used comprise immunological, chemical and enzymatic methods
as well as electrophoresis, LC-MS and GC-MS. Most of the analyses are performed with
highly automated instruments; the chromatographic instruments are all equipped with
autosamplers.

Case:
At 1:00 a.m. a 23 year old male patient is admitted to the emergency department of the
University Hospital in Basel. He was very agitated, had a combative violent behaviour and
hallucination. He has been found in his home standing on his bed complaining of mice
everywhere. He was given the antidote for opiate intoxications without any effect.
The classical drugs of abuse screening tests in the laboratory were negative. The physicians
then suspected the intake of legal highs or research chemicals and sent a urine and a blood
sample to the laboratory.
Questions:
1. Which compounds are used as legal highs or research chemicals?
2. What is the action of these substances?
3. Which is/are the method(s) of choice for the analysis of these compounds? Which are the
advantages or the disadvantages of the different methods?
4. How is the legal situation with these compounds in Switzerland?

Literature:
1. Clinical Toxicology 2011;49:499-505
2. Clinical Toxicology 2012;50:15-24
3. The American Journal of Drug and Alcohol Abuse 2012;38:176-180
4. http://www.sscc.ch/scdat/en/guidelines.html “Guidelines for drugs of abuse testing”
TheAmericanJournalofDrugandAlcoholAbuse,38:176–180,2012
Copyright©InformaHealthcareUSA,Inc.
ISSN:0095-2990print/1097-9891online
DOI:10.3109/00952990.2011.643999
“Bath Salt” Ingestion Leading to Severe Intoxication
Delirium: Two Cases and a Brief Review of the
Emergence of Mephedrone Use
David P.Kasick,M.D.,CurtisA.McKnight,M.D.,andEleonoraKlisovic,M.D.
DepartmentofPsychiatry,TheOhioStateUniversityCollegeofMedicine,Columbus,OH,USA
2
1 “bath salts,” which have been found to contain the stim-
9/ Background:Recreationaluseofdesignersubstances
09/1 containingsyntheticcathinonessuchasmephedrone, ulant compound mephedrone (4-methylmethcathinone;
n Table 1) (1,2). Mephedrone is among several synthetic
o commonlysoldas“bathsalts,”hasrecentlybeen
el derivativesofcathinone,ascheduleIstimulantsubstance
Bas increasingintheUnitedStates(NationalInstituteon found in the khat (Catha edulis) plant grown in east
of DrugAbuse.Availableat:http://www.nida.nih.gov/ Africa. These synthetic stimulant compounds have been
sity about/welcome/MessageBathSalts211.html.Accessed previouslyreportedintheUnitedKingdomandelsewhere
er March25,2011;TheWashingtonPost.Availableat:
v inEuropetoproduceaprofounddeliriogenictoxidrome,
Uni http://www.washingtonpost.com/national/ generatingintenseagitationandhallucinations.Similarto
m by officials-fear-bath-salts-becoming-the-next-big- otherabusablestimulantagents(cocaine,amphetamines,
co drug-menace/2011/01/22/ABybyRJ_story.html. methylenedioxymethamphetamine (MDMA)), patients
nformahealthcare.ersonal use only. apAgauesrcsnotcohfeeocrosiuasraetsntededsdaeMdenwkeailinrittrcohtiheuasnm2ilsge5e,rn,tpsi2fitcs0iylcmi1acn1hnui)cotl.aisma“ninsBto,sartaobttnohxidditsdihaotryeltot.h”pmOeoirebntemjagennecetstddiitaviihlcoeaanfsol:scrTabanehndeen whetlaarawihavnloeeehdnhhofaaspovdphreicysteaeisnmlvicgaeeaedrnlesmt,taehipndsarsdositothvbrneeaerchfsitofiaterivedmiadotduotrelhaxaqelinudtpsarseroteqefmsoumeeuenslnacandteeha.oiagnAftemmrl“etbheeqanoputtuhihrgeoedhsfargsolUeutnsnsSe”--
d from iFor p sbeerhieasv.ioRreaslusletqs:uWelaeedoefsc“rbibaethosuarltr”ecuesnet.eMxeptehroiednsc:eCase asanldtso,”thweerasryenuthneatwicarceatohfinaonnyepudberliisvhaetidvecsonfofiurmndedinpa“tbieantht
de withtwohighlyagitatedanddeliriouspatients
a casesoutsideofEurope,possiblyduetohospitaltoxicol-
o
wnl following“bathsalt”ingestionandofferabrief ogylabsnotyetroutinelytestingforthepresenceofthese
o reviewoftheemergenceofthisphenomenon.
D compounds. We anticipate that clinicians will increas-
e Conclusions:Challengesandstrategiessurrounding
us ingly encounter similar delirious toxidromes as the use
b diagnosisandtreatmentaredescribed,whichmaybe
A becomes more prevalent. Maintaining awareness of this
ol usefulas“bathsalt”usebecomesmorewidespread.
h phenomenon when evaluating patients with toxic inges-
Alco ScientificSignificance:Asanemergingtrend,bath tions will be helpful until confirmatory testing becomes
ug saltintoxicationdeliriumappearstocauseintense more widely available in clinical settings. We report our
Dr psychosisthatcanbemanagedwithantipsychotic recent experiences with two patients seen in psychiatric
m J medications.Cliniciansshouldbeawareofthis consultationonageneralhospitalmedicalunitfollowing
A phenomenonuntilmoreprecisedetectionmethods
thepurposefulingestionof“bathsalts.”
areavailable.
Keywords:bathsalts,mephedrone,delirium CASE1
“Mr. A,” a 38-year-old Caucasian male without prior
history of psychosis, was taken to an outside hospital
INTRODUCTION by Emergency Medical Services (EMS) after his signif-
Since late 2010, news media outlets in the United States icant other called to report that Mr. A was seeing snakes
have reported a recent surge in the sale, consumption, and acting strangely. The patient was found in his home
and abuse of synthetic stimulants packaged and sold as standingonhisbedcomplainingof“snakeseverywhere.”
AddresscorrespondencetoDavidP.Kasick,DepartmentofPsychiatry,TheOhioStateUniversityCollegeofMedicine,1670UphamDrive,
Suite130,Columbus,OH43210,USA.Tel:[phone].E-mail:[email protected]
176
“BATHSALTS”ANDTHEEMERGENCEOFMEPHEDRONEUSE 177
TABLE1. Variousreported“bathsalt”tradenames(1,2). obtained 9 hours after the initial drug screen, which was
positive for benzodiazepines, but negative for PCP or
Bathsalttradenames
anyothersubstances.Hebecameprogressivelycalmeras
IvoryWave the day progressed, but continued to have difficulty with
PurpleWave awareness,orientation,cognitivespeed,andattention.
RedDove By the following morning, 35 hours after Mr. A’s
BlueSilk first contact with EMS, Mr. A remained guarded and
Zoom
irritable, but his consciousness and awareness were sig-
Bloom
nificantly improved. Mr. A clearly described purchasing
CloudNine
“bath salts” from a local “head shop” and twice drank
OceanSnow
a mix of roughly half a tablespoon of “bath salts” in
LunarWave
a carbonated cola beverage over the 2 days prior to
VanillaSky
WhiteLightning admission.Hecontinuedtostoutlydenyeverusingphen-
Scarface cyclidine, although described more remote history of
HurricaneCharlie alcohol and cannabis use. He denied any history of psy-
2
1 Posh chosis or prior treatment from a psychiatrist. His vital
9/
9/1 ArcticBlast signs and elevated CK had normalized. His physical
0
n and neurological exams were unremarkable. His Mini-
o
el Mental State Examination (MMSE) was 28/30 (missed
s
Ba He was given 2 mg of naloxone twice at the scene with the floor of the hospital, one serial 7). His significant
of noimprovement.After45minutesofverbalde-escalation other was contacted who agreed with the history he
y
sit bymedics,thepatientwasrestrainedtotheEMScotand presented.
er
niv takentoanoutsidehospital. Over the next 24 hours, Mr. A showed sustained
U While in the outside hospital emergency department improvements in attention, awareness, focus, concentra-
y
m b (ED), he was tachycardic (EKG revealed heart rate tion, and speed of thought. Hehad no residual psychotic
co of 144, occasional premature ventricular contractions symptoms and performed normally on further bedside
nformahealthcare.ersonal use only. aTt(1hP0habV0etl.aC8Mpn◦sakF)rt.,e;iteAahnndethdu’wsaeQdastsoiTignrcenfgesieofitasrfrcatseai4ndnt3eht0“dabotbmath“utshset)crrsoeaaprfnlpurtdosiso”vehnidpdissat”eocdtwkebamfeougupcrelteoddhrveauebrtnruietdhredeeisrhwtwoitimhrathyes. cwothoniagtethnohihfteiivtswheesosiucwglrndoeierfinsncotiatnenegxtn.pgoHeatrehigeewenr.cianesHsadeoirsfdecpehhseiacsarrtgliibiefndeegdtaehnshetdiisfowonilna.logsweasditniaogmndaaanyst
d from iFor p npahmyseic“iAanrcdtioccBumlasetn,”tetdwtihceatopvoerlictheefporuinodr2“bdaatyhs.sTalhtes”EiDn
de CASE2
a the patient’s personal effects. In the triage area, Mr. A
o
wnl was complaining of “things crawling on him and in his Mr. B, a 26-year-old Caucasian male, presented to the
o
D hair.” He remained agitated in the ED and received 3 ED2daysafternasallyinsufflating“fourlines”of“bath
e
us mg of IV lorazepam over the course of 4 hours with 2 salts”(laterapproximatedtobe2gof“PoshAromather-
b
A L of IV fluids. Laboratory assessment revealed elevated apy Bath Salts” in an 8-hour period) that he purchased
ol
h hemoglobin and hematocrit, consistent with his history at a local gas station. He reported first consuming “bath
o
c
Al ofpolycythemia.Hiswhitebloodcellcountandplatelets salts” 1 month prior to admission and had been snort-
ug were normal. He also had negative acetaminophen and ingsmalleramountsonadailybasissincethattime.Mr.
J Dr salicylate levels, glucose of 99, and TSH within normal B reported auditory hallucinations, as well as prominent
m limits.Chemistrypanelandliverfunctiontestswereunre- illusionsandfeelingsofdetachmentandderealizationfol-
A
markable. His first urine drug screen had a presumptive lowinghisdailyuse.Hereporteddevelopingtoleranceto
positive for phencyclidine (PCP) only, although this was hisdailyuseofsmalleramounts(between0.25and0.5g)
notabletobeconfirmed.Serumethanolwaszero. anddecidedtousealargeramountpriortobeingadmitted
Thepatientwassubsequentlytransferredtoourtertiary tothehospital.
academic medical center. He remained highly agitated In addition to its usual effects, following his 2 g
and hyperalert and required 4 mg of IV lorazepam due insufflation, Mr. B developed prominent paranoia, suici-
to attempts to leave the hospital. He was persistently dal ideation, confusion, delirium, tremors, hyperreflexia,
anxious and paranoid, believing that people were steal- myoclonus, and amnestic effects. He had significant dif-
ing his belongings. He was also physically combative ficultyrememberingdetailsofhisbehaviorinthe2days
with numerous security officers, at one point undressing thatelapsedsincehisoverdose,althoughweverifiedlater
while attempting to elope from the hospital. Due to his that he was briefly in the custody of law enforcement,
protracted physical aggression, an additional total of 6 having been found after driving his car into a ditch. He
mg of IV lorazepam and 5 mg of IM haloperidol were recalled the desire to die at that time, vaguely recalling
administered. Creatine kinase (CK) level was elevated the desire to jump in front of a car while standing along
at 1468 U/L. He was given IV fluids at a rate of 200 a freeway. He described intense auditory hallucinations
mL/hour over 24 hours. An additional drug screen was and paranoid delusions of being followed by “unmarked
178 D.P.KASICKETAL.
cars” and was picking in the air at apparent visual hallu- Although the synthesis of mephedrone was first
cinations. His chemistries at admission included slightly described in 1929, there is a limited amount of
elevated creatinine (1.33), mildly elevated transaminases published data surrounding its bioactive properties (9).
(ALT64,AST50),andCKof1665.Hewasafebrile,but Mephedrone, one of the numerous beta-keto analogues
hadmildhypertensionandtachycardia,althoughhisEKG of amphetamine, shares psychoactive properties similar
was otherwise unremarkable. His comprehensive urine to cocaine, amphetamines, and MDMA (10). As cathi-
toxicology screen was negative for any identifiable sub- nones bind to noradrenaline, dopamine, and serotonin
stances.HisroommatealsolaterconfirmedthatMr.Bhad transporters,mephedroneisexpectedtoactasastimulant
onlyingested“bathsalts”andnoothersubstances. by promoting the release of monoamine neurotransmit-
While hospitalized, Mr. B continued to remain rest- ters and likely inhibiting their reuptake (9). Experiences
less, paranoid, and at times agitated and inattentive. He with patients who have ingested similar white powdery
had limited awareness of his surroundings and contin- substances,confirmedtocontainmephedrone,havebeen
ued to hallucinate up through 48 hours post-ingestion. reported in the United Kingdom. The most common
HebegantograduallyimprovewithIVfluidsandatotal clinical findings in these cases were tachycardia, hyper-
of 5 mg of IV lorazepam. Additionally, we administered tension, and agitation, similar to the sympathomimetic
2
1 two oral doses of risperidone 0.5 mg, which he tolerated toxidromes observed following MDMA or cocaine use
9/
9/1 without any adverse effects and correlated with a rapid (11). Mydriasis, anxiety, agitation, paranoia, bruxism,
0
n improvement in his symptoms over the subsequent 24 aggression, depression, hallucinations, delusions, and
o
el hours. By 96 hours post-ingestion, his chemistries, liver manicbehaviorandseizureshavealsobeenreportedfrom
s
Ba function tests, CK, and vital signs all normalized. His mephedroneuse(9,12,13).
of deliriumresolved,andhisthinkingwasorganized,aware, Serious complications of mephedrone ingestion have
y
sit andgoaldirected,withanMMSEof29/30(missingone been reported in the UK hospitals, including serotonin
er
v recall item). His neuromuscular exam was normal. His syndrome,deliriumduetomephedrone-inducedhypona-
ni
U fluids,lorazepam,andrisperidonewerediscontinued,and tremia, as well as acute myocarditis (14–16). Forensic
y
m b hewasdischargedhome. examinersintheNetherlandsrecentlyattributedthedeath
co ofa36-year-oldmantomephedroneingestion,following
nformahealthcare.ersonal use only. DOtwiauhIlSricfCcohUarsaSaerSsseIerOvebpeNerrceeo,smetonixntigtchedmeeolmirreeiurwgmiindggeelanywerauarsteeenddebsasynod“fbctahotehnspsuaomlttesen,d”- ammcapeasLennertaiismsgoeedifrtmoieoerdefsnmedtpxaeuctopbaifhtleeiesoddxht,rihesoaedtgnriertieansgtytoaemtxrdhdipeddianreUtoglhimnrotiihmeuteesmi.dmmH(eK1oto7siiwcnt).geetdvfofoexermic,dtairvsosuempinteprsoet,arhtteas-
d from iFor p fforormrecthreeaNtioantiaolnianltoInxsictiatutitoenoinnDthreugUnAibteudseStsautgegs.esAtltehratst tchiaeteudsewofitbhenthzeodaiaczuetepintoexsifdorromtreeat(i1n1g)t.heBaasgeitdatioonnathsesose-
e
d
a thistrendisincreasing,reportingthatcallstopoisoncon- previously published reports in Europe, poison control
o
wnl trol centers reporting cases of “bath salt” intoxication in protocols, and concerns for exacerbation of hyperther-
o
D the first 2 months of 2011 exceeded the total number mia,rigidity,orseizureswithantipsychoticuse,amixture
e
us of calls for this reason received for the entirety of 2010 of benzodiazepines, intravenous fluids, and other sup-
b
A (1). Sold in gas stations, convenience stores, over the portive measures was initiated following arrival to the
hol Internet,anddrugparaphernalia“headshops,”numerous ED. Being unaware of other confirmed cases of “bath
o
Alc stateshaveenactedlegislationtoclassifymephedroneand salt”ormephedronetoxicityreportingtheuseofantipsy-
ug similarsyntheticcathinone-derivativecompoundsascon- chotics for the treatment of post-ingestion delirium, our
J Dr trolled substances (2). The United States Drug Enforce- patients were closely monitored on the general medical
m ment Administration has reported that mephedrone is floor (telemetry, seizure precautions, constant observa-
A
present in products promoted as “bath salts,” as well tion)onceantipsychoticswereinitiatedfortheprotracted
as in other substances sold on the Internet as “research delirioussymptomsthatdidnotshowsustainedresponse
chemicals” or “plant food” (3). Similar to “bath salts,” to initial treatment. The use of intramuscular haloperi-
mephedroneandothermixedsyntheticcathinonederiva- dol and oral risperidone in our patients did not lead to
tives have been detected in samples purchased and ana- anyobservableadverseeffectsandcorrelatedwitharapid
lyzed in the United Kingdom sold as “plant food” and reductionoftheirresidualagitationanddeliriousfeatures.
“NRG-1” (4,5). Mephedrone has been detected in simi- Among the potential diagnostic challenges for clini-
larsubstancesseizedbyEuropeanlawenforcementwith cians in the diagnosis of “bath salt” intoxication delir-
increasing frequency since 2008, culminating its desig- ium is the lack of routine toxicology screening for
nation as a controlled substance in the United Kingdom mephedrone and other synthetic cathinones. Assays for
in April 2010 (6,7). The rapid growth of the popularity thesecompoundsforcliniciansseekingsame-dayresults
ofmephedroneandothercathinone-derivativestimulants have not yet been developed for widespread routine
soldas“bathsalts”inashortperiodoftimehasbeenpar- hospital use in the United States (Michael Bissell, per-
tially attributed to aggressive Internet marketing as well sonal communication, August 3, 2011). To our knowl-
as social networking sites serving as a forum to spread edge, only one facility nationally provides access to
interestamongyoungadults(8). “send-out”testing,whichmaynotbeimmediatelyuseful
“BATHSALTS”ANDTHEEMERGENCEOFMEPHEDRONEUSE 179
for practicing clinicians (18). Novel methods developed more ominous neurologic and cardiac sequelae derived
to detect mephedrone in urine have only been recently from“bathsalt”ingestion.
described (19). Furthermore, we also encountered each
of our patients more than 18 hours following their “bath
DeclarationofInterest
salt” ingestions. This could complicate further post- The authors report no conflicts of interest. The authors
metabolismdetectionefforts,asthehumantoxicokinetics alone are responsible for the content and writing of this
ofmephedronehavenotbeenclearlyestablished(19). article.
However, as government law enforcement bulletins
reportthat“bathsalts”foundintheUnitedStatescontain
mephedrone and other synthetic cathinones, we believe REFERENCES
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Clinical Toxicology (2012), 50, 15–24
Copyright © 2012 Informa Healthcare USA, Inc.
ISSN: 1556-3650 print / 1556-9519 online
DOI: 10.3109/15563650.2011.645952
REVIEW ARTICLE
‘ Legal Highs ’ – novel and emerging psychoactive drugs:
a chemical overview for the toxicologist
SIMON GIBBONS
Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, London, UK
2 Introduction. ‘ Legal highs ’ are psychoactive chemicals which are sold from ‘ head shops ’ , the internet and from street suppliers and may
1
9/ be possessed without legal restriction. An increase in the marketing of these materials has resulted in a corresponding increase in published
1
9/ reports of their adverse effects. However, a lack of primary literature pertaining to their chemistry, pharmacology and toxicology, makes
0
on an evaluation of their harm diffi cult. This review covers the basic chemistry of these novel psychoactive compounds and relates them
el to endogenous neurotransmitters and existing drugs of abuse. Methods. A survey of the internet was used to identify websites that are
s
a
B marketing ‘ legal highs ’ in the UK. Trivial and systematic chemical compound names, for example methoxetamine, 4-methoxyphencycline,
y of 4-fl uorotropacocaine and ethyl phenidate were entered into PubMed to retrieve data on these compounds.This search elicited no
sit citations. Other search terms which were more fruitful included desoxypipradrol, diphenylprolinol, methylenedioxy-2-amino-indane
er
v and methylenedioxy-2-amino-tetralin, alpha-methyltryptamine and 5-methoxy-N ,N -diallyl-tryptamine. R esults. ‘ Legal highs ’ from the
ni
U phenylethylamine, cocaine, tryptamine and phencyclidine classes are increasingly being marketed and, in the majority of cases, little is
y
b cited in the literature on their true chemical identity, pharmacology or toxicology. Conclusions. ‘ Legal highs ’ are gaining in popularity
m
coy. and present clear challenges to toxicologists and society as a whole. Whilst improved use of existing legislation and development of new
hcare.se onl lwegitihs l ‘a lteigoanl chaignh bse ’ iuss nedee tdoe dre. duce the supply of these materials, investment in better education for young people on the harms associated
healtnal u
maso Keywords Amphetamines; Cathinones; Cocaine; Herbal highs; Mephedrone; Neurotransmitters ; PCP; Phenylethylamines; Tryptamines
orper
m infFor
o
d fr
e
d
a
o Introduction data relating to the pharmacology and toxicology of these
nl
w materials. Consequently, it is highly probable that there
o
D ‘ Legal highs ’ are novel psychoactive substances which are
y will be considerable harms associated with the inges-
g either synthetic chemicals, plant or fungal material which
o tion of some of these compounds. Users of ‘ legal highs ’
xicol are intended to elicit a psychoactive response, being either may be playing ‘ Chemical Russian Roulette ’ with these
o stimulant, hallucinogenic, sedative or a combination of the
T unstudied novel chemotypes. The probability of harms
al three phenomena.1 Europe, and the UK in particular, has
c associated with new psychoactive substances should not
ni seen an explosion in the numbers of new compounds 2 that
Cli be underestimated; there have been 70 suspected mephed-
are appearing on the internet which display high and close
rone-related deaths in the United Kingdom and the deci-
structural similarity with existing and controlled drugs of
sion to ban this compound4 and closely related synthetic
abuse, but which are invariably marketed as ‘ not for human
compounds by the UK Government in 2010, has been
consumption ’ or even as ‘ plant food ’ , ‘ bath salts ’ or even
vindicated, particularly given the acute toxicity associated
‘ pond cleaner ’ .3
with this material.
Unfortunately, there is little published data pertaining
The risks of taking uncharacterised chemicals with no
to their chemical analysis and even a greater paucity of
toxicological assessment is highlighted by the case in 1976
where a young graduate student, Barry Kidston, whilst
attempting to synthesise synthetic opiates, in particular
pethidine analogues, made MPTP (1-methyl-4-phenyl-
1,2,3,6-tetrahydropyridine). After ingesting this compound
he developed mild Parkinson ’ s disease-like symptoms. 5
Received 4 August 2011 ; accepted 29 November 2011 .
It was later found that MPTP is converted in vivo to
Address correspondence to Prof. Simon Gibbons, Department of MPP (cid:2) (1-methyl-4-phenylpyridinium), which is a potent
Pharmaceutical and Biological Chemistry, UCL School of Pharmacy,
29-39 Brunswick Square, London WC1HN 1AX, UK. Tel: (cid:2)44-207-753- neurotoxin to dopamine-producing neurons in the substantia
5913. Fax: (cid:2)44 (0)207-753-5964. E-mail: [email protected] nigra.6
15
16 S. Gibbons
OCH Nature as a source of psychoactive compounds
3
HO OCH
3 Nature is an astounding chemist and has the ability to pro-
OH
duce compounds that have profound effects on the Central
O Nervous System (CNS). Examples range in severity and tox-
N icity from the Opium poppy ( Papaver somniferum ) which
O
CH3 N O produces morphine, 7 the precursor of heroin, to C annabis
HO H3C ( Cannabis sativa ), producing tetrahydrocannabinol,8 to
Morphine Tetrahydrocannabinol Mesembrine drugs of limited ethnic usage such as the South African plant
(THC)
Kanna ( Sceletium tortuosum ), which produces the phenyl-
Fig. 1. Structures of natural product psychoactive compounds. ethylamine alkaloid mesembrine (Fig. 1).9
More exotic sources of psychoactive compounds include
the fungal natural products muscimol and ibotenic acid
This review will describe the various sources of psycho-
from Amanita muscaria 10 (Fly Agaric), which are analogues
active compounds in nature and show that many of the ‘ legal of γ -aminobutyric acid (GABA) and show structural and
highs ’ currently emerging (and our existing controlled drugs electronic similarity with the drugs γ -hydroxybutyric acid
of abuse) have a high degree of structural similarity with- (GHB),1 1 its lactone, γ -butyrolactone (GBL)1 2 and the related
2
1 endogenous neurotransmitters. Examples of naturally occur-
9/ butane-1,4-diol (1,4-BD) (Fig. 2).1 3
9/1 ring phenylethylamines and their synthetic derivatives will Magic mushrooms of the genera P silocybe , Conocybe
0
on be described and compounds that are related to the natural and H ygrocybe are still marketed as ‘ legal highs ’ , notably
sel product cocaine and the dissociative anaesthetics ketamine the spores and mycelia of P silocybe cubensis , which are
Ba and phencyclidine will also be highlighted. Some of the new
of synthetic tryptamine analogues will also be mentioned and sold with sand as ‘ specimens for microscopy ’ ; the addition
y of water allows fruiting of the mushrooms after a few days.
sit their structural similarity to serotonin and the older psyche-
er These species contain the phosphate ester psilocybin which
niv delic drugs such as LSD-25 will be demonstrated. Herbal is hydrolysed i n vivo to psilocin, which shows marked simi-
y U and fungal ‘ l egal highs ’ will also be described and their larity with serotonin (Fig. 3).1 4
b
m structural similarity to neurotransmitters demonstrated. More exotic psychoactive compounds originate in the
coy.
e.nl skins of poison arrow frogs from Central and South Amer-
hcarse o Methods ica. Epibatidine1 5 (Fig. 4) from E pipedobatides tricolor is a
healtnal u A survey of the internet was used to identify websites that highly potent analgesic compound which binds to the nico-
ormaperso are marketing ‘ legal highs ’ in the United Kingdom. Trivial tinic acetylcholine receptor.1 6
m infFor and systematic chemical compound names such as methoxet-
amine, 4-methoxy-phencyclidine and 3-methoxy-phencycline
o
d fr were also entered into PubMed in an attempt to retrieve data Structural similarity of many ‘ legal highs ’ and endogenous
ade on these compounds. This search elicited no citations. Other neurotransmitters
o
nl search terms which were more fruitful included desoxypip- Many of the synthetic and natural psychoactive substances
w
Do radrol, diphenylprolinol, methylenedioxy-2-amino-indane and not only bind to receptors and exert their effects, but also
gy methylenedioxy-2-amino-tetralin, alpha-methyltryptamine are analogues of endogenous neurotransmitters and have the
o
ol and 5-methoxy-N ,N -diallyl-tryptamine. ability to bind to the dedicated transport systems for these
c
xi
o
T
Clinical N O NH N O CNOH2H O NH O OH OH
2 2 2
HO HO HO HO HO
Muscimol Ibotenic acid GABA GHB 1,4-BD
Fig. 2. Natural and synthetic GABA-mimetics.
O
HO
P
O OH
O
HN N HO NH2
N
N N
H
H H
Serotonin
Psilocybin Psilocin
Fig. 3. Psilocybe psychoactive alkaloids have similarity to serotonin.
Clinical Toxicology vol. 50 no. 1 2012
Legal Highs – Novel Psychoactive Drugs 17
H NH
2
Cl N N
Phenylethylamine
O
Epibatidine H3CO NH2 NH2
Fig. 4. Epibatidine, an analgesic pyridine alkaloid from Epipedobatides
tricolor . H CO
3
OCH
3
Mescaline Cathinone
neurotransmitters and inhibit their reuptake. The similarity
that exists between the psychoactive substance phenyleth- CH3 OH H
ylamine, amphetamine (amfetamine) and tryptamine and N N
CH CH
3 3
dopamine, norepinephrine (noradrenaline) and serotonin
can be seen readily (Fig. 5). The simple structural motif of HO HO
phenylethylamine exists in dopamine and norepinephrine, as Hordenine Synephrine
2 it does in amphetamine ( α -methyl phenylethylamine). The
1
9/19/ methyl group of amphetamine is in the alpha position next to Flaimg.i n6e. nCuecrlteauins. plant-derived stimulants are based on the phenylethy-
0 the nitrogen atom. One can also see how similar tryptamine
n
el o is to serotonin, differing only in the absence of a hydroxyl
Bas group on the aromatic ring. These similarities undoubtedly synephrine,2 1 a phenylethylamine related to ephedrine (Fig.
of contribute to the ability of phenylethylamine, amphetamine 6). Weight-loss preparations are being marketed globally
y
sit and tryptamine-related compounds to elicit psychoactivity. through the internet and contain extracts of bitter orange
ver Further examples include the hallucinogen, mescaline, peel, presumably because of the stimulant properties of syn-
Uni from the psychoactive cactus Peyote1 7 ( Lophophora wil- ephrine, but there are the same risks of tachycardia, hyper-
m by liamsii ) and cathinone from Khat (C atha edulis ). 18 Peyote is tension and palpitations associated with this compound as
coy. widely available in the United Kingdom as a house plant and there are with phenylethylamines in general.2 2
care.e onl Khat is fl own in daily from East Africa, and the leaves are
hs chewed by members of the Somali and Yemeni communities
healtnal u in the United Kingdom in a social setting. 19 Both of these Mephedrone and the cathinones
ao
m informFor pers prreisnsygecm,h aob talwecsot ip-vchea ernnbayotluner tcahhly apliarnmo wdiunitceht (s aF hingai.vt r6eo) gt, hepeno ssasttreousmcsit nuagrtta aalc nmh aeordot imtfo ta htthaicet c Imnae thp2ihn0eo0dn9re osnt hede2 ur3ee a tnowd ta hvse eirray ns ismi ‘m eilxiaplralirot ysc itooomn c ’p aotihunin ndtohsn eeb rimotsaaedrlklfy e( tFtienigrgm. 7eo)df.
o
d fr end of the chain. This nitrogen atom may be further substi- Mephedrone is the 4' -methyl-N -methyl analogue of cathi-
e
d tuted with many other alkyl groups to give the wide range of none and was marketed as Miaow-Miaow and MCAT and
a
o
nl phenylethylamine psychoactive compounds seen. sold through many internet websites as ‘ plant food ’ , ‘ pond
w
o Common horticultural plants and trees, particularly cleaner ’ and even ‘ bath salts ’ . This compound has clear simi-
D
y those of the pea family (Fabaceae) also contain psychoac- larity to the amphetamines, but having a ketone group beta
g
o
ol tive phenylethylamines such as hordenine2 0 and surprisingly to the nitrogen atom and directly next to the aromatic ring
c
xi even food plants such as the peel of bitter orange ( Citrus (Fig. 7). Other cathinone analogues that were appearing at the
o
T
al aurantium ) have small amounts of compounds such as same time included methylone,2 4 which is similar to Ecstasy
c
ni
Cli
OH
NH
2
HO NH2 HO NH2 HO
HO HO N
H
Norepinephrine (NE)
Dopamine (DA) Serotonin (SER)
(Noradrenaline)
NH
2
NH NH
2 2
N
H
Amphetamine
Phenylethylamine Tryptamine
Alpha-methyl phenylethylamine
Fig. 5. Many drugs of abuse share structural similarity with our endogenous neurotransmitters.
Copyright © Informa Healthcare USA, Inc. 2012