, France; MedicalToxicology3:1-17(1988)

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.lick, Bost0_ © ADIS Press Limited

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, Scotland; _.

Jo,usA;j_: 'Designer Drugs'T A Problem in Clinical Toxicology

.'ne M. Sorki(:rick H. Say_vid'R,artt_ James F. Buchanan and Christopher R. Brown)tt A. Mata_ San Francisco Regional Poison Control Center, San Francisco General Hospital,meth J. Gract University of California, San Franciscotedical aslx_md avoidanQ

I to encou_omprehensb:linical studit Contents Summary ........................................................................................................................................ I !

ag experiene I. Mescaline Analogues (Phenylethylamines) ............................................................................. 3_pes ofani_ 1.1 Methamphetamine .............................................................................................................. 5

limited large_ 1.2 TMA-2 ................................................................................................................................. 5and industfi: 1.3 DOM/STP ........................................................................................................................... 5he focus ofsi 1.4 PMA .................................................................................................................................... 6

1.5 DOB .................................................................................................................................... 6

: reports), ar_ 1.6 2-CB/MFT ........................................................................................................................... 6i. Case reporl 1.7 MDA .................................................................................................................................... 6ve priority fo: consideredi 1.8 MDMA/MDEA .................................................................................................................. 7an be includa 1.9 Clinical Toxicology of Phenylethylamines ....................................................................... 7

2. Synthetic Opioids ...................................................................................................................... 9

xick H. Saye 2.1 Fentanyl Derivatives .......................................................................................................... 9

the back pag 2.2 Clinical Toxicology of Fentanyl Derivatives ................................................................. 10

2.3 Meperidine Derivatives ................................................................................................... 10

Subscriptim 2.4 Clinical Toxicology of MPTP ......................................................................................... I 1

ption agent._ 3. Arylhexylamines ...................................................................................................................... I Illy. within a:

l/or circulate 3.1 Phencyclidine Analogues ................................................................................................. 12nply with th 3.2 Clinical Toxicology of Arylhexylamines ......................................................................... 12

4. Methaqualone Derivatives ..................................................................................................... 13

5. Role of the Toxicology Laboratory. ...................................................................................... 13

anghorne,PA 6. Legal Considerations .............................................................................................................. 13 ' i

ye,Mancheslel 7. FutureTrends 14 I:......................................................................................................................... I

8. Conclusion ............................................................................................................................... 15 !(3) 272-721 I. i

,an. Tel.: Osab tI'

'[.

i. Hong Kon_ Summao, 'Designer drugs' are substances intended for recreational use which are derivatives of_tion to enstW approved drugs so as so circumvent existing legal restrictions. The ternt as popularised byway liable fe the lay press lacks precision. Contrary to the popular belief that 'designer drugs' are ori-_hcther arisi_ ginal creations, the majority of these agents are 'borrowed'from legitimate pharmaceutical

research. The. t' merely represent the most recent developments in the evolution of mind-

;2 Middlcto_' ahering chemicals.

200 Meachar The most e.vtensively studied class of psychoactive compounds is the phenylethylamines

New Zeala_ (mescaline analogues). This class includes catecholamines, therapeutic agents and nu-merous illicit derivatives..¥ubtle alterations of the phenylethylamine molecule give rise to

a spec?rum q/'l_harmacologica/properties ranging .l?om pure sympathomimettc stimula-

'DesignerDrugs' 'DesignerDrugs'

tion to primarily psychoactive effects. Ahhough most of these compounds are only of_ 'J le-d one totorical interest, amphetamine, methamphetamine, 3,4-methylenedioxyamphetamine (Mbt_ woum a , .and 3,4-methylenedioxymethamphetamine (MDMA) continue to be used recreationa_ 'designer drugs el:

. Many deaths have been ascribed to this class of compounds. In overdose the differe_-_be 'developed' and

'_' between these compounds blur and the clinical presentation is similar to that of amp._,only been a few th;0 -:'_' amine overdose characterised by tachycardia, hypertension, hyperthermia, diaphor_ The concept of

mydrtasis, agitation, muscle rigidity, and hyper-refiexia. Death usually results frorn_nnt include new fc'_'_,_ rhvthmias, hyperthermia or intracerebral haemorrhage. Treatment is aggressive and _'_ ..... ,

- c- I portive with careful attention to temperature, blood pressure and seizure control. _orugs, sucn as cocSynthetic opioid derivatives, which representthe second major class of 'designer dru_ base form (crack).

are derivatives of fentanyl (e.g. a-methylfentanyl, 3-methylfentanyO or pethidine (me_i lhough abused,idined and are extremely potent compounds responsible for numerous overdose de_?'stanees' phenylproAttempts to synthesise pethidine have resulted in the accidental production of MPTP_41nd butyl nitrite f{methyl-4-phenyl-1,2,3,6-tetrahydropyridine),a compound which t)r metabohsed in the btl"_, not refer -'....... (IOCS IO

by the monoamme oxtdase system to a toxtc mtermedtate (MPP+) whtch selecttvelyl:R,,/k _ stroys the sustantta ntgra, resulttng tn the raptd onset of severe Parkinsonian symptom? nd Blues (talwm

Naloxone will antagonise the opiate effects of this drug class, although high doses nlI?_coeaine or amp[

be required. .i_.*carch' (cocaine atArylhexylamines constitute the third class of 'designer drugs' The predominant m$' If the term 'des

'd_ her of this class is phencyclidine (PCP) a derivative of the anaesthetic ketamine I]i · ,_, _:' ' ' ,imeanmg pernaps J

unique class of psychoactive agents exhibits broad and complex pharmacological eff_. _ .xv &_ Overdose may result in extreme agitation, psychosis, sympathomimetic excess, hy_?ntent o! the user

_'_' ...... '_Bearin this in m') thermla and CATSand resptratory depresswn. Supportive care, benzodtazepmes, halo_ gidol, and repeated doses of activated charcoal are the mainstay of treatment. :ircview lhose drugs

; t Methaqualone derivatives comprise the fourth class of'designer drugs'. Although Ca!of restricted drugsmonly abused, especially in regional waves of popularity and availability, these prima_imedica I u¢,' h,,t _,

V/x_[ _i sedative agents rarely t'esult in intoxication more serious than general central nervd , .o_ .,,_,,,,,/ _ system (CNS) depression. __'arcn activities De,

·gL[../ 'i , _ · -- ,.v_Witlfin each chemThe toxicology laboratory has a limited role in the evalua, ion ol intoxtcauon resutafrom designer drugs. Most laboratories do not have the capability to rapidly and accurat!discussed for whi_

'3, assay for these synthetic analogues, nor are there sufficient data to aid in the interpreta_!nble. Important to

_'"'- of measured drug concentrations when available. Instead, the clinician must evaluate and managementintoxicated patient based on clinical presentation and routine laboratory measureme k.omplications ass_

i In the/uture, .further derivatives of these classes may appear in recreational use, :: perhaps new classes will emerge. The line between legality and i/legality is so fine fors_ 'drugs. Finally, we

:0 _:c- substances that the determination will need to be made in court. Potential therapeutici licipate future ire4,','., of these agents will be difficult to explore because of their automatic designation as a labuse.

_,_ trolled substances. The practising clinician must approach 'designer drug'-intoxic_'.

patients symptomatically and continually be alert for new or unusual presentations 1, Mescaline.i substance abusers.

i (Phenylethylat/'7i '_

i _ The phenyleth_

7_?//¢; The term 'designer drug' was first coined by Dr chemist' can produce a made-to-order drug t0i_hemical structure_ Gary Henderson, a pharmacologist at the Univer- place restricted ones by way of innovative res_ nnd neurotransmit

f_,_/&[_ sity of California at Davis, to describe chemical is generally incorrect. The majority of abused s_lJt' agents; for e:congeners of illicit drugs synthesised with the pur- stances available for recreational use are ,l_ephedrine.. metarm

j pose of circumventing the law. The expression, as rowed' from legitimate pharmaceutical resea__s fl}c structure fro· [8lances of abuse._ it is used today, lacks precision. The concept of With a reasonable knowledge of chemistry it ls ·

-; ' ril_ncdioxvamphetanL- ._-_ developing chemical congeners of therapeutically difficult for an interested individual to gathe _ -',, ' .;_, No molecule se,:' .::, useful molecules, in essence 'designing' drugs, is a necessary information from var ous professJ_

'/' traditional and fundamental activity of the phar- publications to synthesise any number ofll_ubtle, variations imaceutical industry. Thc implication that the 'street choactive compounds. Although media puo _'l[ormation can hax

i

.Designer Drugs' 3 !

?

unds are only ofg would lead one to believe that there are legions of ical actions than phenylethylamine (see fig. 1). In_mphetamine (M13,_.used recreationd_ 'designer drugs' either already in use or waiting to addition to the sympathetic agonist property of

'rdose the differe_ be 'developed' and 'marketed', in reality there have many phenylethylamine compounds, other chem-ir to that ofampk only been a few that have caused clinical concern, ical modifications have been found to elicit a spec-hermia, diaphore_. The concept of 'designer drug' specifically does trum of psychoactive effects as well.

tally results from i not include new forms or new dosing routes of old The prototype psychoactive phenylethylamine

s aggressive and s_ drugs, such as cocaine used in the crystalline free- is mescaline (3,4,5-trimethoxyphenylethylamine),;zure control.

ss of'designer drug base form (crack). Nor does it include legal, al- an alkaloidal component of the peyote cactus. Al-or pethidine (mel_ though abused, alternatives to controlled sub- though peyote has been recognised for its psy,·ous overdose deat_ stances: phenylpropanolamine, ephedrine, caffeine choactive properties for centuries, it was not until

,duction of MPTP (_ and butyl nitrite, for example. 'Designer drugs' also 1896 that the structure of mescaline was identified,tabolised in the bra docs not refer to such drug combinations as 'T's and subsequently synthesised in 1918. Structuralwhich selectively d

kinsonian sympto_ and Blues' (talwin and tripellenamine), 'speedballs' modifications of the mescaline molecule have re-9ugh high doses _ (cocaine or amphetamine and heroin) or 'star suited in a plethora of psychoactive compounds.

search' (cocaine and phencyclidine). In 1947 researchers produced the first psychoactivete predominant ma if the term 'designer drug' is to have any useful analogue of mescaline, TMA (3,4,5-trimethoxyam-

thetic ketamine. Th meaning, perhaps it should include reference to the phetamine), with twice the psychoactive potency of,armacological effe_

intent of the user to circumvent legal restrictions, mescaline (Shulgin et al. 1973). Experimentationtimetic excess, hygrodiazepines, halot_ Bearing this in mind, the ensuing discussion will with ring substitution produced compounds withtreatment, review those drugs which, (a) are novel derivatives even greater potency. The a-methylation of mes-

drugs'. Although co_of restricted drugs, or (b) have no acknowledged caline to produce TMA yielded a compound struc-

zbility, these priman medical use but are borrowed from legitimate re- turally similar to amphetamine, yet without pro-?neral central nero i._2arch activities because of their unrestricted status, found sympathomimetic properties. Further

rintoxication result_Within each chemical class various agents will be research has produced many such 'hallucinogenic

rapidly andaccurauldiscussed for which toxicological data are avail- amphetamine' analogues (phenylisopropylamines),id in the interpretatifible. Important to the clinician is the recognition although few are truly hallucinogenic.

cian must evaluateJand management of the potential toxicological The term 'hallucinogenic amphetamine', while>ratorYmeasuremes complications associated with the use of these commonly used, is in fact a misnomer. At nominaln recreational use aality is sofine for sol?rugs. Finally, we will discuss legal issues and an- psychoactive doses these compounds exhibit nei-.tentialtherapeuticw ticipate future trends in 'designer drug' use and ther true hallucinogenic activity (visualisation of:tic designation as _ abuse, unreal objects) nor amphetamine-like stimulation.igner drug'-intoxic_ What are often referred to as 'hallucinations' are

tusual presentatiom L Mescaline Analogues actually alterations in colour, cotour intensity, tex-

(Phenylethylamines) ture, or the elaboration of'fantasy' states. At larger---- doses, as in overdose, the hallucinogenic and/or

The phenylethylamine molecule is the basic sympathomimeticpotentialoftheseagents maybe

-to-order drug to'i chemical structure for endogenous catecholamines expressed, sometimes with serious consequences.f innovative rese a_and. neurotransmitters as well as several therapeu- Phenylethylamine derivatives exert a variety of

t_c agents; for example, phenylpropanolamine, direct and indirect effects upon the aminergic sys-jority of abused su,l_'cphedrine, metaraminol, and amphetamine. It also tems of the brain (McCall 1986; Nichols 1981).:tonal use are

maceutical resea g;s the structure from which are derived many sub- These properties include agonist effects at seroto-.xmnces of abuse, such as mescaline, 3,4-methyl- nin, noradrenaline (norepinephrine) and dopamineof chemistry, it is_ ' '

· t enedioxvamphetamme (MDA) and others, receptors. The degree to which a given compoundividual to gather , -

various professi 0_ No molecule serves as a better model for how affects these various neurotransmitter systems var-of ,*ubtle variations in chemical structure and con- les such that each compound can have its ownmy number I_ubli_"°rmation can have widely varying pharmacolog- spectrum of activity. The subtle differences in psy-mgh media p .,

['DesignerDrugs' 4[ .DesignerDrugs'

twhich have appear,

NH2 NM2 [,_ IT '[ CH3 available.Whichat least mini

1.1Methamphet:

1¥Ii_ Phenylethylamine Amphetamine Methamphetamine

Methamphetami3

monly used phenyl¢H3CO H3CO

,, H3CO __NH2 5[__NH2 __NH2 it'meth'recreati°nalusersitwasalso°r'crystalcalledmesirH3COf -,_ HaCO,/_,,/ CH3 H3C..,'/'__._ CH3 use of phencyclidin

OCH3 H3CO H3CO opedbecausethe te

R,,._/:xI Mescaline TMA-2 DOM/STP to phencyclidine. A-'_-' , of'crystal' must be e

'-w'-'_J H3CO HaCO an amphetamine pj

_ ,<?.' such as phencyclidirThe introduction

2?'":_;_ H3CO_'"'""_ j CH3 Br_ CH3 Br minal amine of amlH3CO H3CO phetamine,a compo

_ J _ i PMA DOB 2-CB/MFT etration and a more

The pharmacologica

V_kt _ is qualitatively simi

(O __ _CH3 (O ./,_ O-.-_ _'x NH_CH3 phetamine, but mayO .... NH2 NH'_cH3 _O _._ _GH more. In addition 1O.,.-2"_..j CH3 3 creased sympathetic

aminemayresultinMDA MDMA MDEA tracranial haemorrt

-'- hyperthermia and d

_' Kalant&Kalant191t22.-_'Y Fig. 1. Chemicalstructuresof phenylethylamines.

· 'I;_. Key.'TMA-2= 2,4,5-trimethoxyamphetamine;DOM/STP= 4-methyl-2,5-dimethoxyamphetamine;PMA = para-methoxyamphetaminq:_ DOB = 4-bromo-2,5-dimethoxyamphetamine;2-CB/MFT= 4-bromo-2,5-methoxyphenylethylamine;MDA = 3,4-methyl-enedi0_ Concern has been

amphetamine;MDMA---3,4-methylenedioxymethamphetamine;MDEA= 3,4-methylenedioxyethamphetamine. icity of potential cent:_i clandestine synthesis

-_ 7! aleetal.1985).The/(/

,- .., _ chological effects of these agents can only be iden- stimulation is not typical of recreational intoxi0 produce phenylaceto

tiffed by carefully conducted human trials, tion but instead frequently accompanies seriousir mine and methamp

As a class, the phenylethylamines share a num- toxication or overdose, control, may also rest

f_Z\ 1 bet of similar pharmacological effects. The psy- The number of mescaline analogues which ha_ zylphenethylaminechoactive effects often involve a feeling of eu- been chemically synthesised in research laborat* cthylamine. These co:

: phoria, mood intensification and empathy, and may ies is enormous. Only a fraction of these co_ vulsant properties as

include the visual changes noted above which are pounds have been tested in humans, and the. Depending on the so[I/ x"_'--: ,5' often misinterpreted as hallucinations. Some studies have been limited· Thus, for the majodl production facilities,

.<-'(., phenyl-ethylamines do produce true hallucina- of these compounds, human pharmacological a_ tribute substantially:' '"". tions, especially in overdose. Despite the structural toxicological data are sorely lacking. The c0_ reational methamphe

similarity to amphetamine, gross sympathetic pounds discussed below represent those mated/ lead may be a fi

·DesignerDrugs' 5

' which have appeared in recreational use and for amphetamine, which has resulted in at least 2 cases

-I which at least minimal toxicological experience is of acute lead intoxication (Allcott et al. 1987). One_'CH3 available, synthesis procedureinvolves generatingphenyl-

acetone by reacting lead acetate with phenylacetic

1.1Methamphetamine acid. The subsequent material, if not carefully pur-ified, can leave significant amounts of lead in the

i

Methamphetamine is perhaps the most corn- final methamphetamine product. Patients with such

monly used phenylethylamine compound. Among lead intoxication may present with gastroenteritis,recreational users it is known as 'speed', 'crank', anaemia, encephalopathy, myalgias or hepatitis.

NH2·meth' or 'crystal meth'. In the late 1960s and 1970s Common laboratory tests (blood lead concentra-it was also called simply 'crystal'. However, as the tions, free erythrocyte protoporphyrin, urinary co-use of phencyclidine increased, confusion devel- proporphyrin) are useful to assess the degree ofin-

oped because the term 'krystal' was used to refer toxication and need for chelation therapy.to phencyclidine. A patient who admits to the useof'crystal' must be evaluated for exposure to either 1.2 TMA-2

an amphetamine product or an arylhexylamine, The chemical structure and pharmacology of

.NH2 such as phencyclidine. TMA-2 (2,4,5-trimethoxyamphetamine) resemblesThe introduction of a methyl-group on the ter- both mescaline, with respect to the ring substi-

minal amine of amphetamine produces metham- tuents, and amphetamine, due to the methylationphetamine, a compound with improved CNS pen- of the basic phenylethylamine structure. It was firstetration and a more prolonged duration of action.

synthesised in 1933 but its psychoactive potentialThe pharmacological profile of methamphetamine was not recognised until 1962. A more potent psy-is qualitatively similar to that produced by am- choactive drug than mescaline, TMA-2 shows

NH_CH3 phetamine, but may persist for 6 to 24 hours ormore. In addition to CNS stimulation, the in- qualitatively similar effects on mood alterations andsensory enhancement as mescaline. The difference

43 creased sympathetic tone due to methamphet- in the amount of drug causing the desired psy-amine may result in tachycardia, hypertension, in- choactive effects and that resulting in toxicity istracranial haemorrhage, seizures, arrhythmias, small (Shulgin 1976).hyperthermia and death (Delaney & Estes 1980;

Kalant & Kalant 1975; Kojima et al. 1984). 1.3 DOM/STP

lethoxyamphetarn_

3,4-methyl-enedi0_. Concern has been expressed regarding the tox- The next amphetamine-analogue to be investi-icity of potential contaminants produced during the gated following TMA-2, and which became avail-clandestine synthesis of methamphetamine (Nog- able recreationally in 1967, was DOM (4-methyl-gle et al. 1985). The use of phenylacetic acid to 2,5-dimethoxyamphetamine). Users of this drug

eational intoxia produce phenylacetone, a precursor to ampheta- gave it the hame'STP', representing'serenity, tran-

panies seriousi_ mine and methamphetamine under US Federal quility and peace'. High initial doses (10 to 20mg)control, may also result in the production ora-ben- with attendant untoward responses gave the drug

ogues which hal zylphenethylamine and a-benzyl-N-methylphen- an unfavourable reputation on the street and lira-:search laboratO ethylamine. These contaminants have marked con- ited its acceptance (Shulgin 1977; Snyder et al.)n of these c0_ vulsant properties as evidenced by studies in mice. 1967).

lmans, and th_ Depending on the sophistication of the clandestine As was noted for TMA-2, the therapeutic index;, for the majod production facilities, these contaminants may con- of DOM is narrow (Snyder et al. 1967). Low dosesarmacological a_ tribute substantially to the overall toxicity of rec- of 2 to 3mg produce mild sympathetic stimulation,icking. The c0_ reational methamphetamine use. euphoria and perceptual distortions. Amounts int those materii Lead may be a further contaminant of meth- greater than 5mg consistently produce a halluci- '

t

'Designer Drugs' .._! .DesignerDrugs'ii

natory reaction and more significant sympathetic 1.6 2-CB/MFT of the chemical.stimulation. I willproducethe

Removal of the methyl group at the a-carb0_, dioxybenzylaceto1.4 PMA of DOB results in the phenylethylamine analogu_ compound HMD

% 4<_;_ 2-CB or MFT (4-bromo-2,5-methoxyphenylethy_ f man pharmacolo..Para-methoxyamphetamine (PMA)appeared as amine). 2-CB/MFT has one-tenth the potency of it has been shoa

_ a recreational drug in the early 1970s, and was DOB and, at 'therapeutic' doses, produces art (Davis & Bornequickly associated with several fatalities (Cimbura laxed mood and sensory altering effect. However, adverse effects an

1974). The drug exhibits potent hallucinatory and at high doses it can cause agitation and hallu6 may have been dstimulatory properties. Overdoses with PMA have nations. Hallucinations were described in a grou[ ication. Shulgin abeen characterised by marked adrenergic excess. It of students drinking spiked punch, but no clini_ recognise the poleappears from the history of these exposures that details were given (Ragan et al. 1985). In San Fra_ as was later confi

PMA was a contaminant or substitute for what was cisco, 2-CB is known by the name 'afterburner'. section 2.3).[_t often thought to be MDA. It is not generally a

sought after drug, but rather an example of a mis- 1.7 MDA 1.8 MDMA/Mrepresented street drug.

3,4-methylenedioxyamphetamine(MDA)al_ Acloserelativ__%._"=_' 1.5 DOB peared in recreational use in 1967 as the 'love drug', methamphetamim>_ °43 It held the reputation of being a mild intoxicant in street use in 19'

Laboratory research found that replacing a producing feelings of empathy and euphoria witl} Although first pat_methyl-ring substituent of DOM with a bromo- out frank hallucinations. Subsequent experiene become widely usegroup dramatically increased the psychoactive po- demonstrated that large doses can cause agitatiot 1980s, first as an

'_t%t _ tency of the compound, termed bromo-DOM or delirium and hallucinations, asa substance of asimply, DOB. One of the most potent phenyleth- A number of fatalities have been attributed tc concentrated in Caiylamine compounds yet synthesised, DOB exhibits intoxication with MDA and confirmed by labor_ York (Siegel 19861at least 100 times the potency of mescaline (Buhr- tory analysis. Cimbura (1972) reported 5 deaths il 'Ecstasy', but is aichetal. 1983). It is one ofthe few drugs, like LSD, Canada related to the ingestion of MDA. AIIf 'MDM', and 'M &that are sold as drug-impregnated pieces of paper, patients developed agitation and hallucinations;2 Psychologists h:

The course of intoxication is quite prolonged, patients had seizures. Other reports of MDfi. hance the psychotl _

t0 4_+4 Onset of effect following 2 to 3mg is about an hour; related deaths have involved obtundation (Reed _ & Cole 1987; Gri· full intoxication requires about 3 to 4 hours (Shul- al. 1972; Simpson & Rumack 1981) and hypel. 1987),and it was th

'_ _'q:3 gin 1981). A fantasy state and mood enhancement thermia (Likaszewski 1979; Simpson & Rumad was 'redlscovered.' 'with minimal visual distortions persists for about 1981). The case described by Simpson and Re markable facilitatic10 hours, followed by a gradual resolution of ef- mack (1981) is worthy of note. The patient pre mai adverse effec

1

7/t/'_i t_cts over 12 to 24 hours, sented with coma, seizures, hypertension, tach?_ stimulation. Patient__-_,_l Bowen et al. (1983) described a patient who de- cardia, hyperthermia and opisthotonic posturin[ claim mild intoxic_

/_5Ni } veloped diffuse, peripheral vasospasm after a large Despite temporary stabilisation, the patient wev: increased self-esteeroral ingestion of DOB. lntra-arterial administra- on to develop hypotension, acidosis, rhabd0 Perception alteratio

lion of tolazoline, followed by an intravenous nj- myolysis, disseminated intravascular coagulati0n Because of increast,},_\ troprusside infusion, reversed the vasospasm and repeated cardiac arrests, and eventually died. MDMA was placed

the associated tissue ischaemia. Buhrich and col- Shulgin and Jacob (1982) presented a warnin_ drugs(along with hleagues (1983) described 2 DOB-intoxicated patients regarding the potential misrepresentation of MI)A theComprehensive

I/_ ,..::: who developed severe agitation, hallucinations and Piperonylacetone, one of the starting materials fa tlsuse has diminish· · sympathetic excess. Two deaths from DOB intox- synthesising MDA, is an ambiguous term referrir{ Clinical studies c

ication have been reported (Bohn 1981; Winek et to either methylenedioxyphenylacetone or meth_{ Uncontrolled trials (1al. 1981). enedioxybenzylacetone, depending on the sour_ 1986)and descripti,

ii

._t! .DesignerDrugs' 7

0'i'! of the chemical. The use of the former chemical mostly focus on psychoactive effects. MDMA con-will produce the desired MDA, but methylene- sistently causes anorexia, bruxism, increased blood

it the a carb pressure diaphoresis, blurred vis-- _ dioxybenzylacetone will generate the unexpected and heart rate,_mine analogt_! compound HMDA. Little is known about the hu- ion, and ataxia. It may also cause nausea, anxiety,)xyphenyleth_ _ man pharmacology of HMDA; however, in mice insomnia and, often as a delayed effect, lethargy.the potency 0f it has been shown to be more toxic than MDA There have been several reported deaths attrib-

produces a r,: (Davis & Borne 1984). Conceivably, some of the uted to MDMA, though most have not had la-ffect. However_ adverse effects and fatalities associated with MDA boratory confirmation. Of the 5 deaths reported by

)n and halluc[ may have been due to inadvertent HMDA intox- Dowling et al. (1987), only I seemed to be the re-ibed in a groul ication. Shulgin and Jacob (1982) were the first to suit of a direct drug effect (ventricular arrhythmia),but no clinicl recognise the potential toxicity of synthetic errors, while the other 4 had either significant underlying5). In San Fra_ as was later confirmed in the case of MPTP (see diseases which were exacerbated by the drug'afterburner'. section2.3). (asthma, coronaryartery disease,cardiomyopathy)

or died of trauma while intoxicated. The authors

1.8 MDMA/MDEA were involved in managing 1 patient who sufferedhyperthermia, high output heart failure, dissemi-

te (MDA) ap A close relative to MDA, 3,4-methylenedioxy- nated intravascular coagulation and toxic hepatitis,; the 'love drug' methamphetamine (MDMA), was first identified but survived without residuem (Brown & Osterlohnild intoxicant in street use in 1972 (Gaston & Rasmussen 1972). 1987; Hayner & McKinney 1986).

euphoria with Although first patented in 1914, MDMA did not After MDMA became restricted, an N-ethyl !_ent experiena become widely used until the late 1970s and early congener, 'Eve' (3,4-methylenedioxyethamphetam- 'cause agitati0_ 1980s, first as an adjunct to psychotherapy, then ine, MDEA), became popular. Experience with this

as a substance of abuse. Its use has been primarily drug is limited although 2 of the deaths reporteden attributed _ concentrated in California, Texas, Florida, and New by Dowling were associated with MDEA use. The:med by iabon York (Siegel 1986). MDMA is most often called use of both MDMA and MDEA has diminished,rted 5 deaths i_ 'Ecstasy', but is also known as 'Adam', 'XTC', since they became restricted, although the drugs stillof MDA. All! 'MDM', and 'M & M'. appear on the streets sporadically and some psy-mllucinations:'. Psychologists have long sought a drug to en- chiatrists are still using them._orts of MD^ hance the psychotherapeutic experience (Chiarello_dation (Reedc & Cole 1987; Grinspoon & Bakalar 1986; Neill 1.9 Clinical Toxicology of Phenylethylamines)81) and hyp_ 1987), and it was through these efforts that MDMA,son & Rumad was rediscovered. Therapists have claimed re- The various types ofphenylethylamines exhibitnpson and R_ markable facilitation of psychotherapy with mini- interesting qualitative differences in the psycho- !Fhe patient pa mai adverse effects beyond mild sympathetic active experience produced at nominal doses.,rtension, tachl stimulation. Patients receiving 50 to 125mg MDMA However, in overdose the underlying potential of,tonic posturinl claim mild intoxication, with euphoria, empathy, these drugs for hallucinogenic effects and, morehe patient wef increased self-esteem and occasionally mild visual importantly, sympathomimetic excess becomes ev-:idosis, rhabd_ perception alterations, but no true hallucinations, ident. Adverse reactions to therapeutic doses anddar coagulati0t Because of increased recreational use, in 1985 overdoses seem to follow a limited, fairly well de-tually died. MDMA was placed on the US list of Schedule I scribed pattern typified by amphetamine, the mostented a warni_ drugs (along with heroin, LSD, and others) under extensively studied and reported phenylethyl-atation of MD/_ the Comprehensive Crime Control Act of 1984, and amine.

lng materials f_ ns use has diminished since then (Shulgin 1986). In overdose, phenylethylamine derivatives actus term referrin Clinical studies of MDMA are limited to a few as sympathomimetic agents, stimulating a- and tS-etone or meth_ uncontrolled trials (Downing 1986; Greer & Tolber adrenergic receptors to various degrees, depending

g on the sou_ 1986) and descriptive repons (Siegel 1986) which on the specific compound. The differences in their

'DesignerDrugs' .DesignerDrugs'

psychoactive effects are blurred by the predomi- haemodynamic status of the patient must be peri with seizures (which

nance of the sympathetic nervous system effects, formed, including rectal temperature. Agitate/[ lular damage, acute JClinically, one sees anxiety, agitation, anorexia, patients may need to be restrained in order to I_} tracerebral haemorr

I nausea, bruxism, tremors, muscle rigidity, hyper- properly assessed. If the drug was ingested, gastric!_O.SxG reflexia, midriasis, diaphoresis, tachycardia, hyper- lavage (with appropriate airway protection) foci suited from exacerbdiseases such as can

_ _/+_ tension, and hyperthermia. In severe cases, a hy- lowed by the administration of activated charcoal': disease, and asthma,I--r-_l perdynamic cardiovascular collapse may occur, is necessary. . . _.ii haviour induced b,.

Laboratory anomalies may include leucocytosis, Further therapy depends on which signs andi deaths are usually fr(hyperglycaemia and elevated concentrations of symptoms predominate. B-Adrenergic blockins5 intoxication or fron

_7I _ serum creatine phosphokinase (CPK). Increases in drugs, e.g. propranolol and esmolol, are effectiff_ decontamination.

lt-/_lT-'l_ serum sodium, chloride and blood urea nitrogen agents in controlling tachycardia but should not lx Enhancing elimin:(BUN) may occur, indicating dehydration, as well used to treat hypertension alone. Hypertension may! in severely intoxicate

[7_A as lowered concentrations of bicarbonate due to be treated with a-receptor blockers (e.g. phent0_ clearance of these drhypermetabolism and impaired perfusion. Ele- amine), combined a- and B-blockers (e.g. labetalol__: ifying the urine to tr

-_- _ rated levels of serum phosphate, uric acid and po- or vasodilators (e.g. nifedipine or nitroprussidel weak base in the uritassium can occur due to rhabdomyolysis, depending on the patient's status. The presence 4, precipitating myoglol

v, _'_ Further complications of acute overdose in- tachycardia and hypertension may be treated byl the rhabdomyolysis,clude seizures (either single or multiple), arrhyth- mixed a-, B-antagonist. In all situations, a .rapidll_ sent to some degree.

? &_; mias (supraventricular or ventricular), intracere- acting, easily titratable drug, preferably intrave_ lion (hepatic metaboli

-__:..__ brai haemorrhage (secondary to a sudden increase ously administered, should be selected. Nifedipin_ the elimination half-Iin blood pressure with or without underlying cere- an oral calcium channel blocker with vasodilatinl pound from 4 to 36 hbrai vascular abnormalities such as a berry aneu- properties, lowers blood pressure rapidly if the cal_ marked improvemenrysm or arteriovenous malformation), muscle rig- sule is punctured and the liquid contents held sub Some may have resic

}l?~// idity with rhabdomyolysis (without localised muscle lingually. . turbances, tachycardi._2 trauma), hyperthermia (usually associated with in- Occasionally, blood pressure cannot be co( several more days.

_/_ creased muscular activity or rigidity), which may trolled without first controlling agitation with I Patients who prese_' lead to disseminated intravascular coagulation benzodiazepine. This should be done cautiously, $_ without significant al

-7]_ (DIC). adult respiratory distress syndrome (ARDS), mental status is an important parameter to foll0_ ferent therapy. Agitatacute renal failure, hepatocellular necrosis and coma in case of a CNS catastrophe; however, the av_ activity respond well

t;_ ,_,,-'_ (Ginsberg et al. 1970; Simpson & Rumack 1981). ability of flumazenil, a new benzodiazepine ant.l?lucinations and para

,<,'_:_ Most severely intoxicated patients will present with agonist, may obviate this concern. : without significant ag· a combination of the above complications, most Hyperthermia is a frequent complication, e_ ditional antipsychotic:

---r-r__],_ commonly supraventricular tachycardia, hyper- pecially in fatal overdoses. Temperatures abo_ ful. Adverse reaction?_i thermia, and seizures, a combination which can 40°C are not uncommon, and require urgert represent either an

_/t/q! easily be fatal without immediate appropriate therapy. The most effective way to lower temper. (possible malignant h'_-lk.,, I treatment, ature is by application of tepid water and fanninl' the authors in one in

l_/_*R_ Additional reported complications from short If this procedure is not effective then muscle l_ an occult underlying Cor long term use include cardiomyopathy (Ayers ralysis with pancuronium, with proper airway prO coronary artery disea

' 1983. Call et al. 1982), diffuse vascular spasm, tection, is recommended (Olson & Benowitz 1984) valve prolapse, berryf(,/k i which may lead to mesenteric ischaemia or necro- Dantrolene may be administered if the precedi_ malformation.

-r _ sis (Bowen et al. 1983), and pyrogenic reactions with measures are ineffective. Salicylates, paracetarn0' Chronic abuse may--' ..... chills, fever, shock, diarrhoea, DIC, and rhabdo- (acetaminophen) and cooling blankets are too si0( clinically indistinguish

%..v myol.vsis(Kendrick et al. 1977). and should probablybe avoided. _ thoughit is usually l

.? 6_I.Ii Phenylethylamine derivative overdoses must be Most amphetamine MDMA, and other a_ drug-free state. ConceI treated as medical emergencies. A rapid assess- phetaminederivative-associateddeathsoccurea_. _ regarding the possible

__.. ! ment of the psychological, neurological and and have been from arrhythmias, hyperthern_, use of these drugs. Ri

.Designer Drugs' 9

t

nust be per. with seizures (which may lead to DIC, hepatocel- ported that MDA, like amphetamine and meth-re. Agitate/! amphetamine, has neurotoxic potential. These

order to tnl lular damage, acute renal failure, or ARDS), or in-tracerebral haemorrhage. Some deaths have re- workers demonstrated that high doses of MDA in:sted, gastric salted from exacerbation of underlying or occult rats destroyed serotonin nerve terminals. More re-tection) fol.i diseases such as cardiomyopathy, coronary artery cently, high doses of MDMA in rats produced ated charcoal disease, and asthma, or from trauma related to be- similar serotonergic neurotoxic effect (Schmidt et

haviour induced by the intoxication. Delayed al. 1986). How these findings relate to the neuro_h signs and' deaths are usually from complications of the acute toxic potential in humans remains to be seen.ic blocking, intoxication or from inadequate gastrointestinal

ire effective decontamination. 2. Synthetic Opioidslould not Ix' Enhancing elimination is difficult to do safelytension may in severely intoxicated patients. Although the renal

Increased law enforcement activity in the US in:.g. phentol, clearance of these drugs can be enhanced by acid- the late 1970s reduced the amount of imported op-;. iabetalol_ ifying the urine to trap the charged moiety of the ium and heroin to the extent that shortages oc-roprusside),' weak base in the urine, this increases the risk of

curred. The response to the diminished availabilitypresence 0t· precipitating myoglobin in the renal tubules from of heroin was the search for synthetic alternativestreated by a the rhabdomyolysis, which is almost always pre- which circumvented legal restrictions. Because ofs, a rapidll' sent to some degree. While the routes of elimina-

the difficult process of synthesising morphine-y intraven, tion (hepatic metabolism versusrenal excretion) and related compounds, effort was instead focussed onNifedipine, the elimination half-life may vary with each corn- creating the more easily synthesised analogues offasodilating pound from 4 to 36 hours, most patients will show fentanyl and pethidine (meperidine).y ifthecal_, marked improvement within the first 24 hours.ts held sub Some may have residual effects such as sleep dis-

turbances, tachycardia, anorexia, and tremor for 2.1 Fentanyl Derivatives (fig. 2)ot be con. several more days.ion with 8 Patients who present primarily with CNS effects The summer of 1980 saw the introduction ofutiously, as_ without significant autonomic effects require dif- the first 'street-synthesised' opioid material, a de-

'r to follo_ ferent therapy. Agitation and anxiety with hyper- rivative of fentanyl, an analgesic used in anaes-· the avai_ activity respond well to benzodiazepines. If hal- thesia, sold as 'synthetic heroin' or 'China White'_epine ant-' lucinations and paranoid psychosis predominate (Ayres et al. 1981; Brittain 1982). The exceedingly

, without significant agitation or hyperactivity, tra- high potency of the material led to several deathsication, e_ ditional antipsychotics such as haloperidol are use- in which no narcotic material could be detected_res above: ful. Adverse reactions to 'therapeutic doses' may in either the drug samples or the patients. The

ire urgent: represent either an idiopathic hypersensitivity ultimate identification of the opiate as a-methyl-,er temper- (possible malignant hyperthermia, as observed by fentanyl proved to be a rigorous exercise in foren-_d fanning* the authors in one instance) or an uncovering of sic toxicology (Kram et al. 1981).muscle pa-, an occult underlying disease such as hypertension, A further homologue, 3-methyl-fentanyl (3MF),tirway pr_ coronary artery disease, cardiomyopathy, mitral has recently appeared in illicit opiate sampleswitz 1984)/ valve prolapse, berry aneurysm, or arteriovenous (Cooper et al. 1986). 3MF is approximately 16timespreceding malformation, as potent as fentanyl,which translatesto a potency

_racetam0l Chronic abuse may lead to a paranoid psychosis about 1600 times that of heroin. Other analogues'e too slo*' clinically indistinguishable from schizophrenia, al- of fentanyl which have appeared in recreational use

though it is usually reversible after a prolonged include para-fluorofentanyl and a-methylacetylfen-other am- drug-free state. Concern has also been expressed tanyl. Since the late 1970s, 9 homologues have ap-)ccur earl_' regarding the possible neurotoxic effects of chronic peared in illicit use, with potencies probably be-)erthermi_. use of these drugs. Ricaurte et al. (1985) first re- tween the extremes of fentanyl and 3MF.

i

'Designer Drugs' .Designer Drugs'

2.2 Clinical Toxico{ogy of Fentanyl _ Injection ofDerivatives

.r_! suited in local t_'_ more dysphoric:

-, o Fentanyl is a specific u-opiate receptor agonil transient visual

12, _,,,+' //____ _ _C_CH2CH_ with approximately 100 times the potency of m0r.! hallucinations. X'J? _ ax._.N/_ _,x__._N phine. The highly lipophilic nature of the drug r_ jections of what

_'_ _ _ suits in rapid penetration of the CNS; the onset 01 heroin, some palsubjective effects is within 90 seconds of intrave_, a severe form of

ous administration. Plasma concentrations of fe_ ments approach:

Fentanyl tanyl rapidly decline as the drug is both metab0_ sionand stare ('r

" ised and distributed into tissues. Repeated dos__ swallowing,hyp_

Z/I of fentanyl lead to accumulation of the drug anl cogwheeling, and/CH30

(/ \__.._ _ /C__CHaCH3 its respiratory depressant effect. Prolonged or r0 lng. Tremor was[_,,.A.I x_/ '-- N. current respiratory depression may occur due II signs were norm

NX,.___ _---_ fluctuating serum concentrations of the drug as_ al. 1985).

---,--_ _ is eliminated. The receptor binding characteristia Although on153" and pharmacokinetics of a- and 3-methylfentan_, ted during this e

47._: 3-Mothyl-fentanyl are not known; however, they appear to be clinic, venous drug abu..

? _;_ allysimilarto fentanyl, lesserformsofp

/_ m_--- Users of 'China White' (a-methylfentanyl)d_ Langston et al. 1

o_ \\ scribe a qualitatively different psychoactive effe0 In addition, ot

' lq N G--CH2CH3 from that of heroin. 'China White' produces moa been seen (Burnt_'x_, <-,u _L}-< H3C analgesia than euphoria, yet the euphoria lasts 2 t_ severe case was se

4 hours; a longer effect than for heroin. The classic by the authors, 2

symptomsof miosis and CNS and respirato_fiscationby the [cr-Methyl-fentanyl

7_ depression are observed in 'China White' intoxi, in Florida (Frank_--. cationas forheroin. Fatalitiesdue to intoxicati0_

/_-_N_ °'N with fentanyl derivatives are due to respiratory ar. 2.4 Clinical Tt

_---1 _ X_C--CH2CH3 rest; patients are often found with the needle sti[,-: in their arms. Naloxoneis a specificantagonistf_ MPTP-induce_

· .7 the CNS- and respiratory-depressant effects of fee in its neuropatho

_q:_ tanyl and its analogues, but high doses (2 to 10rog' kinson's disease. _I

r-- _ may be required, more widespreadi p-Fluoro-fentanyl F dementia, and dec

2.3 Meperidine Derivatives (3-methoxy-4-hydl

/_ °tx metabolite of nor_N/___ /C--CH3 One of the most fascinating and tragic episode vation seen in the

'_7_:i _ H3C N .__ with 'designer drugs' resulted from a garage b have similar clini_K____/

[_,_ _ boratory synthetic error in the San Jose, Californ_ ergic neurons inarea. In an attempt to synthesise MPPP (l-methyl creased levels of H

,,-Methyl-acetylfentanyl 4-phenyl-4-propionoxypiperidine). a synthetil jor dopamine meanalogue of meperidine, an illicit chemist accide_ 1986).

-; tally made a product contaminated with MPTP (I. Ail the patients1/· '_:'_: methyl-4-phenyl-l,2.3.6-tetrahydropvridine) whiCt degree to standard

led to an 'epidemic' of parkinsonism among intff however, they hat

Fig. 2. Chemical structures of fentanyl and its derivatives, venous drug abusers. COmplications of 1

/ILL/_.L. ,

21 .DesignerDrugs' 11I

anyl Injection of MPTP-contaminated samples re- come increasingly severe management problems,i! sulted in local burning and pain and an atypical, (Langston 1985). The long term prognosis of the:_ more dysphoricand'spacey'high, occasionally with exposed, but so far unaffected, patients is un-

receptor agoni_t transient visual distortions and visual or auditory known. Additionally, intellectual changes have de-potency of mot. hallucinations. Within several days of repeated in- veloped in MPTP-induced parkinson patients

of the drug r0 jections of what users thought was a new synthetic (Stem & Langston 1985).NS; the onset of heroin, some patients developed the rapid onset of While MPTP has been a catastrophe for thends of intraver_ a severe form of parkinsonism with akinetic move- patients involved, its discovery has been a boon toatrations of fen ments approaching catatonia, fixed facial expres- neuroscientists. Research has shown that MPTP is

s both metab0_ sion and stare ('masked facies'), drooling, difficulty metabolised in the brain by monoamine oxidase BRepeated dos_ swallowing, hypophonia, 'lead pipe' rigidity with (MAO-B) to MPP + (l-methyl-4-phenylpyridiniumof the drug and cogwheeling, and a shuffling gait with en bloc turn- ion) which selectively destroys the zona compacta'rolonged or re. lng. Tremor was present to a variable degree. Other of the substantia nigra (Langston 1985; Langstonty occur due lc signs were normal, including cognition (Ballard et & Ballard 1984). However, pretreatments with the)fthe drug asil al. 1985). MAO-B inhibitor deprenyl (selegeline)protectsg characteristb Although only 7 known severe cases were stud- against the neuronal damage of MPTP in certain;-methylfentan34 led during this epidemic, hundreds of other intra- models. MPTP is the first chemical substance

,ear to be clinic, venous drug abusers were exposed and some have known to cause a site-specific neurotoxic lesion andlesser forms of parkinsonism (Ballard et al. 1985; it is also the first example of a molecule metab-

hylfentanyl) d, Langston et al. 1983, 1984). olised in the brain to a toxic substance. MPTP now

rchoactive effecl In addition, other cases involving chemists have provides an ideal tool for Parkinson's disease re-' produces mon been seen (Burns et al. 1985). A probable eighth search.phoria lasts 2 t_ severe case was seen in May, 1987 in San Franciscoroin. The classic by the authors, 2 years after the last MPTP con-

3. Arylhexylaminesand respirator, fiscation by the Drug Enforcement Agency (DEA)a White' intox[ in Florida (Frank, personal communication).:to intoxication The arylhexylamines,of which phencyclidine

o respiratory ar. 2.4 Clinical Toxicology of MPTP (PCP) is the most widely abused, represents a dis-the needlesti[ tinctclassof psychoactivecompounds.Phencycli-

_c antagonist fo', MPTP-induced parkinsonism is more specific dine and its related analogues, including the licitnt effects of fee in its neuropathology then classic, idiopathic Par- anaesthetic ketamine, exert effects on a variety ofoses (2 to 10mg_ kinson's disease. The idiopathic form tends to have neurotransmitter systems: muscarinic receptor

more widespread brain pathology, Lewy bodies, blockade, acetylcholinesterase inhibition and agon-dementia, and decreased cerebrospinal fluid MHPG ist actions at dopaminergic, adrenergic and opiate

· (3-methoxy-4-hydroxyphenylglycol, the major brain receptors. The complex pharmacological propertiesmetabolite of noradrenaline) in contrast to the ele- of the arylhexylamines produce a confusing array

d tragic episode ration seen in the MPTP-induced form. Both forms of symptoms in the intoxicated patient.)ma garage 1_ have similar clinical syndromes, loss of dopamin- The ease with which arylhexylamines can beLJose, Californ_ ergic neurons in the substantia nigra, and de- synthesised may lead to even more analogues ap-/IPPP (l-methY} creased levels of riVA (homovanillic acid), the ma- pearing in the future. It is known that structural

lc), a syntheti_ jot dopamine metabolite in the brain (Fruncillo modifications can alter the potency (Shannon et al.:hemist accide_1986). 1983)and the affinityof the analoguefor variousJ with MPTP (I. All the patients studied have responded to some receptors (Kamenka et al. 1982). A variety of ke-

_pyridine) whid degree to standard anti-Parkinsonian medications; famine analogues have been studied, including thesm among into however, they have tended to develop the typical thiophene analogue tiletamine, which conceivably

COmplications of levodopa therapy and have be- may become available on the street. The physio-

'DesignerDrugs' I .DesignerDrugs'

[·

logical effects these compounds will have upon hu- eighth the potency of PCP, yet was only 1.4 t_rne_i Urinary acidifi_mans remains to be determined, less toxic. Doses required to produce phencycl_ ion of phencyclidi

dine-like behavioural effects could more easily pr_ The risk ofexacer[

_:9._x_ 3.1 Phencyclidine Analogues duce toxic effects compared with PCP. [ precipitating myogweighs the increas

A number of synthesis procedures are available 3.2 Clinical Toxicology of Arylhexylamines , that is predominanto the 'street' chemist to produce phencyclidine and severely intoxicate,related arylhexylamine analogues (Shulgin & The psychoactive and somatic effects of phe_ benefit the most fi

MacLean 1976). An intermediate product, PCC cyclidine are dose related. Low doses produce is: is also at greatest(piperidinocyclohexanecarbonitrile), as well as sev- ebriation, euphoria and a feeling of depersonali_ Instead, because s_eral end-product analogues, TCP (a thiophene ation accompanied by signs of sympathetic clidine undergo g_

analogue of PCP) and PCE (an N-ethyl analogue) stimulation. Horizontal and/or vertical nystagm_ peated doses of aclhave appeared in recreational use. Concern has been is a common finding at this stage. The anaesthetic istered to adsorb

_AI expressed that the labile cyano-group of PCC can property of the drug dampens the perception of gastric juice. Conti

-___ be liberatedupon heating(Soineet al. 1979).PCC pain. recommendedbec_may represent 10 to 70% of a phencyclidine sam- As the dose is increased the patient becoma balances.'Haemod

' ple, depending on the sophistication of production, more agitated, combative and paranoid. Violent large volume of di_· , Soine and colleagues (1979)have hypothesised that behaviour is not uncommon in this setting. Tht

,/_ 0% smoking large amounts of such material may re- sympathetic stimulation noted at lower doses is i_ 4. Methaqualolease sufficient amounts of cyanide to produce toxic tensified. Hypertension is typically encountere6effects, but this remains to be proven. Little is accompanied by tachycardia, hyperthermia an_

known about the pharmacological properties or hyperreflexia. The patient's course may be corn. Methaqualone hV_ _ PCC itself, plicated by seizures, acidosis and rhabdomyolysis ularity as an intox

lude', then as illicPCE appeared in Los Angeles in 1969 as a sub- Rhabdomyolysis, a particular concern in the con_stitute for PCP, though with greater potency. TCP, bative, seizing or acidotic patient, may lead to acute verted pharmacewhich first appeared in San Francisco in 1972, was myoglobinuric renal failure. The severely intox_ legitimate prescripfound to be more potent than PCP itself, yet qual- cared patient may progress to become comatose and sequently, as the stitatively similar in effect. It was included in the demonstrate respiratory depression or arrest, has become more

-J---J Controlled Substances Act in 1975. PHP (phenyl- Therapy is supportive in nature. The agitate/ pliers have turned

_b 4_+_' cyclohexylpyrrolidine) has appeared as an abused patient may be calmed with diazepam, while hal0 The synthesis_'_/, substance in Los Angeles, with clinical effects sim- peridol is effective in controlling the combativ_ quinazolinones is r' _';_-, ilar to that of PCP (Budd 1980a; Giannini & Cas- psychotic patient. Chlorpromazine should Ix 1985; Soliman el a

for exogenous sour{tellani 1982; Nakamura et al. 1979), although it has avoided as it may precipitate a hypotensive r_! also been reported to cause an unacceptable degree sponse. Hyperacousis occurs with phencyclidi_ ologues of methm[

?/[/_"i of sedation (Shulgin & MacLean 1976). The use of intoxication; therefore all stimuli should be keptl0, methaqualone) whi_,_._ pyrrolidine to manufacture PHP allows the 'street' a minimum. One should not attempt to 'talk dovd Europe are reporte_chemist to circumvent the restriction on the sale the PCP-intoxicated patient, tine laboratories inof piperidine needed to make PCP. Further, PHP Hypertension should be identified and treat8 Van Boven 1976).

[_,AI could not be detected by the methods originally as earlier described (section 19) for phenylethyt Intoxication is t: used in Los Angeles county to assay for PCP. amines. Seizures are responsive to diazepam. Aci_ although initially a

Phenylcyclohexyl-4-methylpiperidine was iden- osis usually corrects spontaneously if seizures lation may be note(: tiffed from a street sample presumed to be PCP hyperthermia and excessive muscle activity a_ and muscle hype

_/_ ._i_ (Soine et al. 1982). This compound is synthesised controlled. Hyperthermia is an important compli depression is not t..._"'/"I using 4-methylpiperidine instead of the restricted cation to detect and treat promptly, as it is a fro methaqualone has

'_ piperidine. Human pharmacological data are lack- quently overlooked sequela of moderate to seve__ dative potency oflng; however, in mice it was shown to have one- intoxication. ,( qualone.Treatmen

J

I .Ix-signerDrugs' 13

.s only 1.4 time_i Urinary acidification to enhance the eliminat- 5, Role of the Toxicology Laboratory· luce phencycli,i ion of phencyclidine is no longer recommended.more easily pr, The risk of exacerbating an existing acidaemia and Efforts to identify 'designer drugs' by toxico-

PCP. precipitating myoglobin in the renal tubules out- logical analysis are hampered by the inability ofweighs the increased renal elimination of a drug most laboratories to separate these drugs from the

hexylamines that is predominantly hepatically metabolised. The parent compounds they are modelled from. A fur-severely intoxicated patient who would potentially ther limitation is the lack of sufficient assay sen-

effects of phe, benefit the most from enhanced drug elimination sitivity to detect these drugs in the low concentra-

)ses produce i_t is also at greatest risk from acidification therapy, tions in which they occur in human serum.

of depersonali_: Instead, because significant quantities of phency- Common procedures utilising radioimmunoassay_f sympathetic clidine undergo gastrointestinal recirculation, re- (RIA) or high-pressure liquid chromotography'tical nystagmt_I peated doses of activated charcoal may be admin- (HPLC) often lack both the sensitivity and speci-The anaesthetic istered to adsorb the phencyclidine secreted in ficity to conclusively identify these compounds. In

e perception t/ gastric juice. Continuous nasogastric suction is not general, the utility of'tox screens' is sorely lacking,' recommended because of potential electrolyte tm- and specific assay capabilities, if they are available,

)atient becoma_ balances.'Haemodialysis is ineffective due to the are not of immediate use to the clinician faced withranoid. Violent large volume of distribution of phencyclidine, an intoxicated patient. Furthermore, no reliablehis setting.Thc serum concentration-responsestudiesin humans

)wer doses is i_ 4. Methaqualone Derivatives have been performed by which serum measure-ly encountere_ ments could be interpreted even if they were avail-:erthermia and able. Autopsy data are equally difficult to interpret.e may be cor_ Methaqualone has enjoyed a long-standing pop- The limitations of toxicological analysis may be'habdomyolysi_ ularity as an intoxicating sedative, first as 'quaa- exploited by both the 'street chemist' and the rec-em in the con_ lude', then as illicitly produced tablets from di- reational user. A consequence of the extreme po-

lay lead to acut_ verted pharmaceutical methaqualone when tency of the fentanyl derivatives is that serum con-severely intoxi, legitimate prescription sources diminished. Sub- centrations are too low to reliably measure even if_ecomatose and sequently, as the supply of diverted methaqualone one knew to look for a fentanyl product and not

or arrest, has become more difficult to obtain, illicit sup- heroin. Users of phencyclidine who wish to avoid

·e. The agitate_ pliers have turned to synthetic production, detection by the Roche RIA assay for PCP will tend,am, while hale! The synthesis of methaqualone and related toward products such as PHP with limited crossthe combativ_ quinazolinones is not difficult (Angelos & Meyers reactivity (Budd 1981). Similarly, nitromethaqua-ne should ix 1985;Soliman etal. 1978) and obviates the need lone is not strongly reactive using the Roche RIA

hypotensive re forexogenous sources of methaqualone. Two hom- assay for methaqualone, but can be analysed forphencyclidi_ ologues of methaqualone (mecloqualone, nitro- when sufficiently large concentrations exist (Budd

iould be keptt0 methaqualone) which have been in clinical use in 1980b).) Europe are reported to be synthesised by clandes-)t to 'talk down! line laboratories in the United States (Daenens & 6. Legal Considerations

led and treated VanBoven 1976).

Or phenylethy_ Intoxication is typified by ataxia and lethargy, In the wake of the dramatic rise in the illicitliazepam. Aci_ although initially a period of disinhibited stimu- manufacturing and recreational use of various psy-dy if seizure_, lation may be noted. Overdose may result in coma choactive mescaline analogues in the late 1960s,:le activity afl, and muscle hyperactivity. Marked respiratory the US Congress enacted the Controlled Sub-

oortant complY[depression is not commonly encountered. Nitro- stances Act. The provisions of this legislation at-y, as it is a frei methaqualone has approximately 10 times the se: tempted to halt the 'street' production of sub-lerate to dative potency of either mecloqualone or metha- stances deemed to have no medicinal value and

qualone. Treatment is supportive in nature, high abuse potential. The response to this by illicit

'Designer Drugs'·Designer Drugs'

manufacturers was to search for other compounds 7. Future Trends Iwhichdemonstratedsimilarpharmacologicalprop- ._

erties as the 'scheduled' drugs, yet which were not Despite the Controlled Substance Analogue E_listed under the Controlled Substances Act. The forcement Act, further analogues are expectedl0!

_b -_x'cJ, Drug Enforcement Agency soon found itself in the appear in recreational use. One direction in whict_

difficult positionofattemptingtoidentifynewsub- interest has been generated is toward phen$stances of abuse and rapidly include them in the ethylamine materials in which the a-methyl groul_Act. which gives the material an amphetamine-likt

? I[._ In response to this dilemma, the US Drug En- structure, is removed. Specifically, the 2-car_[-k_. forcement Agency has restructured its approach to homologue of DOB and DOM, 2-CB and 2-Ct), Fig.3. Chemicalst_

the control of illicit substances. In place of the re- respectively, are potent agents which produce e_'active approach of placing new abused substances phoria, increase sensory receptiveness and iht, further substanc

__ ,_ under restricted status as they appear, a more pro- grate sensory perception with the emotional sta_ use. The challe_,,d:xI spective method has been adopted in the form of (Shulgin 1979). Cautious experimentation is wa. dromes as well:

1 an amendment to the Controlled Substances Act. ranted since other compounds in this series, no ruminant mater-_-,-_ This amendment, entitled the Controlled Sub- tably 2-CI and 4-thiomescaline, have been ass_ be alert to new,

._ stance Analogue Enforcement Act of 1986, places ated with intense hallucinatory experiences a_·_' under Schedule I restriction those chemicals which: psychotic reactions. 8. Conclusi6.? ._

._ _%, (a) have structures similar to those of existing Already in recreational use on the US East ag

Schedule I or II drugs, (b) are stimulants, depres- West coasts is a substance called 'U-4-E-Uh', 2. 'Designer dru_ sants or hallucinogens, or (c) are represented as amino-4-methyl-5-phenyl-2-oxazoline (fig. 3). U4 stances intended

_ _ such. Human research with these compounds will E-Uh is a methylated derivative of a European a either newly synbe allowed by means of approved new drug ap.pli- orexiant, Aminorex, which was recently withdrav_ imate pharmacetcations or exemptions for investigational use. due to instances of pulmonary hypertension. Iti cumvent legal re:

During the development of legislation aimed at unclear how U-4-E-Uh will be treated under t_ feelings of intoxi7q/ curbing the abuse of'designer drugs', concern has new CSA regulations. :_ tween these anal,

_'_ been expressed that legitimate research with these These new phenylethylamines, and perhap ician to underst:compounds will be stifled. The outcry from the other psychoactive agents, will likely continuer stances produce_

__I medical community claiming a medical use for be investigated by psychotherapists. As happen_ their respective

to ..,c? MDMA took the Drug Enforcement Agency by with LSD and MDMA, their discoveries vt/'lion with any of_

?' "'5:_ surprise when it attempted to place MDMA under eventually be found by recreational users. _ will produce am[Schedule I status. While the present amendment One conceivable scenario of the future involve' lores resulting fr(to the Act allows for investigational uses, few phar- genetic engineering as a means of producing abtll or phencyclidinemaceutical companies are likelyto be interested in able substances. _ withthe parent o

71/_' studying compounds unpatentable and easily Consider the use of bacteria into which has be__exhibit unexpectcL-I{_., manufactured by unsophisticated laboratories, added the gene to generate human endorphi_ iai, e.g. MPTP. S

The present Controlled Substances Act amend- Clandestine bacterial laboratories may replace lg such novel toxicmerit, by addressing the issues of both structural 'street chemists' of today. _ ler adverse effect

[? '_,I similarity and intent, renders the term 'designer As evidenced by the recent 'designer drug' c_ class. New drugsdrug', with its current meaning, obsolete. Whether astrophes, the public health risk of these co_:expected to prese

_ ] illicit chemists will truly design novel compounds pounds is considerable. The extreme potency of_' the future.to circumvent these restrictions or find other means fentanyl derivatives, MPTP-induced parkinsoni_i= The toxicology

_<; ._ to evade the current constraints remains to be seen. and the potential neurotoxic effects of MDA a_ to firmly identify.._'cared Parle..' r'. The current law has yet to be tested in the courts. MDMA are a few examples of the recognised n_ nt, due

7 %. Problems with interpretation can be anticipated as associated with 'designer drugs'. The medical c0_':_ent drug or becaus

new compounds appear (see section 7). munity will be faced with other adverse effects{ assay method, h

I

t14[ .Designer Drugs' 15

i

1dogue Ell. l:pected t0!

in which! O ___ oH3C :NH v H3C NH 2

t pheny_,

hylgroul_,, Htmine-lil_

2-carb0v

nd 2-C]),, F_I.3. Chemical structure of U-4-E-Uh (2-amino-4-methyl-5-phenyl-2-oxazoline).

educe eu.

and inte. further substances find their way into recreational intoxicated patient the clinician must rely on theonal state use. The challenge will be to identify new syn- clinical presentation and direct therapy toward these

m is war. dromes as well as new abused substances and con- findings.

;eries, n,' taminant materials. Clinicians are encouraged to Despite the plethora of compounds described in r

en asso6t be alert to new complications of drug abuse, this article, only a few appear to be currently inraces and use. In the experienceof the authors, thosecom-

B. Conclusion pounds currently in use in the San Francisco area

; East and includeMDMA, MDEA,2-CBand U-4-E-Uh.The

·E-Uh', 2. 'Designer drug' is a term which refers to sub- recent case we observed of presumed MPTP ex-

,. 3). U4 stances intended for recreational use and which are posure demonstrates that this contaminant may

opean an., either newly synthesised or 'borrowed' from legit- also be in circulation.

vithdrava lrnate pharmaceutical research in an attempt to cir- 'Designer drugs' should not be assumed to be a

sion. It is cumvent legal restrictions. Although the subjective new class of abused substances. Contrary to the

under tht feelings of intoxication may vary significantly be- impression gained from recent media attention,

Iween these analogues, it is important for the clin- 'designer drugs' represent only the most recent' perhaff ician to understand that in overdose these sub- developments in the evolution of mind-

retinue 10 stances produce qualitatively similar effects within altering drugs.

happened their respective clinical classes. Serious intoxica-

eries wiV'lion with any of the phenylethylamine compounds Acknowledgement

·s. _ will produce amphetamine-like effects. The symp-

e involv_ toms resulting from an overdose with the fentanyl The authors wish to express their gratitude to Alex-

- _ ander Shulgin, PhD for his invaluable assistance in thecrag ab ' or phencyclidine analogues are similar to those seenpreparation of this manuscript. Dr Brown was supported

i with the parent compound. Some compounds will by US NIH Training Grant GM 07546.has bee_ exhibit unexpected toxicity unique to that mater-

_dorphin_I iai, e.g. MPTP. Since there is no way to predict Referenceseplace tl_ such novel toxic effects, the clinician may encoun-

ter adverse effects beyond that expected for the Allcott JV, Barnhart RA, Mooney LA. Acute lead poisoning in

drug' cat.: class. New drugs and new drug syndromes can be lwousers of illicit methamphetamine. Journal of the AmericanMedical Association 258:510-511, 1987_ese cor_' exPected to present challenges to the clinician in AngelesSA, Meyers JA. The isolation and identification of pre-

ney of the Ire future, cursors and reaction products in the clandestine manufacturei of methaqualone and mecloqualone. Journal of Forensic Sci-_insonis_ The toxicology laboratory is unlikely to be able ence 30: 1022-1047. 1985

MDA ani to firmly identify the 'designer drug' in an intoxi- Ayers PR. Amphetamine cardiomyopathy (letter). Annals of an-ternal Medicine 98: 110, 1983

xised risk! cared patient, due to cross reactivity with the par- Ayres WA, Starsiak MJ. Sokolay P. The bogus drug: three methyl

lical cog: ent drug or because of inadequate sensitivity in the and alpha methyl fentanyl sold as 'china white'. Journal ofPsychedelic Drugs 13: 91-93, 1981

etlbcts_$ assay method. In treating the 'designer drug'- Ballard PA, Tetrud JW, Langston JW. Permanent human par-

ii

'DesignerDrugs' 'DesignerDrugs'

kinsonism due to l-methyl-4-phenyl-l,2,3,6-tetrahydropyri- chotherapeutic process? American Journal ofdine (MPTP), seven cases. Neurology 35: 949-956, 1985 40: 393-404, 1986 Journal of Pharmacolog3

Bohn G. Illegally manufactured 2,5-dimethoxy-4-bromoamphe- Hayner GN, McKinney H. MDMA: the dark side 327-333, 1983tamine in connection with a fatal intoxication. Toxichemistry Journal of Psychoactive Drugs 18: 341-347, 1986 Shulgin AT. Chemistry ofp14: 140-141, 1981 Kalant H, Kalant OJ. Death in amphetamine users: causes Journal of Pychoactive I

Bowen JS, Davis GB, Kearney TE, Bardin J. Diffuse vascular rates. Journal of the Canadian Medical Association 112: Shulgin AT. Profiles of psy_

1_O .Ax_ spasm associated with 4-bromo-2,5-dimethoxyamphetamine 304, 1975 choactive Drugs 13: 99,ingestion. Journal of the American Medical Association 249: Kamenka JM, Chiche B, Goudal R, Geneste P, Vignon J, et Shulgin AT. Profiles of psy1477-1479, 1983 Chemical synthesis and molecular pharmacology chedelic Drugs 9:171-17

Brittain JL. China white: the bogus drug. Journal of Toxicology lated l-(l-phenylcyclohexyl)piperadine derivatives. Journal, Shulgin AT. Profiles ofpsycland Clinical Toxicology 19:1123-1126, 1982 Medicinal Chemistry 25: 431-435, 1982 ehedelic Drugs 8: 169, 1_

Brown CR, Osterloh J. Journal of the American Medical Asso- Kendrick WC, Hull AR, Knochel JP. Rhabdomyolysis Shulgin AT. The backgrounelation. In press, 1987 after intravenous amphetamine administration. Annals ofl of Psychoactive Drugs 11

,'; Budd RD. Methaqualone RIA structure versus reactivity. Clinical ternal Medicine 86: 381-387, 1977 Shulgin AT, Jacob P. Poter

Toxicology 16:209-217, 1980b KojimaT, Uae I, YashikiM, Noda J, Sakai K, et al. Fatal _ ylenedioxyamphetamineBudd RD. Phencyclidine (PCP): structure versus reactivity. Clinical amphetamine poisoning associated with hal of Analytical Toxicol

Toxicology 18: 1033-1041, 1981 sic Science International 24: 87-93, 1984 '[ Shulgin AT, MacLean DE. 11Budd RD. PHP, a new drug of abuse. New England Journal of Kram TC, Cooper DA, Allen AC. Behind the identification_ and several of its analogs.

Medicine 303: 588, 1980a china white. Analytical Chemistry 53: 1379A-1386A, 1981_ Shulgin AT, Sargent T, Na

Px,_k. t BuhriChhallucinogen?N,Morris G, Cook G. Bromo-DMA: the Australasian Langston JW. MPTP and Parkinson's disease. Trends in N_ human pharmacology oAustralia and New Zealand Journal of Psychia- roscience 8: 79-83, 1985 _ propylamine (MMDA). [

try 17: 275-279, 1983 Langston JW, Ballard P. Parkinsonism induced by l-methy_, SiegelRK. MDMA, nonme(

.._x_j Burns RS, LeWitt PA, Ebert MH, Pakkenberg J, Kopin IJ. The phenyl-l,2,3,6-tetrahydropyridine (MPTP): implications fl Psychoactive Drugs 18:2clinical syndrome of striatal dopamine deficiency, parkinson- treatment and the pathogenesis of parkinson's disease. Ca_ Simpson DL, Rumack BH. [description of overdose,ism induced by l-methyl-.4-phenyl-l,2,3,6-tetrahydropyridine dian Journal of Neurological Sciences I' 160-165 1984 ._,_: - ' -' - _ ArchivesofInternalMed

:I_,? (MPTP). New England Journal of Medicine 312:1418-1421, Langston JW, Ballard P, Tetrud JW, Irwin I. Chromc parkms_1985 ism in humans doe to a product of meperidine-analog

,,V %9·· Call TD, Hartneck J, Dickinson WA, Harman CW, Barrel AG. thesis. Science 219: 979-980,' 1983, Acute cardiomyopathy secondary to intravenous ampheta- Langston JW, Irwin I, Langston EB, Forno kS. l-methyl-4-pM'

mine abuse. Annals of Internal Medicine 97: 559-560, 1982 ylpyridinium ion (MPP+): identification of a metabolite!Chiarello RI, Cole JO. The use of psychostimulants in general MPTP, a toxin selective to the substantia nigra. Neurosci¢z

psychiatry. Archives of General Psychiatry 44: 286-294, 1987 Letters 48: 87-92, 1984Cimbura G. 3, 4-methylenedioxyamphetamine (MDA): analytical Lukaszewski T. 3,4-methylenedioxyamphetamine overd%

V'Xc_ _ and forensic aspects offatal poisoning. Journal of Forensic Sci- Clinical Toxicology 15: 405-409, 1979 [ence 17: 329-333, 1972 McCall RB. Effects of hallucinogenic drugs on serotonergic m

Cimbura G. PMA deaths in Ontario. Canadian Medical Associ- ronal systems. Pharmacology Biochemistry Behavior 24: 3_,ationJournal110:1263-1267,1974 363,1986

Cooper D, Jacob M, Allen A. Identification of fentanyl deriva- Nakamura GR, Griesemer EC, Joiner LE, Noguchi TT. DeZ

_/? tives. Journal of Forensic Science 31:511-528, 1986 mination of l-(l-phenylcyclohexyl)pyrrolidine (PHP) in !z_Daenens P, Van Boven M. The identification of quinazolinones mortem specimens: a case report. Clinical Toxicology 14:3_on the illicit market. Journal of Forensic Science 21: 552-563, 388, 1979 i_

1976 Neill JR. More than medical significance: LSD and Amefia Interni Davis WM, Borne RF. Pharmacologic investigation of com- psychiatry 1953 to 1966. Journal of Psychoactive Drugs I_

pounds related to 3,4-methylenedioxyamphetamine (MDA). 39-40, 1987 SCiI_ ,\,._ Substance Alcohol Actions Misuse 5:105-110, 1984 Nichols DE. Structure-activity relationships

, Delaney P, Estes M. Intracranial hemorrhage with amphetamine hallucinogens. Journal of Pharmaceutical Sciences 70:t', use. Neurology 30:1125-1128, 1980 1981

"-I_ Dowling GP, McDonough ET, Bost RO. 'Eve' and 'Ecstasy', a Noggle FI', Clark CR, Davenport TW,report of five deaths associated with the use of MDEA and tification and acute toxicity ofall_MDMA. Journal of the American Medical Association 257: alpha-benzyl-N-methylphenethylamine:

! 1615-1617,1987 destinepreparationof amphetamineand metham--r · Downing J. The psychological and physiological effects of MDMA Journal of the Association of Official Anal' * Under the joix(_/(I on normal volunteers. Journal of Psychoactive Drugs 18: 335- 1213-1222, 1985~... 340, 1986 OIson KR, Benowitz NL. Environmental and Hebrew Univer:

- Fruncillo RJ. Toxin-induced parkinsonism: recent developments, hyperthermia: pathophysiology, University aos-_.gj American Family Physician 33: 251-254, 1986 Emergency Medical Clinics of NcGaston TR, Rasmussen GT. Identification of 3,4 methylene- Ragan FA, Hite SA, Samuels MS, Garey RE. 4-Bromo-2,_ * Sponsored by

dioxymethamphetamine. Microgram 5: 60-63, 1972 mcthoxyphenethylamine: identification of a new street d_ and the hmeric_/O'x I Giannini AJ, Castellani S. A case of phenylcyclohexylpyrrolidine Journal of Analytical Toxicology 9: 91-93, 1985

- (PHP) intoxication treated with physostigmine. Journal of Reed D, Cravey RH, Sedgwick PR. A fatal case involvit

Toxicology and Clinical Toxicology 19: 505-508. 1982 ylenedioxyamphetamine. Clinical Toxicology 5: 3-6, 1972 For further informGinsberg MD, Hertzman M, Schmidt-Nowara WW. Ampheta- Ricaurle G, Bryan G, Strauss L, Selden L. Schuster C. Elka Touitou,

mine intoxication with coagulopathy, hyperthermia, and re- ogenic amphetamine selectively destroys brain

l f.l ,.?_ versible renal failure, a syndrome resembling heatstroke. An- terminals. Science 229: 986-988, 1985 P.O. Box 983,aais of Internal Medicine 73: 81-85, 1970 Schmidt CJ, Wu L, Lovenberg W. Methylenedioxymethar Jerusalem 91009,· r, Greer G, Tolber R. Subjective reports of the eflbcts of MDMA famine: a potentially neurotoxic amphetamine analog. ISRAEL.

'_. in a clinical setting. Journal of Psychoactive Drugs 18: 319. penn Journal of Pharn_acology 124: 175-178, 19861986 Shannon HE, McQuinn RL, Vaupel B, Cone EJ. Effects of{

Grinspoon L, Bakalar JB. Can drugs be used to enhance the psy- cloalkyl ring analogs of phencyclidine on

· ii

· l_igner Drugs' , 17

Journal of Pharmacology and Experimental Therapeutics 224: Snyder SH, Faillace L, Hollister L. 2,5-Dimethoxy-4-methylam-of 327-333, 1983 phetamine (STP): a new hallucinogenic drug. Science 158: 669-

shulgin AT. Chemistry of phenethylamines related to mescaline. 670, 1967: causes Journal of Pychoactive Drugs I h 41-52, 1979 Seine WH, Balster RL, Berglund KE, Martin CD, Agee DT. Iden-)n 112: _ shulgin AT. Profiles of psychedelic drugs: DOB. Journal of Psy- tification of a new phencyclidine analog, I-(I-phenylcycloh-

choactive Drugs 13: 99, 1981 exyl)-4-methylpiperidine, as a drug of abuse. Journal of Aha-

non J, el Shulgin AT. Profles of psychedelic drugs: STP. Journal of Psy- lyrical Toxicology 6: 41.43, 1982chedelic Drugs 9: 171-172, 1977 Seine WH, Vincek WC, Agee DT. Phencyclidine contaminant

ShulginAT. Profiles of psychedelic drugs: TMA-2. Journal of Psy- generates cyanide. New England Journal of Medicine 301: 438,chedelic Drugs 8: 169, 1976 1979

is and Shulgin AT. The background and chemistry of MDMA. Journal Soliman FSG, Shafik RM, Elnenaey EA. Synthesis of methaqua-mnals oftl of Psychoactive Drugs 18:291-304, 1986 lone and its diphasic titration in pure and tablet forms. Journal

._ Shulgin AT, Jacob P. Potential misrepresentation of 3, 4-meth- of Pharmaceutical Sciences 67: 411-413, 1978

Fatal rn_ ylenedioxyamphetamine (MDA): a toxicologic warning. Jour- Stern Y, Langston JW. Intellectual changes in patients with MPTP-'exia. Fona hal of Analytical Toxicology 6: 71-75, 1982 induced parkinsonism. Neurology 35: 1506-1509, 1985

ShulginAT, Maclean DE. Illicit synthesis of phencyclidine (PCP) Winek CL, Collom WD, Bdcker JD. A death due to 4-bromo-2,aificati0_ and several of its analogs. Clinical Toxicology 9: 553-560. 1976 5-dimethoxyamphetamine. Clinical Toxicology 18: 267-271,;6A, 1981 : Shulgin AT, Sargent T, Naranjo C. Animal pharmacology and 1981nds in 1_ human pharmacology of 3-methoxy-4,5-methylenedioxyiso-

propylamine (MMDA). Pharmacology 10: 12-18, 1973

l-methy!4; SiegelRK. MDMA, nonmedical use and intoxication. Journal oflications h' Psychoactive Drugs 18: 349-354, 1986 Authors' address: Dr J. Buchanan and Dr C. Brown, San Fran-,sease. C.aa Simpson DL, Rumack BH. Methylenedioxyamphetamine: clinical,, 1984 _ description of overdose, death and review of pharmacology, cisco Regional Poison Control Center, San Francisco General

ic parkin_ Archives of Internal Medicine 14h 1507-1509, 1981 Hospital IE86, 1001 Potrero Ave, San Francisco, CA 94110 (USA).:-analog s_i

_thyl-4-pM:netaboliteq ellrosci_l_ _

_e overd0_Itonergic m t,vier 24:

dlT.'HP)dogyt4:

International Conference on Pharmaceuticalve Drugs

Sciences and Clinical Pharmacology;70: -,

'nthesis "" Date: 29 May to 3 June 1988hylamine_ _ Venue: Jerusalem, Israelnants ,:__,_

74.Under the joint auspices of the Department of Pharmacy, School of Pharmacy,;xHebrew University of Jerusalem, and the Clinical Pharmacology Unit, Hadassah¢'UniversiW Hospital, Jerusalem, Israel.

°Sponsored by the American Association of Pharmaceutical Scientists (AAPS)street arid the American Society for Clinical Pharmacology and Therapeutics (ASCPT)

3-6, 1972 For [urther in[ormation, please contact:r C. Elka Touitou,

P.O. Box 983,

'Jerusalem 91009,analog. ISRAEL.

_86Effects 0f¢

ior in