Morris Et Al-2014-Drug Testing and Analysis

Drug Testing
Review and Analysis
Received: 9 November 2013 Revised: 15 January 2014 Accepted: 16 January 2014 Published online in Wiley Online Library: 26 March 2014
(www.drugtestinganalysis.com) DOI 10.1002/dta.1620
From PCP to MXE: a comprehensive review of

the non-medical use of dissociative drugs
Hamilton Morrisa and Jason Wallachb*
PCP or phencyclidine was discovered in 1956 and soon became a popular street drug. Dissociatives including PCP, ketamine, and
dextromethorphan have been used non-medically for their mind-altering effects for over 60 years. Many of these compounds have
also been used clinically and in legitimate research. At least 14 derivatives of PCP were sold for non-medical and illict use from the
late 1960s until the 1990s. With the advent of the Internet, the drug market underwent a dramatic evolution. While initially
gray-market chemical vendors offering dextromethorphan and ketamine thrived, most recently the market has shifted to
legal high and online-based research chemical vendors. Starting with the rst dissociative research chemical, 4-MeO-PCP in
2008, the dissociative research chemical market has rapidly evolved and currently comprises at least 12 dissociatives, almost half
of which were unknown in the scientic literature prior to their introduction. Several of these, including methoxetamine, have
reached widespread use internationally. A historical account of non-medical use of over 30 dissociative compounds was compiled
from a diverse collection of sources. The rst complete portrait of this underground market is presented along with the relevant
legal, technological, and scientic developments which have driven its evolution. Copyright 2014 John Wiley & Sons, Ltd.
Keywords: arylcyclohexylamines; research chemicals; methoxetamine; PCP; phencyclidine; ketamine; dissociatives; NMDA; folk
pharmacology; Internet drug forums
Introduction addictive activity.[8] Despite limitations, the number of potential

uses of NMDAR antagonists including the treatment of
The term dissociative anaesthetic was rst used to describe the depression, attention decit hyperactivity disorder (ADHD),
state of consciousness induced by the uncompetitive N-methyl- neuropathic pain, tinnitus, and neurodegeneration continues
D-aspartate receptor (NMDAR) antagonist 2-(methylamino)-2- to grow.[1,9] In addition, use of NMDAR antagonists in neurophar-
(2-chloro-phenylcyclohexanone or ketamine.[1] Though most NMDAR macological research is important in the study of the neural
antagonists display anaesthetic activity at sufciently high doses, not mechanisms in perception and psychosis.[10,11]
all of these agents are used as anaesthetics, thus the broader term With several dozen clinical trials involving NMDAR antagonists
dissociative is often employed. currently recruiting or underway, including use in neurodegenera-
NMDARs role in the pharmacology of 1-(1-phenylcyclohexyl) tive diseases, pain, addiction, and more, the history of non-medical
piperidine (PCP) (Figure 1), ketamine, and related compounds was human use of these compounds provides clinicians and researchers
rst reported in the early 1980s by Lodge et al.[2] NMDAR is a ligand with a deeper understanding of this complex and fascinating class.
and voltage gated cation channel containing several competitive In 1980, neuroscientist Edward Domino stated: I believe the nal
(binding sites for co-agonists: glycine and glutamate) and non- chapter of PCP has yet to be written.[12] Over 30 years later, the dis-
competitive binding sites (primary amine, zinc, Mg2+, PCP). One of sociative story is still being written.
three ionotropic glutamate receptors, NMDAR is named after the This review will focus on uncompetitive NMDAR antagonists
selective glutamate agonist N-methyl-D-aspartate, which is capable with known dissociative activity or their close structural derivatives
of distinguishing NMDAR from other ionotropic glutamate receptors. or so-called analogues. Notably we have chosen not to include
Uncompetitive NMDAR antagonism, via open channel blockade, is selective kappa opioid receptor (KOR) agonists like salvinorin A
believed to be a primary mode of action underlying the dissociative and mixed NMDAR antagonist/KOR agonists exemplied by the
effects of the compounds discussed. PCP, ketamine, and MK-801 psychotomimetic opioids SKF-10,047 and cyclazocine. Discrimina-
have been shown to bind to a common site (PCP site) inside the tive stimulus studies in animals support the separate classication
ion channel of NMDAR.[3] The potency with which these compounds of selective KOR agonists[13] and it is our opinion that the qualita-
induce dissociative effects in vivo correlates strongly with NMDAR tive effects of selective KOR agonists and NMDAR antagonists in
afnity. A number of structurally diverse antagonists at competitive
sites also exhibit dissociative effects in humans.[4,5] In addition to
NMDAR afnity, many dissociatives exhibit afnity for other central
* Correspondence to: Jason Wallach, Department of Pharmaceutical Sciences,
nervous system (CNS) receptors including sigma-1, dopamine, opioid University of the Sciences, 400 South 43rd Street, Philadelphia, PA 19104,
and nicotinic and muscarinic acetylcholine receptors which likely USA. E-mail: [email protected]
modify the activity of the individual compounds.[6,7]
Despite decades of research and pre-clinical success, therapeutic a The New School, Department of Anthropology, 66 W 12th Street, New York, NY,
10011, USA
usage of NMDAR antagonists remains limited. One reason is that
NMDAR antagonists exhibit conicting activity: stimulation and seda- b Department of Pharmaceutical Sciences, University of the Sciences, Pharma-
614
tion, neuroprotection and neurotoxicity, anti-addictive or reinforcing ceutical Sciences, 400 South 43rd Street, Philadelphia, PA, 19104, USA
Drug Test. Analysis 2014, 6, 614632 Copyright 2014 John Wiley & Sons, Ltd.
Drug Testing
PCP to MXE and Analysis
Herein we present the rst comprehensive review of non-medically

used dissociatives with a focus on the historical, synthetic, and
pharmacological factors that have driven the development and
use of these drugs. Table 1 contains the common abbreviations
used and full chemical nomenclature for the compounds discussed.
Arylcyclohexylamines genesis: serendipitous

wonder drug
Although PCP is believed to be the rst arylcyclohexylamine anaes-
thetic synthesized, several arylcyclohexylamines were reported
Figure 1. Structures of clinically signicant dissociative agents. before PCP. The primary amine 1-(1-Phenylcyclohexyl)amine (PCA)
was initially reported in 1907.[24] In 1953, a group of Italian chemists
led by Stefano Chiavarelli investigated a series of synthetic
humans exhibit distinction and thus may warrant separate classi- compounds related to Erythrina spp. alkaloids, one of which
cation. Further research into this possibility is certainly appropriate. was N-ethyl-1-phenylcyclohexylamine (PCE).[25] 1-(1-Phenylcyclohexyl)
The case for mixed NMDAR/KOR ligands like SKF-10,047 and morpholine (PCMo) was described in a German patent led in
cyclazocine is not as clear. While NMDAR is involved in the dis- 1954 along with several related compounds. Interestingly, the
criminative stimulus responses observed with these compounds series of compounds including PCMo were described as potent
in animals and likely the dissociative effects in humans, agonist sedatives yet their biological activity was not explored further.[26]
activity at KOR also appears to contribute. This is further What appears to be the most signicant part of the dissociative
supported by cyclazocine derivative ketazocine, a KOR agonist narrative occurred on 26 March 1956 when the rst synthesis of
which lacks NMDAR afnity yet induces psychoactive effects PCP was performed by Victor Maddox of Parke-Davis. Following
including hallucinations in humans at 0.51.5 mg/kg.[14,15] Due to up an experiment in which 1-(1-ethylcyclohexyl)piperidine was
the issue of NMDAR/KOR polypharmacology, these compounds accidentally formed, 1-piperidinocyclohexanecarbonitrile (PCC)
were not included. However it should be noted that some of these was treated with phenylmagnesium bromide and underwent substi-
compounds have been abused by humans.[16] tution with the grignard reagent rather than the expected addition
The state that characterizes the dissociative intoxication shows to the cyano group of PCC.[27] Though the substitution of alpha-
a high degree of dose-dependent variation. Stimulation and, in aminonitriles, known as the Bruylants reaction, had been reported
certain instances, memory improvement occur at low doses while in the literature, Maddox was unaware of the reaction at this time.[27]
sedation, amnesia, and anaesthesia generally occur at high doses. Preclinical investigations with PCP proved promising and
Perceptual alterations occur in all sensory modalities and include Parke-Davis quickly led a patent application detailing PCPs
proprioceptive distortions, ataxia, and paresthesias such as tingling, synthesis and pharmaceutical preparation.[26] PCPs pharmacol-
oating sensations, and numbness as well as depersonalization, ogy was rst presented at the 1958 meeting of the Federation
derealization, and loss of ego boundaries.[1719] Visual effects range of American Societies for Experimental Biology followed by
from distortions, such as impaired depth perception, frequently publication in 1959.[28] Human trials began in 1957 at the Detroit
manifesting as a attening of the visual eld and ickering or Receiving Hospital and replicated the anaesthetic effect observed
strobing to full-scale generative imagery at higher doses.[17,20,21] experimentally in animals. The trials established PCP as a potent
Synesthesia has also been reported with PCP, dextromethorphan general anaesthetic, unique in its absence of respiratory depres-
(DXM), and ketamine.[11,18,22] Effects on cognition include altered sion. However, adverse effects including agitation, bizarre behav-
thought patterns with a shift towards greater associative thoughts, iour, and catatonia were observed in 10 of the 64 patients.[29]
ideas of reference, and unusual thought content and in some cases Despite the adverse events, the results were promising enough
paranoid and grandiose ideology or full-blown delusions.[17,19] A that PCP was approved by the FDA in 1957 and given the
number of subjective rating scales, including the hallucinogen tradename Sernyl. The adverse effects were soon found to be more
rating scale (HRS) and the altered states of consciousness rating frequent than anticipated or hoped for and resulted in discontinu-
scale (OAV), have been utilized by researchers to quantify the ation of Sernyl.[1] As is common in pharmaceutical development,
qualitative effects of ketamine and/or DXM.[11,23] Parke-Davis investigated numerous derivatives of PCP including
Information was reviewed from scholarly and popular PCA (CI-401), PCE (CI-400), 1-[1-(thiophen-2-yl)cyclohexyl]piperidine
sources including scientic, legal, and patent literature, news- (TCP, CI-421), and N,N-diethyl-1-phenylcyclohexanamine (PCDE,
papers, online discussion forums, and personal interviews. The CI-482).[30] PCE and TCP were evaluated in clinical trials at doses
Internet was of signicant importance to our investigation. of 0.25 to 0.35 mg/kg IV, though they proved to be effective
Online drug discussion forums like www.bluelight.ru along with anaesthetics, emergence delirium remained an issue and research
websites such as www.erowid.org were used for ethnographic was discontinued.[31,32]
data, as time-stamped records of psychoactive drug usage, plat- In 1962, research in the laboratory of Calvin L. Stevens, a Parke-
forms for establishing interview contacts, and to obtain refer- Davis consultant, into alpha-hydroxyimine rearrangements pro-
ence samples from members for chemical analysis. The duced 2-phenyl-2-(ethylamino)cyclohexan-1-one (2-oxo-PCE). Based
anonymity of Internet sources is both an advantage and a limi- on pharmacologic testing in animals this compound was found to
tation of these resources. To limit potential bias, corroboration be a promising drug lead. Stevens lab subsequently synthesized a
from multiple sources was sought when possible and in many number of related aryl-amino-cyclohexan-2-one-based derivatives
instances online forum members were privately contacted for including ketamine (sometimes abbreviated CL-369, CI-581).
615
additional verication. Pharmacological evaluation established ketamine as a short-acting
Drug Test. Analysis 2014, 6, 614632 Copyright 2014 John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/dta
Drug Testing
and Analysis H. Morris and J. Wallach
Table 1. IUPAC chemical nomenclature and common abbreviations

Abbreviation IUPAC Nomenclature
PCA 1-Phenylcyclohexan-1-amine
PCP (phencyclidine) 1-(1-Phenylcyclohexyl)piperidine
TCP (tenocyclidine) 1-[1-(Thiophen-2-yl)cyclohexyl]piperidine
TCPy 1-[1-(Thiophen-2-yl)cyclohexyl]pyrrolidine
PCE (eticyclidine, cyclohexamine) N-Ethyl-1-phenylcyclohexylamine
PCPr (NPPCA) N-Propyl-1-phenylcyclohexylamine
PCiP (NIPPCA) 1-Phenyl-N-(propan-2-yl)cyclohexan-1-amine
PCPy (rolicyclidine, PHP) 1-(1-Phenylcyclohexyl)pyrrolidine
PCMo (PCM) 1-(1-Phenylcyclohexyl)morpholine
4-Me-PCP 1-[1-(4-Methylphenyl)cyclohexyl]piperidine
4-Me-PCP 4-Methyl-1-(1-phenylcyclohexyl)piperidine
BnCP 1-(1-Benzylcyclohexyl)piperidine
PCMEA N-(2-Methoxyethyl)-1-phenylcyclohexan-1-amine
PCMPA N-(3-Methoxypropyl)-1-phenylcyclohexan-1-amine
PCEEA N-(2-Ethoxyethyl)-1-phenylcyclohexan-1-amine
4-MeO-PCP (methoxydine) 1-[1-(4-Methoxyphenyl)cyclohexyl]-piperidine
3-MeO-PCP 1-[1-(3-Methoxyphenyl)cyclohexyl]-piperidine
3-MeO-PCPy 1-[1-(3-Methoxyphenyl)cyclohexyl]-pyrrolidine
3-MeO-PCE (methoxieticyclidine) 2-(3-Methoxyphenyl)-2-(ethylamino)cyclohexane
3-MeO-PCPr 2-(3-Methoxyphenyl)-2-(propylamino)cyclohexane
3-HO-PCP 3-[1-(Piperidin-1-yl)cyclohexyl]phenol
3-HO-PCE 3-[1-(Ethylamino)cyclohexyl]phenol
Ketamine 2-(2-Chlorophenyl)-2-(methylamino)cyclohexan-1-one
Tiletamine 2-(Ethylamino)-2-thiophen-2-ylcyclohexan-1-one
Methoxetamine (MXE) 2-(3-Methoxyphenyl)-2-(ethylamino)cyclohexan-1-one
2-MK (2-MeO-ketamine) 2-(2-Methoxyphenyl)-2-(methylamino)cyclohexan-1-one
N-EK (N-ethylnorketamine) 2-(2-Chlorophenyl)-2-(ethylamino)cyclohexan-1-one
2-oxo-PCE 2-Phenyl-2-(ethylamino)cyclohexan-1-one
DXM (dextromethorphan) (4bS,8aR,9S)-3-Methoxy-11-methyl-6,7,8,8a,9,10-hexahydro-
5H-9,4b-(epiminoethano)phenanthrene
(+)-MK-801 (dizocilpine) [5R,10S]-[+]-5-Methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-
5,10-imine
Memantine 3,5-Dimethyladamantan-1-amine
Amantadine Adamantan-1-amine
Diphenidine 1-(1,2-Diphenylethyl)piperidine
2-MeO-diphenidine 1-[1-(2-Methoxyphenyl)-2-phenylethyl]piperidine
Lefetamine (1R)-N,N-Dimethyl-1,2-diphenylethanamine
Lanicamine (1S)-1-Phenyl-2-pyridin-2-ylethanamine
NPS-1506 (delucemine) 3,3-Bis(3-uorophenyl)-N-methylpropan-1-amine
2-MDP 3-Amino-2-methyl-1,1-di(phenyl)propan-1-ol
Dexoxadrol 2-[(4R)-2,2-Diphenyl-1,3-dioxolan-4-yl]piperidine
Aptiganel 1-(3-Ethylphenyl)-1-methyl-2-naphthalen-1-yl-guanidine
general anaesthetic. The rst human was given ketamine by Edward The urotoxicity of ketamine was reviewed in detail in the recent
Domino and Guenter Corrsen on 3 August 1964.[1] The resultant 10 December 2013 report from the Advisory Council on the
study on ketamines effect in 20 prisoner volunteers was published Misuse of Drugs (ACMD). Since 2007 there have been hundreds
in 1965, establishing ketamine as an effective anaesthetic with a of reported cases of ketamine-associated urotoxicity occurring
reduced side-effect prole relative to PCP.[1,33] This same year, Sernyl with both medical and illicit use.[35]
was voluntarily withdrawn from the market. In 1966, Parke-Davis
patented ketamine and related compounds for use as general
anaesthetics and the rst approved ketamine preparation, Ketalar, Non-medical street use: from the laboratory
was marketed in 1969.[34] to the street
In addition to veterinary use, ketamine continues to be used in
a number of therapeutic areas in humans including general Non-medical PCP use was rst acknowledged in the USA be-
anesthesia, analgesia, depression, and psychiatric treatment and tween 1967 and 1968. Although San Francisco and New York
additional applications are being actively investigated.[1] How- were the rst cities to report non-medical PCP use, ethnographic
ever, increasing reports of urotoxicity associated with chronic studies suggest PCP appeared in Philadelphia, Miami, Seattle, and
616
high-dose ketamine use in medical and illicit users have surfaced. Chicago around this time.[36] PCP was once the most common
wileyonlinelibrary.com/journal/dta Copyright 2014 John Wiley & Sons, Ltd. Drug Test. Analysis 2014, 6, 614632
Drug Testing
drug of deception, being sold as, among other things, LSD, mes- by clandestine chemists, but rather developed through legitimate
caline, psilocybin, cocaine, and THC.[3638] Between 1971 and research. Similarly the number of rst-generation PCP analogues
1975 only 8.7% of the PCP and TCP samples detected by the sold on the non-medical drug market is frequently overestimated
PharmChem Street Drug Program were sold as PCP, TCP, or angel in popular and scientic literature. It has been stated that the
dust. Powder was the most common form detected followed by number is over 30. The true number appears to be closer to 14
tablets and lastly impregnated plant matter.[39] The prevalence (Figure 2) with only three TCP, PCE, and 1-(1-phenylcyclohexyl)
of deceptive use may have been responsible for some of the pyrrolidine (PCPy) becoming prominent with the latter two
adverse responses initially associated with PCP or, alternatively, receiving signicant media coverage. This misconception likely
the mislabelled drug. Although less common in recent years, stems from misinterpretation of an early publication where mention
PCP remains a drug of deception and has even been is made of 30 licit analogues of PCP known scientically.[48,49]
encountered in seized ecstasy tablets.[40] The scheduling of PCP may have hastened the appearance of
By 1976, PCP became a media phenomenon with most major news- analogues on the illicit market. However, PCE was detected in
papers and television networks reporting on PCP use.[41]Although PCP 1969, prior to the 1970 Controlled Substances Act (CSA) scheduling
can induce bizarre psychotomimetic effects, it was often depicted as of PCP, suggesting that the introduction of new compounds can be
something out of science ction. Tales of users with superhuman inuenced by factors other than prohibition.[50] Accordingly, PCP
strength breaking handcuffs, overtaking multiple police ofcers, and remains the most widely available arylcyclohexylamine and no
even tearing locked doors off patrol cars were typical.[22,41] A study reports of rst-generation PCP analogues appearing on the street
on the medias sensationalist portrayals of PCP during this time was were found later than the late 1990s.[51,52]
undertaken by John P. Morgan and Doreen Kagan[42]and is further
discussed by Philip Jenkins in his book Synthetic Panics.[41] In part facil-
itated by the media attention, PCP was moved from Schedule III to 1-Piperidinocyclohexanecarbonitrile (PCC)
Schedule II of the Controlled Substances Act (CSA) on 25 January
1978. Use as a veterinary anaesthetic at the time prevented it from PCC has occasionally been described as an analogue of PCP,
entering Schedule I. though it is more aptly titled a precursor and contaminant. Illicit
Despite reduced media coverage and greater controls, illicit PCP samples often contain PCC, in amounts from 0 to 100
PCP remains common in the USA and Canada, and according to %.[38,53,54] PCC also often contributes to the characteristic odour
some publications usage is rising in the USA following a slight de- of illicit PCP along with various solvents. PCC has been alleged
cline during the late 1980s and 1990s.[43] For reasons that are not to be psychoactive[38,50] and induces rotarod impairment in mice,
clear, PCP use has remained almost entirely conned to the USA a property correlating with arylcyclohexylamine potency, with
and Canada, with only scattered anecdotal reports describing use about a fourth of the potency of PCP.[55] However, PCC is more
in the EU or elsewhere.[44] toxic than PCP[56] and a report exists of an incorrectly synthesized
batch of PCP resulting in severe adverse responses including
abdominal cramps, vomiting, and in the worst cases coma and
First-generation analogues sold on the tradi-
tional street market
The arylcyclohexylamine scaffold contains three distinct regions:
an aromatic ring, a geminally substituted cyclohexane ring, and
a basic amine function. The rst-generation dissociatives distrib-
uted on the street market between 1969 and the 1990s, typically
involved aryl or amino substitution, and no alteration of the cy-
clohexane ring. Retaining the cyclohexane ring is a logical deci-
sion, as cyclohexane substitution generally decreases NMDAR
afnity and PCP-like potency. Though 2-methyl substitution of
the cyclohexane ring can increase potency of PCP and TCP, the
synthesis produces a diastereomeric mixture that is of reduced po-
tency until resolution of the eutomer is undertaken.[45,46] Substitu-
tion of the aryl and amino regions yields several analogues with
equivalent or greater potency than PCP, while at the same time of-
ten allowing clandestine chemists to forgo the use of watched
chemicals. In other cases, for example ketamine analogues, synthe-
sis is more complex and thus the cyclohexanone analogues have
been uncommon.[47]
All rst-generation dissociatives, are simple derivatives of PCP.
Although these compounds have not been reported on the
street drug market since that era, a number of them have been
described by members of online drug forums. In these cases the
drugs appear to have been synthesized by the user or obtained
directly from the chemist as opposed to being openly sold.
Despite the fact that the rst-generation compounds are
often called designer drugs, in all but one, N-(2-ethoxyethyl)- Figure 2. Chemical structures of street analogues of PCP observed from
617
1-phenylcyclohexan-1-amine (PCEEA), they were not designed the late 1960s to 1990s.
Drug Testing
death.[57] Handling PCC has reportedly resulted in physical toxic- detection of 28 PCE samples by the Michigan State Crime lab
ity and psychosis.[44,53] A portion of the reported symptoms likely and seizure of 300 PCE tablets. Police stated hundreds of thou-
result from thermal and metabolic liberation of hydrogen cya- sands of tablets more were on the market.[68] Within a week of
nide.[56,57] PCC and another PCP precursor PCA were placed into this report, two deaths involving PCE occurred in Wayne County
Schedule II of the CSA on 17 May 1978 becoming the rst drug and were described in the toxicological literature.[69] In June
precursors to be scheduled in the US CSA.[58] This practice 1978, a clandestine PCE laboratory was detected in Michigan
should be discouraged as it has been unsuccessful at limiting with several pounds of PCE powder, PCE tablets, and tableting
illicit production and has the potential to disrupt legitimate equipment.[70] PCE entered Schedule I of the US CSA on 25 Oc-
research. tober 1978.[63] Federal scheduling failed to prevent the drugs
distribution and a large number of news reports and legal cases
involving PCE between 1978 and 1984 exist including seizures of
1-[1-(Thiophen-2-yl)cyclohexyl]piperidine (TCP) varying quantities throughout the USA and Canada.[56,7175] Most
recently 15 ounces of PCE were uncovered in a Pennsylvania
Substituting PCPs benzene ring for thiophene gives TCP, which
clandestine laboratory in 1991.[76] In all of the cases where data
was rst reported in the patent literature by Parke-Davis in
was available PCE was reported as tablets or powder as opposed
1960.[59] TCP was evaluated clinically as an IV anaesthetic in
to a liquid solution or impregnated plant mater, which are common
humans by Parke-Davis and displayed similar activity as PCP
vehicles for smoked PCP. While the reason for this is uncertain, two
and PCE.[32] Although literature from the 1970s generally treat
sources emphasize that clandestinely produced PCE is unpalatable
TCP and other analogues as qualitatively interchangeable with
and malodorous compared to related compounds, especially the
PCP, these analogues do display variations in potency and
freebase, which was said to be too caustic for smoking. While pure
character. Anecdotal reports from the last decade describe TCP
arylcyclohexylamines generally have little odour, it is possible that
as being slightly more potent than PCP by weight, with a longer
an impurity produced during synthesis was responsible.
duration. Some users have described increased hallucinogenic
activity.[60,61] In 1972, TCP was detected in street samples ana-
lyzed by the street Drug Identication Program of the LAC-USC
Medical Center in LA[39] and again identied in Hawaii in N-Propyl-1-phenylcyclohexylamine (PCPr) and
1974[62]; by 1975, TCP and PCP were reported in 25 US states.[49] N-isopropyl-1-phenylcyclohexylamine (PCiP)
Harm reductionists from the Do It Now Foundation distributed
pamphlets in 1975 warning users about a dangerous trend of Two related compounds involve substitution of the piperidine
PCP misrepresentation, mentioning TCP as being similar in effect ring of PCP for N-propylamine and N-isopropylamine giving PCPr
but not as prevalent.[34] A number of TCP samples were detected and PCiP, respectively. PCPr has been reported as a PCP analogue
by the Street Drug Analysis programme (PharmChem,) sold un- by several sources[55,67] and a 1979 DEA Microgram article on PCPr
der different names between 1972 and 1975.[39] Deemed to be (NPPCA) exists.[55] PCPr was detected in Germany in the 1990s along
without medical value and of high abuse potential TCP was en- with several unusual arylcyclohexylalkoxyamine analogues discussed
tered into Schedule I of the US CSA on 11 August 1975, making below leading to its scheduling in Germany.[52,55] Vaupel et al.
it the rst arylcyclohexylamine to be placed into Schedule reported PCiP (NIPPCA) as a recently abused PCP analogue in a
I.[63,64] TCP sold as white powder was reported by several authors 1984 publication citing personal communication with the DEA.[55,58]
in 1980.[57] More recently TCP was synthesized in 2004 and the At 2.5 mg insufated PCiP HCl induced dissociative effects with
effects described on the online drug forum The Hive as described slightly increased potency relative to PCP lasting several hours. The
below.[61] The related, 1-[1-(thiophen-2-yl)cyclohexyl]pyrrolidine details and extent of PCiPs availability are unknown.
(TCPy) was reportedly analyzed in a clandestinely produced
sample, although additional details are lacking.[65] TCPy has
PCP like activity in animal models with slightly reduced potency 1-(1-Phenylcyclohexyl)pyrrolidine (PCPy)
relative to PCP.[55] TCPy entered Schedule I of the US CSA on
Substituting PCPs piperidine ring for pyrrolidine gives PCPy or
6 July 1989.[63]
PHP. In the late 1950s, based on the discovery of PCP, investiga-
tors at Parke-Davis synthesized and then investigated PCPy for its
N-Ethyl-1-phenylcyclohexylamine (PCE) anaesthetic potential. Consistent with the animal literature PCPy
has a similar potency to PCP in humans and is active via smoking,
Substituting PCPs piperidine ring for ethylamine gives PCE. Ani- nasal, and oral routes.[66,77] In addition to classic dissociative ef-
mal behavioural data[66] human clinical data,[31] and recent anec- fects, PCPy exerts a sedating effect that has been compared to
dotal reports show PCE to possess equivalent or slightly greater a barbiturate intoxication by some users.[50] The earliest report
potency than PCP. Supporting this, doses sold in the street of PCPy found was from a sample in Maryland in 1974,[22] and
market were reportedly smaller than those for PCP.[50] PCE was in 1975 the DEA Microgram reported PCPy being sold on leaf
rst documented in Los Angeles in 1969 and appears to be the material in New Jersey.[50] A high-prole case reported exten-
rst PCP analogue detected.[50] A 1970 issue of the Drug Enforce- sively by national media outlets is the fatal 1977 shooting of
ment Administration (DEA) journal DEA Microgram mentions the publicly intoxicated biochemist Ronald Burkholder by the Los
detection of a clandestine laboratory presumably synthesizing Angeles Police Department (LAPD). PCPy was subsequently
PCE;[50] PCE was subsequently encountered in 1971 detected in Burkholders post-mortem blood serum.[78,79] During
misrepresented as PCP.[50] By 1977, PCEs distribution had a 1979 congressional hearing on abuse of dangerous drugs, PCPy
increased and colourless crystals identied as PCE were was mentioned as an example of the growing issue of PCP
detected in Canada.[67] A 1977 article in the Detroit Free Press analogues. This was based on the fact that 14 reported cases of
618
reported an unconrmed non-fatal PCE overdose along with PCPy were detected in 1977, a rise from earlier years.[70] PCPy
Drug Testing
entered Schedule I of the US CSA on 25 October 1978.[64] Sched- Arylcyclohexylalkyoxyamines

uling did not prevent the distribution of PCPy and as early as
June 1979 two individuals were convicted for possession of Allen et al. report secondary amine 2-aminoethan-1-ol ana-
PCPy in Florida.[80] The author of a letter to the New England logs have been encountered from clandestine sources and
Journal of Medicine in 1980 speculated on an increase in PCPy 2-[(1-phenylcyclohexyl)amino]ethan-1-ol (PCHOEA) was also
availability in LA around this time, which he called a new drug mentioned on The Hive forum in 1999.[47,60] It is unclear what
of abuse. The speculation was based on his observation of a sig- analogues Allen was referring to; however, several
nicant rise in PCPy detection in the urine of LA county proba- arylcyclohexylalkyoxyamines along with PCPr were detected
tioners.[81] Soon after PCPy was detected in a number of on the illicit market in the late 1990s in Germany including
hospitalized patients in Ohio with the intoxication said to re- N-(3-methoxypropyl)-1-phenylcyclohexan-1-amine (PCMPA), N-
semble that of PCP.[82,83] Most recently, a clandestine chemist (2-methoxyethyl)-1-phenylcyclohexan-1-amine (PCMEA), PCEEA.[52]
in Boston MA was arrested in 1991 for operating a PCPy labora- While PCMPA and PCMEA were reported in a 1961 Parke-Davis
tory. When arrested, he successfully argued that PCPy was not patent,[90] PCEEA was novel at the time of its appearance on
illegal under MA state law but upon continuing his activity the street market. As stated earlier this makes it the only novel
was soon arrested by the DEA in June 1993 and convicted for rst-generation analogue to have been available. A few
PCPy manufacture under federal law.[84] analytical and metabolic studies of these compounds have been
published,[51,52] but information on their distribution and
psychoactivity in humans is limited. PCMEA and PCMPA were
4-Methyl-1-(1-phenylcyclohexyl)piperidine stated by a couple members of The Hive to be active between
10 and 15 mg with a long duration of action, and PCEEA was
(4-Me-PCP) and related analogues said to be active at doses between 15 and 80 mg.[60,88,91] For
The unusual analogue 4-methyl-1-(1-phenylcyclohexyl)piperi- convenience, a graphical timeline is presented in Figure 3
dine (4-Me-PCP), involving substitution of the piperidine ring showing patterns of usage of 27 dissociative compounds
of PCP with 4-methyl-piperidine, was detected in a street sam- covered in this review.
ple from Northern Virginia published in 1981. Analysis found
the 4-Me-PCP HCl was impregnated onto parsley at a concen-
tration of 1.7 % (w/w). Analytical characterization of 4-Me-PCP
was also reported.[53] 4-Me-PCP is an unusual choice as it has The Hive: a new online scene
one-tenth the activity of PCP in a rat drug discrimination as-
say.[48,56,88] One online forum report from a www.bluelight.ru Several online drug forums have fostered detailed discussion of
member adder described 4-Me-PCP as active at a third of the arylcyclohexylamine synthesis and pharmacology. The Hive
potency of PCP.[85] A related isomer is 1-[1-(4-methylphenyl) (19972004), was an online discussion forum dedicated to the
cyclohexyl]piperidine (4-Me-PCP), where the 4-methyl substitu- synthesis of psychoactive drugs, and run by author and clandes-
ent is on the benzene ring, and was detected in summer of tine MDMA chemist Hobart Huson under the pseudonym
1989 in Canada.[86] At least one report of 4-Me-PCP ingestion STRIKE. Although The Hive ceased operation in 2004, many of
exists from www.bluelight.ru member adder. Unfortunately the threads are archived and available online. Several clandes-
the dose was not given but it was said to be disappointing tine arylcyclohexylamine syntheses were discussed including
and totally inactive.[85] In the same article reporting on those for PCP, ketamine, and various analogues. In many
4-Me-PCP, the detection of 1-(1-benzylcyclohexyl)piperidine instances, the synthetic methods were taken directly from or
(PECP, BnCP), in which the benzene ring is replaced by a inspired by scientic and patent literature, though novel and
benzyl substituent, was also described[86] 4-Me-PCP and BnCP theoretical synthetic routes were also discussed. In late 1999,
were established to be of reduced potency in the scientic Hive member John Q. Beagle (Beagle) posted an extensive
literature and it is unclear why these were chosen for production review of arylcyclohexylamine pharmacology and chemistry.
or the extent of their availability.[66,87] Seven synthetic methods for producing PCP and analogues,
including PCE (PCC, enamine, imine, Geneste method, Ritter
reaction, phenylacetonitrile, and N-benzoyl piperidine routes)
1-(1-Phenylcyclohexyl)morpholine (PCMo) were reviewed. Arylcyclohexylamine SAR, pharmacology, and
previously unpublished human bioassays were also discussed.
Replacing the piperidine ring of PCP with a morpholine ring gives Foreshadowing, if not inuencing the future research chemi-
PCMo. The commonly used abbreviation currently, PCM, is cal (RC) market, several arylcyclohexylamines mentioned later
ambiguous and is inconsistent within current nomenclature. became important RC dissociatives including 3-[1-(piperidin-
PCMo, specifying the morpholine ring, is more appropriate. To 1-yl)cyclohexyl]phenol (3-HO-PCP), 1-[1-(4-methoxyphenyl)
avoid further confusion PCMe will be adopted for N-methyl-1- cyclohexyl]-piperidine (4-MeO-PCP), and 1-[1-(3-metho-
phenylcyclohexylamine. In animal models, PCMo has signicantly xyphenyl)cyclohexyl]-piperidine (3-MeO-PCP). Other relevant
reduced activity relative to PCP.[55,77] Posts on The Hive exist from threads posted on The Hive include detailed, and sometimes
the early 2000s and describe PCMo as weaker and of shorter photographically illustrated, synthetic reports for 4-MeO-
duration than PCP with only minor effects at 150 mg PCP (Bruylants PCC route), [92] PCDE (enamine route), [93] PCMo
insufated.[88,89] In 1977, a laboratory producing PCMo was (enamine route), [89] TCP (enamine route), [61] and N-propyl-1-
detected in California, though a DEA chemist stated PCMo had (thiophen-2-yl)cyclohexan-1-amine (TCPr) (imine route). [94]
not yet been encountered on the street.[58] PCMo, PCPy, and Synthetic schemes illustrating the synthesis of PCP, PCPy,
TCP were made illegal in California in 1979. PCMo is not presently and PCE are shown for the Geneste, Bruylants, enamine, and
619
scheduled by the US CSA. imine route in Figure 4.
Drug Testing
Figure 3. Graphical timeline of twenty-seven dissociatives showing history of rst documented synthesis, non-medical use, medical use, simultaneous
medical and non-medical use, illicit (illegal) use, simultaneous illicit and non-medical use. Black horizontal line length corresponds to time between rst
synthesis and subsequent event. * indicates tentative data due to limited number of available sources.
Non-medical ketamine been rare during this time. In the late 1970s, ketamine began to
attract more attention, including mention in a popular counter-
Unlike PCP, ketamine has global popularity.[44] The ketamine culture comic Fabulous Furry Freak Brothers in 1976 and High
user-base and distribution networks differ from those of contem- Times magazine in 1978. The 1979 Street Drug Analysis Results
porary PCP.[95,96] While PCP has become largely a street drug, reported detecting ketamine in drug samples.[39] In 1978, neuro-
ketamine is popular among rave and club-goers as well as pharmacologist Ronald Siegel published a study on recreational
psychonauts, individuals who use altered states to explore users of PCP and ketamine[97] and the psychoactive effects were
perceptual and spiritual phenomena.[8] Illicit ketamine is often further popularized with two 1978 publications: Journeys into the
encountered as a white crystalline powder or pharmaceutically Bright World[99] by author Marcia Moore and Howard Alltounian,
packaged injectable solution and is generally insufated, and The Scientist by neuroscientist John Lilly.[100] These authors
injected, or less commonly consumed orally. Ketamine has been described unique dissociative landscapes including vivid
sold as a drug of deception as ecstasy in the USA and in the descriptions of the immersive visual hallucinations and per-
EU.[8,44] Clandestine synthesis of ketamine in the USA has not ceived altered realities. Despite FDA concern about non-medical
been reported, though it may occur in rare instances; this is likely use of ketamine, ketamine use remained uncommon[101] and the
due to ketamines relatively low potency and technically DEA turned down a 1981 request from the US Department of
demanding synthesis (Scheme 2).[47] Health and Services (DHHS) for scheduling because the inci-
Interviews by Karl Jansen suggest non-medical ketamine was dence of actual abuse was not sufcient to sustain the schedul-
available as early as 19671968 and was being spread by rogue ing action.[102] By 1995, this changed and the ofce of the US
medicinal chemists from Michigan to the Florida coast offered Director of the Ofce of National Drug Control Policy added
as mean green and rockmesc.[8] In 1971, the year following ketamine to its emerging drugs list[103]; in 1999, ketamine was
FDA approval on 19 February 1970, non-medical use of ketamine placed into Schedule III of the US CSA, allowing continued
solutions was noted in California and the rst scientic report on medical use.
the use of ketamine for psychedelic effects was published in a Prior to scheduling, ketamine was available from chemical sup-
1971 letter to the New England Journal of Medicine.[97,98] Unlike ply companies. The Internet and the international postal system
620
PCP, ketamine use as an psychoactive substance appears to have greatly facilitated ketamine distribution. Mail-order ketamine was
Drug Testing
Figure 4. Four common synthetic routes for the synthesis of arylcyclohexylamines; PCC, Imine, Enamine, and Geneste routes. By substituting interme-
diates in key steps of these reactions a variety of PCP analogues and derivatives can be produced.
acknowledged online as early as 1998 in The DXM Zine, an online frequent, urgent urination and haematuria. Examination revealed
magazine dedicated to the dissociative DXM, as well as discussions a signicant reduction in bladder capacity and abnormal liver
on alt.drugs newsgroups.[104,105] Likewise ketamine continued to function in all patients, with most displaying bilateral
be available through several chemical supply vendors, including hydronephrosis.[106] The publication of these case reports in
The Science Alliance run by Hobart Huson of The Hive who 2007 is the rst known instance of ketamine-associated bladder
imported and resold ketamine from Hong Kong, China. dysfunction, despite ketamine having over 40 years of use. How-
Scheduling in the US did not appear to limit the international ever reports of adverse effects including K pains, described as
availability of ketamine and various online drug forums contain stomach or abdominal pains, by heavy users of ketamine were
posts describing how bulk ketamine was obtained via Internet mentioned by Jansen, though at the time he speculated these
sources. Diversion of pharmaceutical preparations remains com- pains could be psychosomatic.[8] In vitro cell culture studies on
mon and in 2002 several busts of US-based suppliers obtaining human urothelial cells show that ketamine and the metabolite
vials of ketamine from labs in Mexico occurred.[96] norketamine exhibit dose-dependent cytotoxic effects. However
During the early 2000s, ketamine had also become popular in it is unclear if NMDAR is necessarily involved in this urotoxicity
the UK, particularly on the rave dance scene and began to receive as (+)-MK-801 failed to induce these effects. Interestingly how-
attention through media outlets including the London magazine ever, (+)-MK-801 potentiated ketamines toxicity.[107]
Time Out.[8] In the UK, ketamine was classied as a Class C drug Today illicit ketamine is believed to originate from diverted phar-
following an amendment of the 1971 Misuse of Drugs Act in maceutical production or illicit production from producer countries
2005. A recent report from the Advisory Council on the Misuse such as Mexico, European states, India, and China.[44,108,109] These
of Drugs (ACMD) reported on a recent increase in ketamine mis- countries have large pharmaceutical production industries and
use in the UK. A number of topics related to ketamine are access to necessary equipment and precursors with less regulatory
reviewed including chemistry, pharmacology, misuse, and medi- oversight than the USA and the UK. The Internet and mail system
cal and social harms. In addition, a recommendation is made that remain key components of the trade. The recently dismantled
ketamine be reclassied to a Class B drug on the basis of in- SilkRoad website, an Internet-based drug distribution hub, also
creased evidence of physical harm specically related to bladder hosted numerous ketamine vendors. In recent years, some legisla-
toxicity.[35] It is worth mentioning that between 2000 and 2007 tive attempts to disrupt the trade have been made. China reported
physicians in Hong Kong treated a series of ten ketamine abusers seizing two illicit laboratories in 2009 in possession of the ketamine
621
who presented with irritative bladder symptoms including intermediate hydroxylamine hydrochloride, and in 2010, China
Drug Testing
announced implementation of greater controls on the manufac- 1973, but DXM-containing cough syrups remained available due
ture of this intermediate.[44] India has also implemented greater to a perceived lower risk of abuse.[117,129]
controls in recent years.[110] These controls have had little impact In the USA, adolescent abuse of DXM-containing products was
on the global ketamine trade. reported by at least 14 states in the late 1980s. In Utah, this abuse
2-(Ethylamino)-2-thiophen-2-ylcyclohexan-1-one (tiletamine) was led to pharmacies voluntarily moving DXM containing products
developed by Parke-Davis for veterinary anaesthetic use as an behind the counter.[124] In addition to the USA, non-medical
alternative to ketamine.[111] Parke-Davis patented tiletamine in DXM use occurred in Europe and the alleged rst two fatal intox-
1966. Tiletamines pharmacology was published in 1970.[111,112] ications occurred in Sweden in the 1980s.[130]
Telazol, a tiletamine and zolazepam preparation, was placed into Since the mid-1990s, the Internet has become the major con-
Schedule III of the CSA in 1987.[63] Between 1999 and 2001, re- duit for transmission of information on DXM. In 1994, researcher
ports of veterinary tiletamine/zolazepam abuse appeared in the William E. White published an exhaustively referenced review of
USA and in South Korea, including two fatal overdoses.[113,114] DXM psychopharmacology, history, and toxicity on the Internet
Several www.erowid.org experience reports involving tiletamine discussion system Usenet. Special reference was given to
exist. Although more potent than ketamine, many users reported reducing harm from recreational use of cough syrups containing
non-euphoric effects or described tiletamine as unpleasant rela- additional active ingredients.[131]
tive to ketamine.[115,116] A limited number of posts on online drug Starting in 1994, Usenet became an active online forum for dis-
forums such as on www.bluelight.ru on tiletamine usage also cussion of DXM use and DXM cough syrup extraction techniques.
exist and describe similar effects. Although several RC vendors Usenet posts suggest that pure DXM HBr powder was available
have listed tiletamine at various times, evidence suggests it has from gray-market chemical vendors as early as the autumn of
never been widely available or used. 1996. In February 1997, the gray-market chemical supply com-
pany Chemical Resale of Santa Barbara advertised prices for pure
DXM HBr on Usenet. DXM may have been available via mail-order
Dextromethorphan (DXM): origins services earlier but to the best of our knowledge the above repre-
sent the rst instances of pure DXM being openly sold online. The
Morphinan-based dissociative DXM is the d-isomer of the opioid rst issue of the online magazine The DXM Zine, was published in
analgesic methorphan. The methorphan synthesis was rst November 1997. An article on DXM extraction from cough medi-
described in a US patent led by pharmaceutical company Hoff- cines was included along with a listing of powder DXM vendors.[105]
mann-La Roche in 1947.[117] Synthesis and resolution of DXM was The subsequent December 1997 issue includes user reports on
subsequently patented in 1952. DXM was approved by the FDA DXM HBr powder and bulk DXM HBr prices as low as a dollar a
in 1958 and introduced as a non-prescription replacement for co- gram.[104] A 1998 letter to Annals of Emergency Medicine detailed
deine-based antitussives under the brand name Romilar.[118] two case reports involving abuse of DXM powder.[132] By the late
DXM lacks opioid activity but was shown to be a moderate-low 1990s and early 2000s DXM use had become widespread. The foun-
potency NMDAR antagonist.[119,120] The dissociative and active ders of www.erowid.org publicly commented that they were forced
O-demethylated metabolite dextrorphan (DXO) has even greater to reject the majority of DXM experience reports due to an extraor-
NMDAR afnity.[119] DXO has been evaluated clinically in humans dinary large volume of submissions.
and was found to induce dissociative effects including hallucina- Following the DEAs 2004 Operation Web Tryp, a large-scale gray-
tions[121] and may play a role in some the psychoactivity of DXM. market drug bust, DXM powder suppliers became less abundant
DXM was specically excluded from the US 1970 CSA (as it was an and visible. However DXM was not scheduled and DXM HBr
isomer of Schedule II drug levomethorphan and thus would had powder is still offered on the RC market and in bulk from Chinese,
been scheduled as a stereoisomer unless specically exempt). Indian, and European retailers. In the USA, DXM use remains com-
DXM is the subject of numerous books, television specials, mon especially among adolescents[133] and DXM cough medicines
websites, and magazine and newspaper articles, and has earned remain readily available over the counter. Some states have
an almost religious signicance among some proponents.[122] A prohibited sale of DXM-containing products to minors[134] and in
recent clinical study on the psychoactive effects of DXM recent years there have been discussions placing increased restric-
supports the possibility of DXM-induced spiritual effects and tions on the sale of DXM.[135] Finally like other dissociatives DXM
mystical-type experiences.[11] has been used as a drug of deception and has been reported to
DXM appears to be the rst synthetic dissociative used for have been sold as ecstasy, heroin, and ketamine.[134]
non-medical psychoactive effects, starting in the early 1960s with
several members of the Beatnik generation reported to have
ingested the compound.[123] Some of the earliest scientic MK-801
literature published in the early 1960s on DXM intoxication come
from Europe and Australia.[124126] The psychoactivity of DXM The dibenzocyloheptene MK-801 was rst synthesized in 1979 by
containing cough syrup was noted in a 1968 US drug abuse Marcia Christy and Paul Anderson at Merck Pharmaceuticals.
publication under the heading other drugs with abuse potential. Pharmacological tests in rodents established MK-801 to have sympa-
The article stated DXM cough syrups produce a central effect in thomimetic activity and extraordinarily potent anticonvulsant
large doses. Interestingly the altered state was partially attributed activity.[136,137] Beginning in 1985, a number of small open-label
to the antihistamine and decongestant co-additives.[127] A clinical investigations of MK-801 were undertaken. Areas investi-
controlled study on dextromethorphans psychoactive effects in gated included use as a supplemental therapy for refractory epilepsy,
humans was published in 1971 and revealed that DXM has prom- anxiety, depression, and adult attention decit disorder (ADD).[136]
inent psychotomimetic effects at doses 610 times greater than Results were mixed and further clinical research was halted due to
therapeutic antitussive doses.[128] Concerns about recreational inconsistent efcacy, behavioural side effects, and observed neuro-
622
use led to removal of Romilar tablets from the US market in toxicity in rats (described below).[9]
Drug Testing
Due to its mixed stimulant and depressant effects, MK-801 was Adamantines
initially thought by some clinicians to represent a novel pharmaco-
logical class. However, in 1986, MK-801s action as a high potency 3,5-Dimethyladamantan-1-amine (memantine) and adamantan-
uncompetitive NMDAR antagonist was discovered.[138] Despite the 1-amine (amantadine) (Figure 1) are both adamantan-amine
lack of clinical use, MK-801 has become one of the most common based uncompetitive NMDAR antagonists.[150] These drugs have
glutamatergic ligands in neuropharmacological research.[139] important therapeutic uses in Alzheimers and Parkinsons
Non-medical MK-801 ingestion was traced back to a 1998 Disease and are generally considered well-tolerated.[151]
Usenet post describing an intravenously administered 100 g Memantine substitutes for PCP or (+)-MK-801 in rats and mon-
dose that compared favourably to PCP and ketamine.[140] In key drug discrimination paradigms. Full substitution occured
2002, a MK-801-associated fatality was reported implicating a at relatively high doses that generally cause a reduction in re-
25-mg dose co-ingested with ethanol, diazepam, and sponse rate. Likewise intravenous memantine and amantadine
temazepam. The decedents (+)-MK-801 maleate had been serve as a positive reinforcers in rhesus monkeys trained to
obtained from a mail-order biochemical supplier.[141] Consistent self-administer PCP.[151] Isolated reports have been posted to
with this, online forum posts and interviews suggest legitimate websites such as www.erowid.org and the counter-culture
chemical suppliers are the predominant means by which many magazine The Entheogen Review of human use at supra-therapeutic
users acquired MK-801. However, at least one RC source, doses to induce dissociative effects, with users describing 100 mg
New-Jersey-based Jmar Chemical, offered (+)-MK-801 maleate oral doses of memantine and oral doses of amantadine in excess
from 2003 to 2004. In May 2004, a www.bluelight.ru member of 2 g.[152154] Results from clinical studies support these reports
posted repeatedly about his experiences injecting (+)-MK-801 of dissociative activity.[155,156] While many users described the
IM obtained from Jmar Chemical, suggesting the drug was effects as positive, neither compound has been widely used as a
dysphoric and gave him telepathic abilities.[142] dissociative likely due to the long duration of action (over 40 h).
Non-medical MK-801 use is very limited and less than a dozen Factors that may limit abuse-liability are discussed in greater
user reports have appeared online as reports on www.erowid.org detail in the future perspectives section. Memantine is used off-
or on drug forum posts for example on the private forum www. label in a number of areas and active clinical investigations are
dextroverse.org since 2004.[142,143] These reports indicate MK- ongoing including use in depression, ADHD, pain and more.[157]
801 has remained unobtainable or undesirable for prospective Therapeutic doses (~10 mg) of memantine induced a mild altered
users. Though these reports differ in their qualitative assessment, state with cognitive stimulation and altered thought patterns with
there is agreement that MK-801 is a potent dissociative via oral some parallels to low dose arylcyclohexylamines.
and parenteral routes with a long duration, often in excess of
24 h. Classic dissociative and stimulant activity are reported at
doses ranging from 250 g to 3.5 mg orally, with doses over 2 Anisylcyclohexylamines
mg often producing immersive closed-eye visualizations that
are sometimes accompanied by external auditory hallucinations, A 1965 article published by Maddox[158] described the synthesis
sensed presence or entity hallucinations, speech disuency, and of two of the three isomeric 1-anisylcyclohexylpiperidines
anterograde amnesia.[142,143] 1-[1-(2-methoxyphenyl)cyclohexyl]-piperidine (2-MeO-PCP) and
In 1989, Olney et al. reported an apparent neurotoxic effect 4-MeO-PCP. Preparation of 3-MeO-PCP was described later in
occurring with (+)-MK-801, PCP, tiletamine, and ketamine in 1979 by Geneste et al.[159] NMDAR binding of the
adult female Sprague Dawley rats.[144] Following subcutaneous anisylcyclohexylamine isomers has been characterized, with
injection, morphological changes were observed using light 3-MeO-PCP displaying greatest NMDAR afnity followed by 2-
and electron microscopy and included formation of vacuoles MeO-PCP.[7,160] Psychoactive effects of 3-MeO-PCP and 4-MeO-
in the cytoplasm of varying sizes. Neurons affected were me- PCP in humans (Figure 5) were rst described by Hive member
dium to large sized neurons in layers III and IV of the posterior hms_beagle around 1999 in his review Synthesis and Effects of
cingulated and retrosplenial cortices. The effect was sex, age PCP Analogs A Review by John Q Beagle. Beagle describes
and dose dependent. While the lesions generally disappeared 3-MeO-PCP as producing effects in man that are extremely similar
over time, high doses of (+)-MK-801 and PCP induced necrosis to PCP in potency and quality. Beagle went on acknowledging the
in susceptible cells. Potency of the toxicity correlated with potential of several additional anisylcyclohexylamines including
NMDAR afnity[144] and competitive NMDAR antagonists also three future RC dissociatives 2-(3-methoxyphenyl)-2-(ethylamino)
induce these lesions.[145] However, the role of NMDAR in lesion cyclohexane (3-MeO-PCE) and the novel 1-[1-(3-methoxyphenyl)
induction is unknown, as some NMDAR antagonists do not ap- cyclohexyl]-pyrrolidine (3-MeO-PCPy) and 2-(3-methoxyphenyl)-
pear to induce lesions to the same degree, including 2-(propylamino)cyclohexane (3-MeO-PCPr).[60] Beagle also de-
gacyclidine[146] and remacemide.[147] scribed the rst documented clandestine synthesis of an
While the etiology is unknown, compromised energy me- anisylcyclohexylamine, 4-MeO-PCP, which was posted to The Hive
tabolism has been speculated to play a role. Interestingly le- on 11 September 2001. Executed under primitive conditions in a
sions are prevented by co-administration of a number of residential laboratory, Beagle states that the 4-MeO-PCP produced
pharmacological agents including 5-HT2a agonists, anticholin- was active in humans with a reduced potency (rough estimate of
ergics, and barbiturates.[148,149] Karl Jansen discussed the mat- 70%) and reduced duration relative to PCP.[92]
ter in his book Ketamine: Dreams and Realities, presenting Beagles 4-MeO-PCP report remained a subject of intermittent
results from several unpublished studies which found ketamine discussion on online forums but no further bioassays were
(10 mg/kg) and MK-801 did not produce vacuoles in monkeys.[8] conducted. The Hive was taken ofine in 2004, disrupting Internet
Unfortunately specic details of these studies are lacking and discussion of clandestine chemistry. At the time the burgeoning
more work is needed to determine the relevance of these lesions Internet trade of psychoactive RCs was largely focused on serotoner-
623
to humans. gic tryptamines and phenethylamines, and the only dissociatives
Drug Testing
Figure 5. Research chemical anisylarylcyclohexylamines and aryl-amino-cyclohexan-2-ones.
sold online were compounds with pre-established medical or scien- medical use, and the perceived lack of signicant adverse reactions
tic utility such as DXM, ketamine, and to a lesser extent MK-801. reassured vendors and users alike that PCP derivatives could be
Horror stories of the previous 40 years appear to have stigmatized circulated as RCs. Yet, in the opinion of many users, 4-MeO-PCPs
PCP among many drug users and this stigmatization was reinforced low potency and long duration left room for improvement.
by inuential members on drug forums like www.bluelight.ru who In April 2009, Swiss chemist and www.bluelight.ru member
cautioned against the disastrous behavioural toxicity that could hugo24 rst reported positively on the psychoactive effects of
result from the introduction of gray-market PCP derivatives. 3-MeO-PCP in a number of posts.[164] 3-MeO-PCP is active via oral
This changed in December 2008 when UK-based vendor www. and parental routes and induces dissociative activity beginning at
chembay.co.uk began offering 4-MeO-PCP for 75.00 per gram. 5 mg, although many users ingest signicantly higher doses. The
Reports of use on multiple drug forums such as www.bluelight. effects are often described as more euphoric and mentally clearer
ru and www.drugs-forum.com followed but contrasted Beagles than many related compounds. Shortly after hugo24s initial re-
initial description when users found 4-MeO-PCP to be at least ports, a number of other prominent www.bluelight.ru members
an order of magnitude less potent than PCP with comparable conrmed these claims reporting enthusiastically on the
or longer duration. In addition, reports indicated varying potency psychoactive effects of 3-MeO-PCP. These members had
between batches and vendors, with some users requiring several initiated a collaborative research effort where international www.
hundred milligrams to achieve threshold effects. A possible ex- bluelight.ru members participated in designing, synthesizing and
planation is documented variations in purity of analyzed samples, characterizing various arylcyclohexylamines including 3-MeO-PCP,
with one sample predominantly containing the precursor PCC, 3-MeO-PCE, 2-oxo-PCE, and several novel compounds including 3-
the same intermediate that frequently contaminates illicit PCP MeO-PCPy, 3-MeO-PCPr and 2-(3-methoxyphenyl)-2-(ethylamino)
samples. Regarding this particular analysis, the analysis company, cyclohexan-1-one (methoxetamine, MXE). A signicant feature of
www.ecstacydata.org, stated: This is probably the dirtiest Re- this project was the apparent interest in novel compounds for psy-
search Chemical weve ever seen, in 15 years of watching analyses chotherapy and treatment of phantom limb pain (fastandbulbous
of gray market and black market chemicals.[161] Despite the issue pers. comm.).
of variability 4-MeO-PCP was overall positively received by users.
By 2010, a second vendor of 4-MeO-PCP had emerged in Denmark
called www.RCstandards.com and availability gradually increased. 2-(3-Methoxyphenyl)-2-(ethylamino)cyclohexan-
A sample of material from www.RCstandards.com obtained in 1-one (methoxetamine, MXE): origins
October 2010 was also analyzed by www.ecstacydata.org by gas
chromatographymass spectrometry (GC-MS) and was predomi- The rst of the bluelight research groups compounds to become
nantly 4-MeO-PCP.[161] 4-MeO-PCP was rst reported to the widely available appears to be MXE. Although theoretical proper-
European Monitoring Centre for Drugs and Drug Addiction ties of 2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone were
(EMCDDA) on 11 January 2011 in Finland. The rst adverse initially described in a 2006 www.bluelight.ru thread on novel
response to 4-MeO-PCP involving a 4-MeO-PCP-polydrug psychoactive drugs by member fastandbulbous, it was not synthe-
intoxication was reported to the EMCDDA in Norway in August sized until a few years later. After a series of positive self experi-
2011.[162] The DEA published a 2011 Microgram article with ments with a variety of anisylcyclohexylamines, fastandbulbous
GC-MS and nuclear magnetic resonance (NMR) data and acknowl- suggested the structure of MXE to collaborator hugo24, who
edged 4-MeO-PCP as an RC.[163] synthesized the compound. fastandbulbous speculated that the
The introduction of 4-MeO-PCP was a watershed moment for 3-MeO- substitution would provide an opioid analgesic effect,
gray-market dissociatives and marked an important bridging of clas- while substituting the N-methyl to an N-ethyl would increase
sic clandestine chemistry with the new Internet-mediated drug trade. duration and potency, while the 2-keto group would allow the
For the rst time a dissociative anaesthetic without pre-established compound to retain the relative safety and character of ketamine.
624
medical or scientic utility was being sold for the purpose of non- The rst public report on MXEs qualitative effects was posted by
Drug Testing
fastandbulbous on www.bluelight.ru on 13 May 2010. Titled First envelopes of 35 mg pellets.[177] Additionally, packets of MXE
Time: Heaven on Earth, the post describes a 25-mg IM injection powder labeled Special K, a common slang term used for keta-
and praised MXE, placing emphasis on the resultant state of bliss. mine, were available. These are the rst instances of such brand-
The emphasis on opioid activity is an example of folk pharmacol- ing being used with an RC dissociative we have encountered.[178]
ogy and is based on the fact that 3-HO-PCP has high afnity for Scientic publications on MXE intoxication and fatalities soon
the -opioid receptor (MOR).[165,166] Despite the intent, 3-MeO- appeared with increasing frequency.[179181] While designed in
PCP and MXE do not appear to have MOR afnity below 10,000 part to have a decreased potential for urotoxicity due to an
nM.[7] Still this myth is commonly acknowledged as fact on online increased potency (fastandbulbous, pers. comm.) preliminary
drug forums and has even appeared in recent peer-reviewed research from animal studies suggest MXE (30 mg/kg for three
literature.[167] Notably, phase I metabolic demethylation of MXE months) can cause bladder and kidney toxicity in mice.[182]
does produce a 3-hydroxylated metabolite, which may exhibit Reports of urotoxicity with MXE in humans have not been
MOR activity however this remains to be established.[168,169] documented. As the urotoxicity appears to be dose dependent,
Immediately following the report, fastandbulbous received it is possible if lower doses are used that MXE may have lower
several inquiries regarding MXE, including one from the proprie- potential for urotoxicty. On 5 April 2012, MXE was placed under
tor of a London-based RC vendor who was interested in making temporary class drug control prohibiting import and sale in the
MXE commercially available (fastandbulbous, pers. comm.). On UK for 12 months. Upon request from the UK, the EMCDDA
10 September 2010, three months after the initial report, www. began collecting available information on MXE. The subsequent
buyresearchchemicals.co.uk (BRC) announced its intent to market response was used by the ACMD in its 18 October 2012 report
MXE as methoxetamine, a name fastandbulbous originally to suggest a Class B scheduling status. The ACMD also suggested
coined as a contraction of methoxy-ketamine. the implementation of a generic denition to control arylc-
On 14 September 2010, the rst 15 free 50-mg samples of MXE yclohexylamines.[162] On 26 February 2013, MXE along with
were offered by BRC to UK customers. Within days, a series of derivatives of 1-phenylcyclohexylamine became Class B drugs in
user reports appeared on www.bluelight.ru and at least one the UK effectively banning all existing RC dissociatives available at
vendor, www.blueagricultural.co.uk, exploited demand by selling the time and many additional arylcyclohexylamines.[183] This report
caffeine powder misrepresented as MXE. An initial misidentication also described the receptor binding prole of MXE and two addi-
of this sample as N-methyl-1-(thiophen-2-yl)cyclohexanamine tional RC dissociatives 3-MeO-PCP and 3-MeO-PCE, showing them
(TCM or TCMe) based on GC-MS appeared on www.bluelight.ru. to have signicant afnity for the PCP site of NMDAR.[184] This
There was great interest in MXE, which initially sold for 80.00 a pharmacological work was later published in more detail.[7]
gram from BRC, a particularly high price relative to illicit ketamine Shortly after the introduction of MXE, BRC continued to offer
in the UK, which was reportedly as inexpensive as 10.00 per gram. novel anisylcyclohexylamines from the www.bluelight.ru research
An unpublished analysis of an early BRC sample was consistent group. The rst to become available was the novel chemical
with high purity racemic MXE HCl based on optical rotation, high 3-MeO-PCE, sometimes called methoxieticyclidine by vendors
performance liquid chromatography (HPLC), 13C and 1H NMR and and users. BRC announced 3-MeO-PCE as an invite only chemical
C, H, N elemental analysis. A 2012 DEA Microgram article reported on 28 October 2010. The invite only subsection was introduced
the analytical characterization of MXE (MS, 1H and 13C NMR and specically for 3-MeO-PCE, which was deemed to have a relatively
FTIR)[170] and several RC samples of MXE have been analyzed.[171] high propensity for behavioural toxicity and psychosis. To place an
MXE was immediate cause clbre among drug forum members order, prospective buyers had to contact BRC directly and describe
and Internet discussion continued at rapid pace. The rst MXE over- a proposed research use before ordering. Shortly after the BRC re-
dose was reported on 21 October 2010 by the UK-based Harlow lease, 3-MeO-PCE was reported to the EMCDDA on 17 November
Star newspaper. An emotionally unstable woman attempted 2010 by the UK.[173] In addition, a large number of experiences
suicide by reportedly consuming 80100 mg MXE which was with 3-MeO-PCE describing largely positive dissociative effects
suggested to induce a psychosis that warranted medical interven- with potency slightly lower than PCP began to appear on a
tion. Reporters looking to identify the compound, which had not number of drug forums including www.bluelight.ru and www.
yet been described in media circles, came upon a discussion of drugs-forum.com. 11 mg of 3-MeO-PCE HCl insulfated induced a
TCM (TCMe) and MXE online, and arbitrarily used the name strong dissociative state characterized by sensory enhancement,
Methoxthenyl.[172] A subsequent unconrmed overdose described euphoria, analgesia and tactile numbness lasting 3-5 hours.
the fatal overdose of a Swedish man who injected 400 mg of the In April 2011, 3-MeO-PCP was offered in limited quantities by
serotonin releaser RC MDAI (5,6-methylenedioxy-2-aminoindane) BRC and reports appeared on www.bluelight.ru and other drug
and 100 mg of MXE, dampening some initial enthusiasm about forums soon after. 3-MeO-PCP is active via oral, insulfation,
the safety of MXE among users.[167] MXE was rst reported to the inhalation, and injection and is slightly more potent than PCP,
EMCDDA on 9 November 2010 by the UK.[173] The rst publicized exhibiting threshold activity at 35 mgs and generally strong
and detailed discussion of MXEs origins and psychoactive dissociative effects at 1020 mgs. Consistent with earlier posts
effects were published as an interview with MXEs inventor by the www.bluelight.ru research group, the effects were gener-
fastandbulbous in the February 2011 issue of Vice magazine.[174] ally positive. A number of other vendors also offered 3-MeO-PCP.
The rst reference to MXE in the scientic literature appeared as In September 2011, BRC informed customers that it would offer
an August 2011 letter to Clinical Toxicology describing a single ad- two novel invite only compounds 3-MeO-PCPy and 3-MeO-PCPr.
verse response from an intravenous user.[175] Attesting to MXEs These materials originally researched by hugo24 and fastandbulbous
growing popularity at this time, the EMCDDA identied 58 websites were absent from the scientic literature at the time. By the end of
in July 2011 offering MXE; although it is uncertain how many of September, experience reports on 3-MeO-PCPr and 3-MeO-PCPy
these websites were legitimate vendors the large number clearly appear on several drug forums including www.bluelight.ru and
attests to MXEs increasing popularity.[176] In addition to powder, www.drugs-forum.com. Both compounds are active, inducing
625
MXE was sold online and in bricks-and-mortar shops in foil characteristic dissociative intoxication at 510 mgs via oral ingestion
Drug Testing
and insulfation. Although reports are limited, many users described based RC market for ketamine-like dissociatives. The rst discus-
the effects positively. Following the success of these compounds, sion of 2-MK being offered as an RC appeared on www.
additional vendors soon emerged offering 3-MeO-PCP and 3-MeO- bluelight.ru in early February 2012. Sometime in May 2012, BRC
PCE.[160] 3-MeO-PCP was reported to the EMCDDA by the UK on 29 offered samples of 2-MK and reports of psychoactive effects soon
March 2012.[185] The identity of RC samples of 3-MeO-PCP and appeared on www.bluelight.ru and other forms.[165] Availability
3-MeO-PCE have been conrmed through MS and NMR analy- of 2-MK increased over the preceding months. Conrming 2-MK
sis[149] and detailed analytical characterization of 4-MeO-PCP, availability, unpublished analysis of a white crystalline solid la-
3-MeO-PCP, 3-MeO-PCPy and several analogues has been belled as 2-MK from www.buyanychem.com was consistent with
published.[186] 3-MeO-PCP continues to be available from a num- high purity racemic 2-MK (optical rotation, 1H and 13C NMR and
ber of non-UK-based RC vendors as of March 2014. GC-MS). A beige crystalline solid marketed as 2-MK was obtained
in January 2014 from an European based RC vendor and proved
consistent with high purity 2-MK based on GC-MS and 1H and 13C
3-[1-(Ethylamino)cyclohexyl]phenol (3-HO-PCE) NMR. 2-MK was reported to the EMCDDA by Sweden on 30
and 3-HO-PCP August, 2012.[185] Despite much initial interest and adders claims,
2-MK proved disappointing to many users; potency was low and
3-HO-PCP and 3-[1-(ethylamino)cyclohexyl]phenol (3-HO-PCE) effects varied enormously between users.
have been offered as RCs. While 3-HO-PCP has been exten- The rst online forum report from a user obtaining an RC sam-
sively researched, 3-HO-PCE was novel. 3-HO-PCP has high ple of N-EK appeared on www.bluelight.ru on 7 August 2012. A
afnity for NMDAR as well as MOR afnity.[166] 3-HO-PCP number of additional posts appeared describing receiving sam-
frequently appears in underground arylcyclohexylamines ples of N-EK and the psychoactive effects following ingestion.[190]
discussions. Its varying psychoactive effects were described by On 7 September 2012, BRC announced it would be offering N-EK
several www.bluelight.ru members including the www.bluelight. stating they could not take credit for the material but that it
ru research group prior to its availability as an RC around 2009. A popped up out of the blue. N-EK was offered through several
post discussing 3-HO-PCE as an RC appeared on www.bluelight.ru sources and a large number of posts on the psychoactive effects
in early May 2012. Several reports on Swiss drug forum www.ash- of N-EK followed on www.bluelight.ru and www.drugs-forum.
back.org exist through 2013.[187,188] Posts on www.bluelight.ru and com. N-EK received mixed reviews, while many described effects
www.drugs-forum.com discussing 3-HO-PCE availability as an RC positively, often comparing it to ketamine, reduced potency and
began in July 2012. Some forum members speculated the 3-HO- adverse effects including nose bleeds were reported by others.
PCE circulating the market was fake, based on a lack of Misrepresentation may be partially responsible for the inconsistent
psychoactivity.[187] No analytical data on the material sold as reports. While N-EK was reported to the EMCDDA on 17 September
3-HO-PCP or 3-HO-PCE currently exists in the literature and 2012 from the UK,[185] a sample of N-EK supplied to us from a
widespread use of these compounds has not occurred. www.bluelight.ru forum member, obtained from a UK vendor, when
analyzed was found to be MXE (melting point and GC-MS). A sample
consisting of a white powder marketed as N-EK obtain in January
Aryl-amino-cyclohexan-2-ones revisited: 2014 from an European based RC vendor proved consistent with
2-methoxy-ketamine and N-ethylketamine high purity N-EK based on GC-MS and 1H and 13C NMR. In addition
to potential misrepresentation, a number of factors may contri-
On 20 May 2010, Polish chemist and www.bluelight.ru member, bute to the variable responses including purity and inter-subject
adder, posted a summary on www.bluelight.ru reviewing the variability, or a combination of these factors.
psychoactive effects of over 30 arylcyclohexylamine-based dissocia- In conjunction with the 2012 UK arylcyclohexylamine ban, UK-
tives, stimulants, and opioids he claimed to have synthesized and based RC vendors removed arylcyclohexylamines from their sites.
tested along with several collaborators. Of particular importance As of February 2014, MXE, 4-MeO-PCP, 3-MeO-PCP, N-EK, and
were adders largely positive descriptions of two aryl-amino- 2-MK remain unscheduled in many countries including the
cyclohexan-2-ones 2-(2-methoxyphenyl)-2-(methylamino)cyclohexa- USA and are still available as of March 2014 through several
none (2-MeO-deschloroketamine, 2-MK) and 2-(2-chlorophenyl)-2- non-UK online RC vendors.
(ethylamino)cyclohexan-1-one (N-ethylnorketamine, N-EK). Calvin
Stevens 1963 and 1966 patents described the synthesis of 2-MK
and legally covered, but did not specically describe, MXE and N- The diarylethylamines
EK.[34,189] An interesting part of this story is that some www.
bluelight.ru members have questioned the authenticity of this The most recent class of dissociatives to emerge on the RC market
2010 adder post. Critics cite inconsistencies between doses reported are the diarylethylamines, which at the time of writing are repre-
with subsequent ndings, the large number of compounds said to sented by 1-(1,2-diphenethyl)piperidine (diphenidine) and 1-[1-(2-
be produced in a short period, and the fact that he appears to have methoxyphenyl)-2-phenylethyl]piperidine (2-MeO-diphenidine)
been 20 at the time of the post. adder maintains the authenticity, (Figure 6). The rst synthesis of diphenidine was published in
noting he was part of a larger research group a claim which is 1924 by Christiaen who used a modied Brulyants reaction, similar
supported by the original post (adder, pers. comm.). This dispute to the reaction later used by Maddox in the rst PCP synthesis.[191]
serves as an example of the potential complications of using infor- Since 1924, diphenidine has been the subject of several synthetic
mation from anonymous Internet sources. Authentic or not, adders and pharmacological investigations.[191193] Importantly diphenidine
2010 post has inuenced the RC dissociative market. has been shown to act as an NMDAR antagonist[193] and can be
Prior to the 5 April 2012 temporary ban, MXE had been the viewed as an MK-801 homeomorph and shares structural features
only aryl-amino-cyclohexan-2-one sold online aside from keta- with arylcyclohexylamines. While diphenidine was never used
626
mine and possibly tiletamine. The MXE ban left a void in the UK or investigated medically, several related compounds have been
Drug Testing
Figure 6. Diarylethylamines used as research chemicals (diphenidine and 2-MeO- diphenidine) and two used clinically (lefetamine and lacicemine).
and include the withdrawn analgesic lefetamine and investiga- diphenidine and 2-Meo-diphenidine as legal replacements for
tional compounds such as AstraZenicas NMDAR antagonist banned arylcyclohexylamines like 4-MeO-PCP and methoxetamine.
antidepressant Lanicemine, and neurodegenerative disease 2-MeO-diphenidine appears to be slightly more active than
and anti-epileptic agent Remacemide.[194] diphenidine with dissociative effects beginning at 80 mg. Both com-
On 26 February 2013, the UK arylcyclohexylamine ban came into pounds show variably in qualitative effects and duration, with higher
effect. Two weeks after the ban, a member of the forum www. doses having residual psychoactive effects that can last several days.
ukchemicalresearch.org stated he received an e-mail from the RC Users also report a steep dose response curve.[197,198] Importantly
vendor www.chemicalwire.com saying diphenidine was available some users have begun to report troubling responses including tachy-
to advanced customers. In the following weeks various users cardia, hyperthermia, and hospilization due to seizures with higher
began posting experiences with diphenidine on a number of doses of diphenidine and/or 2-MeO-diphenidine.[196198] Although an-
forums including www.ukchemicalresearch.org, www.bluelight.ru, ecdotal, there is some basis in that the related compound lefetamine
and www.drugs-forum.com.[195] A sample of diphenidine powder has been observed to cause seizure in rats.[199] These adverse
and diphenidine crystal were obtained from UK based RC vendor responses should be closely monitored for harm-reduction purposes.
www.discofood.com in January 2014 and were found to be consis- Until a generic diarylethylamine ban is implemented, it seems
tent with a reference sample of diphenidine using GC/MS and melt- possible additional diarylethylamine-based dissocative RCs will
ing point. Diphenidine users have reported mild effects at doses of become available. In fact there is suggestion that some vendors
50100 mg, with strong dissociative effects starting at oral doses of have already begun pursuing and actively testing the next genera-
110 mg and higher doses inducing bizarre somatosensory phe- tion of diarylethylamines based on online forums and interviews
nomena and transient anterograde amnesia, lasting 36 h.[196] with forum members.
With diphenidines success, it was only a matter of time until
additional RC diarylethylamines were marketed. During the initial
review phase of this publication, 2-MeO-Diphenidine was rst Abuse liability
marketed by www.chemicalwire.com as a dissociative RC in late
Novemeber 2013. On the www.chemicalwire.com product page, An area important to the current development of CNS active drugs is
2-MeO-diphenidine is said to be an NMDAR antagonist similar to abuse liability, i.e. the ability of a drug to produce positive subjective
Methoxetamine and Ketamine but also acts on the dopamine or reinforcing effects which is believed to predict risk of non-medical
transport. Although it is unknown why 2-MeO-diphenidine was use or abuse.[200,201] The factors which determine abuse liability are
chosen, 2-MeO-Diphenidine is not novel, its synthesis and NMDAR complex, and can be classied as pharmacological and non-
binding afnity are described in a 1989 patent.[193] Information of pharmacological. Important pharmacological factors include drug
the activity of diphenidine or 2-MeO-diphenidine on the dopamine formulation, route of administration, and pharmacokinetic and phar-
transporter could not be found. macodynamic properties of the drug. Non-pharmacological factors
The rst 2-MeO-diphenidine-related post, stating it was avail- include age, socioeconomic status, cultural perspectives, cost, and
able from an RC vendor, appeared on www.ukchemicalresearch. availability of the drug. For example, DXM usage is more common
org on 23 November 2013 and shortly thereafter posts appeared among teens partially as a result of availability and cost relative to
on www.bluelight.ru.[197,198] In the short time since, availability alternatives.[202] Another example is tiletamine abuse by veterinar-
from vendors and online forum posts on 2-MeO-diphenidine ians.[114,203,204] One nal example worth looking at is memantine.
have steadily increased. A white powder obtained from UK based Despite being available from Internet retailers, non-medical use of
RC vendor www.discofood.com in January 2014 was consistent memantine has remained rare. In the published reports it
with a reference sample of 2-MeO-diphenidine using GC/MS and appears to be used by curious psychonauts interested in its nov-
melting point. Many vendor sites have specically marketed elty rather than as a drug of choice or recreation. While reports
627
Figure 7. Some known uncompetitive NMDAR antagonists with potential to serve as structural leads to future RC dissociatives.
Drug Testing
from users of memantine generally related the subjective effects While the UK generic arylcyclohexylamine ban and to a lesser ex-
as positive, the long duration of action (> 40 h) was stated to be tent similar laws in the USA cover many simple arylcyclohexylamines,
undesirable by many users.[153,154] In the case of memantine, the com- many laws fail to cover more conformationally restricted deriva-
bination of the longer half-life with availability of more desirable alter- tives, a large number of which have been described in the
natives likely contribute to the current limited non-medical use. scientic literature. Examples include such classes as the
Abuse liability of NMDAR antagonists has been discussed by phenanthrenamine and uorenamine-based NMDAR antagonists.
FDA staff[205] and others.[200] Carrol has reviewed research on abuse Likewise, the UK arylcyclohexylamine ban fails to cover derivatives
liability of PCP and related compounds including pre-clinical animal in which the aromatic ring is replaced with aliphatic chain substitu-
models such as drug discrimination, self-administration, tolerance, ents. The allyl and propargyl derivatives, 1-[1-(prop-2-en-1-yl)
and physical dependence.[206] While a number of uncompetitive cyclohexyl]piperidine (AlCP) and 1-(1-ethynylcyclohexyl)piperidine
NMDAR antagonists including aptiganel, remacemide, and (PrCP) have been described as active in the literature (Figure 7).[210]
gacyclidine, have been stated to have reduced PCP-like effects in pre- In addition, non-arylcyclohexylamine based uncompetitive NMDAR
clinical trials subsequent clinical evaluation showed dissociative activ- antagonists based on diphenidine, dexoxadrol, 2-MDP, aptiganel,
ity.[4,146,207] Some promise has however been observed with glycine or NPS 1506 (Figures 6 and 7) could become future RC dissociatives.
site-competitive antagonists such as 1-aminocyclopropanecarboxylic Supporting this psychoactive dissociative effects of dexoxadrol,
acid (ACPC) in preclinical and clinical evaluations.[4] Non-competitive aptiganel and 2-MDP have already been described on online drug
allosteric antagonists targeting NR2B subunit containing NMDARs forums. While these classes could themselves be scheduled, a
including ifenprodil and eliprodil have also been reported to demand exists and newer classes will almost certainly take the
exhibit reduced PCP like effects in animals and humans.[4] Thus place of those banned. It must be considered that generic bans
targeting specic sub-units of the NMDAR channel may be a tend to have the unintentional consequence of adversely
strategy to reduce dissociative effects and limit abuse liability. How- impacting scientic and medical research. Generic bans will likely
ever, as NMDAR antagonism appears involved in both therapeutic continue to be ineffective as clandestine chemists and the new
and dissociative effects, it is unclear what effect a reduced abuse breed of RC vendors have a well established history of skirting
potential will have on the therapeutic activity. Legitimate medical legislative roadblocks. The fact that diphenidine was available on
users must be considered, and should not be penalized due to the RC market only weeks after the UK arylcyclohexylamine ban
non-medical use/abuse which is likely to continue despite legislative exemplies both the resilience of these markets and the ineffec-
and regulatory efforts or medical advancements in abuse liability. tiveness of current legal strategies.
Acknowledgements
We would like to acknowledge Alexandra Kammen for assistance
Conclusion with this manuscript. In addition we would like to thank the
anonymous online forum members who contributed valuable
Early scientic and medical research with dissociative agents oc-
information and reference samples.
curred in a pre-Internet era; likewise the rst clandestine
arylcyclohexylamine chemists operated without easily accessible
synthetic and pharmacological information now facilitated by the References
Internet. Still many early clandestine chemists clearly accessed [1] E.F. Domino. Taming the ketamine tiger. Anesthesiology 2010, 113, 678.
the existing arylcyclohexylamines literature for inspiration and [2] N. Anis, S. Berry, N. Burton, D. Lodge. The dissociative anaesthetics,
synthetic knowledge. This is exemplied by the fact that despite ketamine and phencyclidine, selectively reduce excitation of central mam-
being commonly called designer drugs, all but one of the 14 malian neurones by n-mfethyl-aspartate. Brit. J. Pharmacol. 1983, 79, 565.
[3] A. Mori, Y. Noda, T. Mamiya, Y. Miyamoto, A. Nakajima, H. Furukawa,
pre-2000 analogues reviewed were rst reported in the scientic
T. Nabeshima. Phencyclidine-induced discriminative stimulus is
literature (Figure 3). While PCP remains readily available in numer- mediated via phencyclidine binding sites on the n-methyl-d-
ous US cities, street analogues have virtually disappeared with no aspartate receptor-ion channel complex, not via sigma1 receptors.
reports found after the 1990s. It is noteworthy that in the late Behav. Brain Res. 2001, 119, 33.
1990s as arylcyclohexylamines began to disappear from the [4] P.L. Herrling. Excitatory Amino Acids: Clinical Results with Antago-
nists. Academic Press, California, 1997.
streets, various dissociatives began to traded on the Internet.
[5] G.W. Albers, W.M. Clark, R.P. Atkinson, K. Madden, J.L. Data, M.J.
While ketamine and DXM were offered for a time via gray- Whitehouse. Dose escalation study of the NMDA glycine-site antag-
market sources, the modern dissociative RC market began in 2008. onist licostinel in acute ischemic stroke. Stroke 1999, 30, 508.
Starting with 4-MeO-PCP, the dissociative RC market has rapidly [6] R.B. Rothman, A.A. Reid, J.A. Monn, A.E. Jacobson, K.C. Rice. The psy-
evolved in four years to encompass at least a dozen dissociatives. Im- chotomimetic drug phencyclidine labels two high afnity binding
sites in guinea pig brain: Evidence for n-methyl-d-aspartate-
pressively, half of these dissociatives are novel, and their origins can coupled and dopamine reuptake carrier-associated phencyclidine
be traced to a handful of inuential members of The Hive or www. binding sites. Mol. Pharmacol. 1989, 36, 887.
bluelight.ru drug forums. One of these novel RCs, methoxetamine, [7] B.L. Roth, S. Gibbons, W. Arunotayanun, X.-P. Huang, V. Setola, R. Treble,
is a rare instance of a true designer drug, rationally designed for L. Iversen. The ketamine analogue methoxetamine and 3-and 4-
methoxy analogues of phencyclidine are high afnity and selective
the gray-market based on a combination of scientic and folk phar-
ligands for the glutamate NMDA receptor. PloS One 2013, 8, e59334.
macology principles. Accordingly, MXE has become emblematic of [8] K.L.R. Jansen. Ketamine: Dreams and Realities. MAPS, California, 2004.
underground drug development in the Internet age and a unique in- [9] D. Lodge, W. Danysz, C.G. Parsons. Ionotropic glutamate receptors as
sight into the factors that allow these markets to evolve. While many therapeutic targets. F.P Graham Publishing Co., 2002.
see little benet to the RC market in some cases scientic and [10] F.X. Vollenweider, K.L. Leenders, C. Scharfetter, P. Maguire, O.
Stadelmann, J. Angst. Positron emission Johnson City, TN tomogra-
medical uses can evolve out of these agents. For example, despite phy and uorodeoxyglucose studies of metabolic hyperfrontality
misuses, MXE and 4-MeO-PCP have been proposed for therapeutic and psychopathology in the psilocybin model of psychosis.
628
and research applications that may be realized in the future.[208,209] Neuropsychopharmacology 1997, 16, 357.
Drug Testing
[11] C.J. Reissig, L.P. Carter, M.W. Johnson, M.Z. Mintzer, M.A. Klinedinst, [39] G.D. Lundberg, R.C. Gupta, S.H. Montgomery. Phencyclidine:
R.R. Grifths. High doses of dextromethorphan, an NMDA antago- Patterns seen in street drug analysis. Clin. Toxicol. 1976, 9, 503.
nist, produce effects similar to classic hallucinogens. Psychophar- [40] Drug Enforcement Agency. Information bulletin. PCP tablets sold as
macology 2012, 223, 1. MDMA. Available at: www.justice.gov/archive/ndic/pubs0/661/in-
[12] E.F. Domino. History and pharmacology of PCP and PCP-related an- dex.htm [7 January 2014].
alogs. J. Psychoactive Drugs 1980, 12, 223. [41] P. Jenkins. Synthetic Panics: The Symbolic Politics of Designer Drugs.
[13] B.A. Killinger, M.M. Peet, L.E. Baker. Salvinorin A fails to substitute New York University Press, NY, USA, 1999.
for the discriminative stimulus effects of LSD or ketamine in [42] J.P. Morgan, D. Kagan. The dusting of America: The image of phencycli-
SpragueDawley rats. Pharmacol. Biochem. Behav. 2010, 96, 260. dine (PCP) in the popular media. J. Psychoactive Drugs. 1980, 12, 195.
[14] S. Herling, J.H. Woods. IV. Discriminative stimulus effects of narcotics: Ev- [43] Drug Enforcement Adminsitration. Ofce of Diversion Control. Phencycli-
idence for multiple receptor-mediated actions. Life Sci. 1981, 28, 1571. dine. Available at: http://www.deadiversion.usdoj.gov/drug_chem_info/
[15] K.M. Kumor, C.A. Haertzen, R.E. Johnson, T. Kocher, D. Jasinski. Human pcp.pdf [7 January 2014].
psychopharmacology of ketocyclazocine as compared with cyclazo- [44] UNDOC. World Drug Report 2010. United Nations Ofce on Drugs
cine, morphine and placebo. J. Pharm. Exp. Ther. 1986, 238, 960. and Crime, United Nations Publications, New York, 2010.
[16] C.D. Chambers, J.A. Inciardi, R.C. Stephens. A critical review of pen- [45] R.L. McQuinn, E.J. Cone, H.E. Shannon, T.-P. Su. Structure-activity
tazocine abuse. HSMHA Health Rep. 1971, 86, 627. relationships of the cycloalkyl ring of phencyclidine. J. Med. Chem.
[17] K.L. Krystal JH, Seibyl J.P., Freeman G.K., Delaney R., Bremner J.D., 1981, 24, 1429.
Heninger G.R., Bowers M.B. Jr, Charney D.S.. Subanesthetic effects [46] A. Thurkauf, B. De Costa, S. Yamaguchi, M.V. Mattson,
of the noncompetitive NMDA antagonist, ketamine, in humans. A.E. Jacobson, K.C. Rice, M.A. Rogawski. Synthesis and anticonvul-
Psychotomimetic, perceptual, cognitive, and neuroendocrine sant activity of 1-phenylcyclohexylamine analogs. J. Med. Chem.
responses. Arch. Gen. Psychiat. 1994, 51, 199. 1990, 33, 1452.
[18] E.D. Luby, B.D. Cohen, G. Rosenbaum, J.S. Gottlieb, R. Kelley. Study [47] A.C. Allen, J. Robles, W. Dovenski, S. Calderon. PCP: A review of
of a new schizophrenomimetic drugsernyl. AMA. Arch. Neurol. synthetic methods for forensic clandestine investigation. Forensic
Psychiatry 1959, 81, 363. Sci. Int. 1993, 61, 85.
[19] J.W. Newcomer, N.B. Farber, V. Jevtovic-Todorovic, G. Selke, A.K. [48] R.E. Garey. PCP (phencyclidine): An update. J. Psychoactive Drugs
Melson, T. Hershey, S. Craft, J.W. Olney. Ketamine-induced NMDA 1979, 11, 265.
receptor hypofunction as a model of memory impairment and psy- [49] R.C. Petersen, R.C. Stillman. Phencyclidine: An overview, in Phency-
chosis. Neuropsychopharmacology 1999, 20, 106. clidine Abuse: An Appraisal. (Eds: R.C. Peterson, R.C. Stillman). NIDA
[20] J.S. Meyer, F. Greifenstein, M. DeVault. A new drug causing symptoms Res. Monogr.: Rockville, Maryland, 1978, 21, pp. 117.
of sensory deprivation: Neurological, electroencephalographic and [50] A.T. Shulgin, D.E. MacLean. Illicit synthesis of phencyclidine (PCP)
and several of its analogs. Clin. Toxicol. 1976, 9, 553.
pharmalogical effects of sernyl. J. Nerv. Ment. Dis. 1959, 129, 54.
[51] C. Sauer, F.T. Peters, R.F. Staack, G. Fritschi, H.H. Maurer. New designer
[21] D. Carpenter. A psychonauts guide to the invisible landscape: The topog-
raphy of the psychedelic experience. Inner Traditions, Vermont, 2006. drugs N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA) and N-(1-
[22] R.L. Linder, S.E. Lerner, R.S. Burns. PCP, the Devils Dust: Recognition, phenylcyclohexyl)-2-methoxyethanamine (PCMEA): Studies on their
Management, and Prevention of Phencyclidine Abuse. Wadsworth metabolism and toxicological detection in rat urine using gas
Publishing Company, California, 1981. chromatographic/mass spectrometric techniques. J. Mass Spectrom.
[23] E. Studerus, A. Gamma, F.X. Vollenweider. Psychometric evaluation 2008, 43, 305.
of the altered states of consciousness rating scale (OAV). PloS One [52] P. Roesner, T. Junge, G. Fritschi, B. Klein, K. Thielert, M. Kozlowski.
2010, 5, e12412. Neue synthetische drogen: Piperazin-, Procyclidin-und alpha-
[24] N. Kursanov. Phenyl derivatives of naphthenes, second paper, some de- Aminopropiophenonderivate. Toxichem. Krimtech. 1999, 66, 81.
rivatives of phenylcyclohexane. Zh. Russ. Fiz.-Khim. O-va. 1907, 38, 1295. [53] W.H. Soine, R.L. Balster, K.E. Berglund, C.D. Martin, D.T. Agee. Identi-
[25] S. Chiavarelli, E.F. Rogers, G.B. Marino-Bettolo. Researches on cation of a new phencyclidine analog, 1-(1-phenylcyclohexyl)-4-
synthetic products with erythrina akaloids as a model. Gazz. Chim. methylpiperidine, as a drug of abuse. J. Anal.Toxicol. 1982, 6, 41.
Ital. 1953, 83, 347. [54] J.R. Ballinger, J.A. Marshman. GLC quantitation of 1-
[26] K. Thomae. Verafahren zur herstellung von tertiren aminen, ihren piperidinocyclohexanecarbonitrile (PCC) in illicit phencyclidine
sureadditionssalzen und quaternren ammoniumverbindugen. (PCP). J. Anal.Toxicol. 1979, 3, 158.
Patent No. 1124496, 1962. [55] D.B. Vaupel, D. McCoun, E.J. Cone. Phencyclidine analogs and pre-
[27] V.H. Maddox. The historical development of phencyclidine, in PCP cursors: Rotarod and lethal dose studies in the mouse. J. Pharm.
(Phencyclidine): Historical and Current Perspectives. (Ed: E. Domino). Exp. Ther. 1984, 230, 20.
NPP Books: Michigan, 1981, pp. 18. [56] E.J. Cone, D.B. Vaupel, W.F. Buchwald. Phencyclidine: Detection and
[28] G. Chen, C.R. Ensor, D. Russell, B. Bohner. The pharmacology of 1-(1- measurement of toxic precursors and analogs in illicit samples.
phenylcyclohexyl) piperidine-HCl. J. Pharm. Exp. Ther. 1959, 127, 241. J. Anal.Toxicol. 1980, 4, 119.
[29] F.E. Greifenstein, J. Yoshitake, M. DeVault, J.E. Gajewski. A study of [57] A. Reed, A.W. Kane. Phencyclidine (PCP). STASH Capsules. 1970, 44, 1.
1-aryl cyclohexylamine for anesthesia. Anesth. Analg. 1958, 5, 283. [58] Second session, on S. 2778, June 7 and 21, 1978. Phencyclidine (PCP
[30] G. Chen. The neuropharmacology of phencyclidine, in PCP (phency- or angel dust). Joint hearings before the Subcommittee on Alcohol-
clidine), historical and current perspectives, (Ed: E.F. Domino). NPP ism and Drug Abuse of the Committee on Human Resources and
Books, Michigan, 1981, pp. 9. the Subcommittee to Investigate Juvenile Delinquency of the
[31] E. Lear. Intravenous anesthesia: A survery of newer agents. Anesth. Committee on the Judiciary, United States Senate, Ninety-fth
Analg. 1968, 47, 154. Congress, US Government Printing Ofce, Washington DC, 1978.
[32] E.F. Domino. Chemical dissociation of human awareness: Focus on [59] Parke, Davis & Co. Heterocyclic compounds for use as central
non-competitive NMDA receptor antagonists. J. Psychopharmacol. nervous system depressants. UK Patent No. 838748, 1960.
1992, 6, 418. [60] J.Q. Beagle. Synthesis and effects of PCP analogs. Rhodium.
[33] E.F. Domino, P. Chodoff, G. Corssen. Pharmacological effects of Available at: http://www.erowid.org/archive/rhodium/chemistry/
CI-581, a new dissociative anaesthetic, in man. Clin. Pharmacol. pcp/ [7 January 2014].
Ther. 1965, 6, 279. [61] The Hive. Xicori. TCP synthesis. Available at: http://chemistry.mdma.
[34] C.L. Stevens. Aminoketones and methods for their production. US ch/hiveboard/methods/000484668.html [7 January 2014].
Patent No. 3254124, 1966. [62] S.E.B. Lerner, R. Stanley. Phencyclidine use among youth: History,
[35] ACMD. Ketamine Report. Available at: https://www.gov.uk/govern- epidemiology, and acute and chronic intoxication. California School of
ment/publications/ketamine-report [7 January 2014]. Professional Psychology at Berkeley, Berkley, CA, USA, 1978.
[36] H.W. Feldman. PCP use in four cities: An overview, in Angel Dust, an [63] Drug Enforcement Administration. Lists of: Scheduling actions,
Ethnographic Study of PCP Users. (Eds: H.W. Feldman, M. Agar, G.M. controlled substances, regulated chemicals. US Department of Jus-
Beschner). Lexington Books: Massachusetts, 1979, pp. 29. tice, Washington DC, USA, 2013.
[37] P.C.P. "T.H.C." and the Ripoff Syndrome. Do It Now Foundation, [64] S.E. Lerner, R.S. Burns. Phencyclidine use among youth: History,
Institute For Chemical Survival, Arizona, 1975. epidemiology, and acute and chronic intoxication. NIDA Res.
629
[38] Anon. The 1977 street drug analysis results. Clin. Toxicol. 1979, 14, 619. Monogr. 1978, 21, 66.
Drug Testing
[65] T.A. Dal-Cason, E. Franzosa. Occurrences and forms of the halluci- [97] R.K. Siegel. Phencyclidine and ketamine intoxication: A study of four
nogens, in Hallucinogens: A Forensic Drug Handbook. (Ed: R.R. populations of recreational users. NIDA Res. Monogr. 1978, 21, 119.
Laing). Academic Press: London, UK, 2003, pp. 3764. [98] C.E. Reier. Ketamine" dissociative agent" or hallucinogen? New
[66] A. Kalir, H. Edery, Z. Pelah, D. Balderman, G. Porath. 1- Engl. J. Med. 1971, 284, 791.
Phenylcycloalkylamine derivatives. II. synthesis and pharmacologi- [99] M. Moore, H.S. Alltounian. Journeys into the Bright World. Para
cal activity. J. Med. Chem. 1969, 12, 473. Research, Massachusetts, 1978.
[67] K. Bailey. Identication of a street drug as N-ethyl-1-phenylcyclohexylamine, [100] J.C. Lilly. The Scientist: A Metaphysical Autobiography. Ronin
a phencyclidine analog. J. Pharm. Sci. 1978, 67, 885. Publishing, California, 1978.
[68] P. Magnusson. PCP-like drug hits street here. The Detroit Free Press. [101] Ketamine abuse. FDA Drug Bulletin. U.S. Department of Health
1977, 18A. and Human Services. Food and Drug Administration: Silver
[69] J.E. Smialek, J.R. Monforte, R. Gault, W.U. Spitz. Cyclohexamine Spring, MD, 1979.
(rocket fuel)-phencyclidines potent analog. J. Anal. Toxicol. [102] U.S. Department of Justice. Lists of: Scheduling Actions Controlled
1979, 3, 209. Substances Regulated Chemicals. Drug Enforcement Administra-
[70] Abuse of dangerous licit and illicit drugs-psychotropics, phencycli- tion. Available at: http://www.deadiversion.usdoj.gov/schedules/
dine (PCP), and talwin. Hearings before the Select Committee on orangebook/orangebook.pdf [7 January 2014].
Narcotics Abuse and Control, House of Representatives, Ninety- [103] L.P. Brown. Pulse Check: National Trends in Drug Abuse. DIANE Pub-
fth Congress, second session. US Government Printing Ofce, lishing, Pennsylvania, 1995.
Washington DC, USA 1979. [104] The Dextroverse. The DXM Zine. Issue 2. Available at: http://
[71] Anon. 3-Year term given. Kokomo (Ind.) Tribune, 20 October 1981. dextroverse.org/zine/zine2/ [7 January 2014].
[72] Anon. 26 people face drug charges. The Globe and Mail, 16 September [105] The Dextroverse. The DXM Zine. Issue 1. Available at: http://
1978, 3. dextroverse.org/zine/zine1/ [7 January 2014].
[73] Anon. L.A. Daniels. Professor on L.I. accused of plot to make drugs. [106] P.S. Chu, S. Kwok, K. Lam, T. Chu, S.W. Chan, C. Man, W. Ma, K. Chui,
The New York Times, 28 May 1980, B1. M. Yiu, Y. Chan. Street ketamine-associated bladder dysfunction: A
[74] Anon. Charged for drugs. Ironwood Daily Globe, 18 August 1981, 2. report of ten cases. Hong Kong Med. J. 2007, 13, 311.
[75] U.S. v. Wisniewski. United States Court of Appeals. Seventh Circuit. [107] K. Shahzad. Understanding mechanisms of ketamine-induced hu-
741 F.2d 138. No. 841089, 1984. man urinary tract damage, MSc by research thesis. University of
[76] Anon. Lewisberry man, 20, to face drug charge. The Patriot-News, 19 York: York, UK, 2011.
July 1991, [108] EMCDDA. Report on the risk assessment of ketamine in the framework
[77] K.T. Brady, R.L. Balster. Discriminative stimulus properties of phen- of the joint action on new synthetic drugs. EMCDDA, Lisbon. Available
cyclidine and ve analogues in the squirrel monkey. Pharmacol. at: http://www.emcdda.europa.eu/html.cfm/index33341EN.html
Biochem. Be. 1981, 14, 213. [7 January 2014].
[78] R. Lindsey. Los Angeles police scored on shooting. The New York [109] R.R. Laing. Hallucinogens: A Forensic Drug Handbook. Academic
Times, 15 August 1977, 13. Press, 2003.
[79] G.R. Nakamura, E.C. Griesemer, L.E. Joiner, T.T. Noguchi. Determina- [110] T. Thacker. Ketamine to be sold only with prescription. The Indian
tion of 1-(1-Phenylcyclohexyl) pyrrolidine (PHP) in postmortem Express, 1 November 2010.
specimens: A case report. Clin. Toxicol. 1979, 14, 383. [111] G. Chen, C.R. Ensor, B. Bohner. The pharmacology of 2-
[80] U.S. v Worthington, 642 F.2d 150. No. 805306. United States Court (ethylamino)-2-(2-thienyl)-cyclohexanoneHCl (CI-634). J. Pharm.
of Appeals, Fifth Circuit, 1981. Exp. Ther. 1969, 168, 171.
[81] R.D. Budd. PHP, a new drug of abuse. New Engl. J. Med. 1980, 303, 588. [112] R.F. Parcell. 2-(Ethylamino)-2-(2-thienyl)cyclohexanone and acid
[82] A.J. Giannini, S. Castellani. A case of phenylcyclohexylpyrrolidine addition salts. US Patent No. 3522273, 1970.
(PHP) intoxication treated with physostigmine. Clin. Toxicol. 1982, [113] H. Chung, H. Choi, E. Kim, W. Jin, H. Lee, Y. Yoo. A fatality due to in-
19, 505. jection of tiletamine and zolazepam. J. Anal.Toxicol. 2000, 24, 305.
[83] A.J. Giannini, W.A. Price, R.H. Loiselle, D.W. Malone. Treatment of [114] C.C. Lee, Y.Y. Lin, C.W. Hsu, S.J. Chu, S.H. Tsai. Movement disorder
phenylcyclohexylpyrrolidine (PHP) psychosis with haloperidol. Clin. caused by abuse of veterinary anesthesia containing tiletamine.
Toxicol. 1985, 23, 185. Am. J. Emerg. Med. 2009, 27, 1022 e56.
[84] U.S. v. Talladino, 38 F.3d 1255. No. 941122. United States Court of [115] Toad. Trick or Treat? Available at: http://www.erowid.org/experi-
Appeals. First Circuit, 1994. ences/exp.php?ID=10352 [7 January 2014].
[85] Bluelight. Adder. PCP analogs (cumulative). Available at: http:// [116] Erowid. Undervet. Careful with this Benzo/Dissociative Combo.
www.bluelight.ru/vb/threads/504286-PCP-analogs-(Cumulative) Available at: http://www.erowid.org/experiences/exp.php?ID=86014
[7 January 2014]. [7 January 2014].
[86] B.A. Lodge, R. Duhaime, J. Zamecnik, P. MacMurray, R. Brousseau. [117] O. Schnider, A. Grssner. Hydrophenanthrene derivatives and
New street analogs of phencyclidine. Forensic Sci. Int. 1992, 55, 13. process for the manufacture of same. US Patent No.
[87] E.J. Cone, R.L. McQuinn, H.E. Shannon. Structure-activity relationship stud- 2,524,855, 1950.
ies of phencyclidine derivatives in rats. J. Pharm. Exp. Ther. 1984, 228, 147. [118] Roche Products Ltd. The resolution of 3-hydroxy- and 3-methoxy-
[88] The Hive. Xicori. Bioassay. Available at: http://chemistry.mdma.ch/ N-methyl-morphinanes and process for the manufacture of the
hiveboard/methods/000386595.html [7 January 2014]. latter. Patent No. 684,367, 1952.
[89] The Hive. Xicori. PCM synthesis. Available at: http://chemistry. [119] J. Church, D. Lodge, S.C. Berry. Differential effects of dextrorphan
mdma.ch/hiveboard/methods/000475049.html [7 January 2014]. and levorphanol on the excitation of rat spinal neurons by amino
[90] Parke, Davis & Co. Pharmaceutical compositions and methods for pro- acids. Eur. J. Pharmacol. 1985, 111, 185.
ducing phenylcyclohexane compounds. US Patent No. 861350, 1961. [120] Y.C. Chou, J.-F. Liao, W.-Y. Chang, M.-F. Lin, C.-F. Chen. Binding of
[91] The Hive. Aurelius, Ethoxyethyl analogue. Available at: http://chemistry. dimemorfan to sigma-1 receptor and its anticonvulsant and loco-
mdma.ch/hiveboard/methods/000451447.html [7 January 2014]. motor effects in mice, compared with dextromethorphan and
[92] The Hive. 4-methoxy PCP-Beagle. Available at: http://chemistry. dextrorphan. Brain Res. 1999, 821, 516.
mdma.ch/hiveboard/novel/000212050.html [7 January 2014]. [121] G. Albers, R. Atkinson, R. Kelley, D. Rosenbaum. Safety, tolerability,
[93] The Hive. Zealot: Synthesis and bioevaluation of PCDE. Available at: and pharmacokinetics of the N-methyl-D-aspartate antagonist
http://chemistry.mdma.ch/hiveboard/novel/000369598. dextrorphan in patients with acute stroke. Stroke 1995, 26, 254.
html#Post369598 [7 January 2014]. [122] J. Gelfer. Towards a sacramental understanding of dextromethor-
[94] The Hive. Beagle. Novel PCP analog. Available at: http://chemistry. phan. JASANAS 2007, 3, 80.
mdma.ch/hiveboard/novel/000108806.html [7 January 2014]. [123] R. Chapman. Soft Machine. Mojo 1997.
[95] National drug threat assessment: Ketamine. National Drug Intelli- [124] R.H. Schwartz. Adolescent abuse of dextromethorphan. Clin.
gence Center. Available at: http://www.justice.gov/archive/ndic/ Pediatr. 2005, 44, 565.
pubs8/8731/odd.htm#Ketamine [7 January 2014]. [125] A. Dodds, E. Reval. Toxic psychosis due to dextromethorphan. Med.
[96] National Drug Intelligence Center. Intelligence Bulletin: Ketamine. J. Aust. 1967, 2, 231.
Available at: http://www.justice.gov/archive/ndic/pubs10/10255/ [126] R. Degkwitz. Dextromethorphan (romilar) as an intoxicating agent.
630
10255t.htm [7 January 2014]. Der Nervenarzt. 1964, 35, 412.
Drug Testing
[127] R.E. Long, P.P. Penna. Drugs of Abuse. A guide for the professions [151] C. Parsons, W. Danysz, G. Quack. Memantine is a clinically well
drug abuse education. American Pharmaceutical Association: tolerated n-methyl-d-aspartate (NMDA) receptor antagonist a
Washington, DC, 1968. review of preclinical data. Neuropharmacology 1999, 38, 735.
[128] D. Jasinski, W. Martin, P. Mansky. Progress report on the assessment of [152] Lazyvegan. Memantine hydrochloride: A few words of caution.
the antagonists nalbuphine and GPA-2087 for abuse potential and Etheogen Rev. 2003, 12, 132.
studies of the effects of dextromethorphan in man. National Academy [153] Erowid. CaptainOubliz. Almost Mushroomesque. Available at: http://
of Science/National Research Council, Washington DC, 1971, pp. 143. www.erowid.org/experiences/exp.php?ID=100894 [7 January 2014].
[129] A.T. Shulgin. Drugs of abuse in the future. Clin. Toxicol. 1975, 8, 405. [154] Erowid. E.-d. tripper. Nearly Neverending Trip. Available at: http://
[130] L. Rammer, P. Holmgren, H. Sandler. Fatal intoxication by dextro- www.erowid.org/experiences/exp.php?ID=52958 [7 January 2014].
methorphan: A report on two cases. Forensic Sci. Int. 1988, 37, 233. [155] R. Monastero, C. Camarda, C. Pipia, R. Camarda. Visual hallucina-
[131] W.E. White. The Dextromethorphan FAQ. 1994. Available at: http:// tions and agitation in Alzheimers disease due to memantine:
www.zoklet.net/totse/en/drugs/rare_and_exotic_drugs/dext.html Report of three cases. JNNP 2007, 78, 546.
[7 January 2014]. [156] D.R. Spiegel, M.R. Leader. Psychosis induced by the interaction
[132] S.P. Nordt. DXM: A new drug of abuse? Ann. Emerg. Med. 1998, 31, 794. of memantine and amantadine: Lending evidence to the
[133] M.D. Wilson, R.W. Ferguson, M.E. Mazer, T.L. Litovitz. Monitoring glutamatergic theory of schizophrenia. Clin. Schizophr. Relat.
trends in dextromethorphan abuse using the national poison data Psychoses. 2007, 1, 273.
system: 20002010. Clin. Toxicol. 2011, 49, 409. [157] K. Zdanys, R.R. Tampi. A systematic review of off-label uses of
[134] National Drug Intelligence Center. Intelligence Bulletin: DXM (dex- memantine for psychiatric disorders. Prog. Neuropsychopharmacol.
tromethorphan). Available at: http://www.justice.gov/archive/ndic/ Biol. Psychiatry. 2008, 32, 1362.
pubs11/11563/ [7 January 2014]. [158] V.H. Maddox, E.F. Godefroi, R.F. Parcell. The synthesis of phencycli-
[135] FDA Drug Safety and Risk Management Advisory Committee. dine and other 1-arylcyclohexylamines. J. Med. Chem. 1965, 8, 230.
Abuse Potential of Dextromethorphan. Available at: http://www. [159] P. Geneste, J.M. Kamenka, S.N. Ung, P. Herrmann, R. Goudal,
erowid.org/chemicals/dxm/dxm_article4.pdf [7 January 2014]. G. Trouiller. Conformational determination of phencyclidine de-
[136] K.W. Muir, K.R. Lees. Clinical experience with excitatory amino acid rivatives in view of structure-activity correlation. Eur. J. Med.
antagonist drugs. Stroke 1995, 26, 503. Chem. - Chim. Ther. 1979, 14, 301.
[137] M.E. Christy, P.S. Anderson, S.F. Britcher, C.D. Colton, B.E. Evans, [160] J. Vignon, J.-P. Vincent, J.-N. Bidard, J.-M. Kamenka, P. Geneste,
D.C. Remy, E.L. Engelhardt. Transannular reactions of dibenzo S. Monier, M. Lazdunski. Biochemical properties of the brain
[a, d] cycloalkenes. 1. Synthesis of dibenzo [a, d] cycloocten-6, phencyclidine receptor. Eur. J. Pharmacol. 1982, 81, 531.
12-imines and dibenzo [a, d] cyclohepten-5, 10-imines. J. Org. [161] Ecstasydata. 4-MeO-PCP. ID Nos. 2425, 2446, 2339. Available at:
Chem. 1979, 44, 3117. http://www.ecstasydata.org/ [7 January 2014].
[138] E.H. Wong, J.A. Kemp, T. Priestley, A.R. Knight, G.N. Woodruff, [162] EMCDDA. 2011 Annual report on the state of the drugs problem in
L.L. Iversen. The anticonvulsant MK-801 is a potent N-methyl- Europe. Available at: http://www.emcdda.europa.eu/publications/
D-aspartate antagonist. P. Natl. Acad. Sci. 1986, 83, 7104. annual-report/2011 [7 January 2014].
[139] L. Velek, P. Mare. Developmental aspects of the anticonvulsant [163] J. Casale. 4-Methoxyphencyclidine: An analytical prole. Microgram
action of MK-801 in Multiple sigma and PCP receptor ligands: mech- J. 2011, 8, 39.
anisms for neuromodulation and neuroprotection. (Ed: J.M. [164] Bluelight. hugo24. 1-{1-(3-Methoxiphenyl)-cyclohexyl}-piperidin. Avail-
D. Kamenka). NPP Books: Ann Arbor, Michigan, 1992, pp. 779795. able at: http://www.bluelight.ru/vb/archive/index.php/t-427958.html
[140] Cat. alt.religion.psychedelic.moderated. Available at: https://groups. [7 November 2013].
google.com/d/msg/alt.drugs.chemistry/FkteiXaZIqM/p4CL3U-Trd8J [165] J.M. Kamenka, B. Chiche, R. Goudal, P. Geneste, J. Vignon, J.P. Vincent,
[7 November 2013]. M. Lazdunski. Chemical synthesis and molecular pharmacology of
[141] A. Mozayani, P. Schrode, J. Carter, T.J. Danielson. A multiple drug hydroxylated 1-(1-phenylcyclohexyl) piperidine derivatives. J. Med.
fatality involving MK-801 (dizocilpine), a mimic of phencyclidine. Chem. 1982, 25, 431.
Forensic Sci. Int. 2003, 133, 113. [166] Y. Itzhak. High and low afnity psychotomimetic opioid binding sites: Char-
[142] Bluelight. Tantric. mk-801 trip report, all systems go. Available at: acterization by a novel 3H-PCP analog. NIDA Res. Monogr. 1986, 75, 173.
http://www.bluelight.ru/vb/threads/141296-MK-801-rst-few-expe- [167] O. Corazza, S. Assi, F. Schifano. From "special k" to "special m": The
riences-All-systems-go [7 January 2014]. evolution of the recreational use of ketamine and methoxetamine.
[143] Erowid. Viscosity. The Most Beautiful Lobotomy I Ever Had. CNS Neurosci. Ther. 2013, 19, 454.
Available at: http://www.erowid.org/experiences/exp.php?ID=94476 [168] M.R. Meyer, M. Bach, J. Welter, M. Bovens, A. Turcant, H.H. Maurer.
[7 January 2014]. Ketamine-derived designer drug methoxetamine: Metabolism in-
[144] J.W. Olney, J. Labruyere, M.T. Price. Pathological changes induced in cluding isoenzyme kinetics and toxicological detectability using
cerebrocortical neurons by phencyclidine and related drugs. GC-MS and LC-(HR-)MSn. Anal. Bioanal. Chem. 2013, 405, 6307.
Science 1989, 244, 1360. [169] E.L. Menzies, S.C. Hudson, P.I. Dargan, M.C. Parkin, D.M. Wood, A.T.
[145] M. Schmutz, A. Arthur, H. Faleck, G. Karisson, A. Kotake, L. Lantwicki, Kicman. Characterizing metabolites and potential metabolic path-
L. LaRue, S. Markabi, D. Murphy, M. Powell, D. Sauer. Selfotel ways for the novel psychoactive substance methoxetamine. Drug
(CGS19755), in Excitatory Amino Acids: Clinical Results with Antago- Test. Anal. 2013. DOI: 10.1002/dta.1541
nists. (Ed: P. Herrling), Academic Press: London, 1997, pp. 16. [170] P.A. Hays, J.F. Casale, A.L. Berrier. The characterization of 2-(3-
[146] H. Hirbec, M. Gaviria, J. Vignon. Gacyclidine: A new neuroprotective methoxyphenyl)-2-(ethylamino) cyclohexanone (methoxetamine).
agent acting at the N-methyl-D-aspartate receptor. CNS Drug Rev. Microgram. J. 2012, 9, 3.
2001, 7, 172. [171] G. De Paoli, S.D. Brandt, J. Wallach, R.P. Archer, D.J. Pounder. From the
[147] G.C. Palmer, J.B. Hutchison. Preclinical and clinical aspects of street to the laboratory: Analytical proles of methoxetamine, 3-
remacemide hydrochloride, in Excitatory Amino Acids: Clinical Re- methoxyeticyclidine and 3-methoxyphencyclidine and their determi-
sults with Antagonists. (Ed: P. Herrling). Academic Press: London, nation in three biological matrices. J. Anal. Toxicol. 2013, 37, 277.
1997, pp. 109124. [172] Anon. Police treated after drug contamination in Harlow. Harlow
[148] A.S. Fix, J.W. Horn, K.A. Wightman, C.A. Johnson, G.G. Long, R.W. Star, 21 October 2010.
Storts, N. Farber, D.F. Wozniak, J.W. Olney. Neuronal vacuolization [173] EMCDDA. EMCDDAEuropol 2010 Annual Report on the Implemen-
and necrosis induced by the noncompetitive n-methyl-d- tation of Council Decision 2005/387/JHA. Available at: http://www.
aspartate (NMDA) antagonist MK (+) 801 (dizocilpine maleate): A emcdda.europa.eu/publications/implementation-reports/2010
light and electron microscopic evaluation of the rat retrosplenial [7 January 2014].
cortex. Exp. Neurol. 1993, 123, 204. [174] H. Morris. Interview with a ketamine chemist, or to be more precise,
[149] N.B. Farber, J. Hanslick, C. Kirby, L. McWilliams, J.W. Olney. Seroto- an arylcyclohexylamine chemist. Vice Magazine 2011, 18, 98.
nergic agents that activate 5HT2A receptors prevent NMDA antag- [175] J. Ward, S. Rhyee, J. Plansky, E. Boyer. Methoxetamine: A novel ke-
onist neurotoxicity. Neuropsychopharmacology 1998, 18, 57. tamine analog and growing health-care concern. Clin. Toxicol.
[150] J. Kornhuber, M. Weller, K. Schoppmeyer, P.J. Riederer. Amantadine 2011, 49, 874.
and memantine are NMDA receptor antagonists with neuroprotective [176] EMCDDA. Brieng paper: Online sales of new psychoactive sub-
631
properties. J. Neural Transm. Suppl. 1994, 43, 91. stances/ legal highs: Summary of results from the 2011
Drug Testing
multilingual snapshots. Available at: http://www.emcdda.europa. [193] N.M. Gray, B.K. Cheng. Preparation of 1,2-diarylethylamines for
eu/publications/scientic-studies/2011/snapshot [7 January 2014]. treatment of neurotoxic injury. EU Patent No. EP346791A1, 1989.
[177] Ofcial benzo fury. MXE pellets. Available at: http://www. [194] M.O. Kwon, F. Fischer, M. Matthisson, P. Herrling. List of drugs in
ofcialbenzofury.com/products/MXE-Pellets.html# [7 January 2014]. development for neurodegenerative diseases. Neurodegener. Dis.
[178] D.M. Wood, S. Davies, A. Calapis, J. Ramsey, P.I. Dargan. Novel 2004, 1, 113.
drugsnovel branding. QJM 2012, 105, 1125. [195] UK Chemical Research. Diphenidine - 1,2-diphenylethylpiperidine. Avail-
[179] D.M. Wood, S. Davies, M. Puchnarewicz, A. Johnston, P.I. Dargan. able at: http://www.ukchemicalresearch.org/Thread-Diphenidine-
Acute toxicity associated with the recreational use of the ketamine 1-2-diphenylethylpiperidine?pid=47802#pid47802 [7 January 2014].
derivative methoxetamine. Eur. J. Clin. Pharmacol. 2012, 68, 853. [196] Bluelight. The big & dandy diphenidine [1-(1,2-diphenylethyl)piperi-
[180] J.E. Shields, P.I. Dargan, D.M. Wood, M. Puchnarewicz, S. Davies, dine] thread. Available at: http://www.bluelight.ru/vb/threads/
W.S. Waring. Methoxetamine associated reversible cerebellar toxicity: 668291-The-Big-amp-Dandy-Diphenidine-1-%281-2-diphenylethyl
Three cases with analytical conrmation. Clin. Toxicol. 2012, 50, 438. %29piperidine-Thread [7 January 2014].
[181] K.E. Hofer, B. Grager, D.M. Mller, C. Rauber-Lthy, H. Kupferschmidt, [197] Bluelight. The big & dandy methoxphenidine (2-MeO-Diphenidine)
K.M. Rentsch, A. Ceschi. Ketamine-like effects after recreational use of thread. Available at: http://www.bluelight.ru/vb/threads/700834-
methoxetamine. Ann. Emerg. Med. 2012, 60, 97. The-Small-amp-Handy-Methoxphenidine-%282-MeO-Diphenidine
[182] D.M. Wood, D.T. Yew, W.P. Lam, P.I Dargan. Chronic %29-Thread [7 January 2014].
methoxetamine exposure in a mouse model demonstrates that [198] UK Chemical Research. Methoxphenidine 1-(1-(2-methoxyphenyl)-2-
methoxetamine is not a bladder friendly alternative to keta- phenylethyl)piperidine. Available at: http://www.ukchemicalresearch.
mine. Clin. Toxicol. 2012, 50, 574. org/Thread-Methoxphenidine-1-1-2-methoxyphenyl-2-phenylethyl-
[183] EMCDDA. 2012 Annual report on the state of the drugs problem in piperidine [7 January 2014].
Europe. Available at: http://www.emcdda.europa.eu/publications/ [199] H. Fujimura, K. Kawai. Pharmacological studies on diphenylalkylamine
annual-report/2012 [7 January 2014]. derivatives.(I). Bull. Inst. Chem. Res. Kyoto Univ. 1961, 39, 67.
[184] ACMD. Methoxetamine report. Available at: https://www.gov.uk/ [200] R.L. Balster, G.E. Bigelow. Guidelines and methodological reviews
government/uploads/system/uploads/attachment_data/le/119087/ concerning drug abuse liability assessment. Drug Alcohol Depend.
methoxetamine2012.pdf [7 January 2014]. 2003, 70, S13.
[185] EMCDDA. EMCDDAEuropol 2012 Annual Report on the Implemen- [201] K. Schoedel, E. Sellers. Assessing abuse liability during drug devel-
tation of Council Decision 2005/387/JHA (New drugs in Europe, opment: Changing standards and expectations. Clin. Pharmacol.
2012). Available at: http://www.emcdda.europa.eu/publications/ Ther. 2008, 83, 622.
implementation-reports/2012 [7 January 2014]. [202] R.H. Schwartz. Adolescent abuse of dextromethorphan. Clin.
[186] J. Wallach, G.D. Paoli, A. Adejare, S.D. Brandt. Preparation and analytical Pediatr. 2005, 44, 565.
characterization of 1-(1-phenylcyclohexyl) piperidine (PCP) and 1-(1- [203] C.J. Cording, R. DeLuca, T. Camporese, E. Spratt. A fatality related to
phenylcyclohexyl) pyrrolidine (PCPy) analogues. Drug Test. Anal. the veterinary anesthetic telazol. J. Anal.Toxicol. 1999, 23, 552.
2013, [epub ahead of print] [204] M.T. Quail, P. Weimersheimer, A.D. Woolf, B. Magnani. Abuse of
[187] Bluelight. The Small & Handy 3-HO-PCP Thread. Available at: http:// telazol: An animal tranquilizer. Clin. Toxicol. 2001, 39, 399.
www.bluelight.ru/vb/threads/647596-The-Small-amp-Handy-3-HO- [205] M. Klein, S. Calderon, B. Hayes. Abuse liability assessment of
PCP-Thread [7 January 2014]. neuroprotectants. Ann. N.Y. Acad. Sci. 1999, 890, 515.
[188] Flashback. 3-OH-PCP (3-[1-(1-piperidyl)cyclohexyl]phenol). Avail- [206] M.A. Javors, C.K. Erikson, W.M. Morgan. Addiction Potential of
able at: https://www.ashback.org/t2100084 [7 November 2013]. Abused Drugs and Drug Classes. Haworth Press, New York, 1990.
[189] C.L. Stevens. Aminotones et leurs procds de prparation. Patent [207] M. Muzet, P. DArbigny, R. Luthringer, M. Jhanwar-Uniyal, P.H.
No. 634208, 1963. Boeijinga, J.M. Andrieux, J.P. Macher. Effects of gacyclidine, a non-
[190] Bluelight. Limitbreaker. (N-ethylnorketamine) - above methoxetamine competitive NMDA receptor antagonist, in human healthy volun-
means godlike for me. Available at: http://www.bluelight.ru/vb/ teers. Soc. Neurosci. Abstr. 1999, 25, 1090.
threads/636582-%28N-ethylnorketamine%29-Above-methoxetamine- [208] M. Coppola, R. Mondola. Methoxetamine: From drug of abuse to
means-godlike-for-me [7 November 2013]. rapid-acting antidepressant. Med. Hypotheses. 2012, 79, 504.
[191] E. Christian. Reaction of organo-magnesium compounds on -amino [209] M. Coppola, R. Mondola. Is methoxydine a new rapid acting antide-
nitriles. Bull. Soc. Chim. Belg. 1924, 33, 483. pressant for the treatment of depression in alcoholics? Med.
[192] M.L. Berger, A. Schweifer, P. Rebernik, F. Hammerschmidt. NMDA re- Hypotheses. 2013, 81, 10.
ceptor afnities of 1, 2-diphenylethylamine and 1-(1, 2-diphenylethyl) [210] A. Kalir. Structure activity relationships of phencyclidine deriva-
piperidine enantiomers and of related compounds. Bioorg. Med. tives, in PCP (phencyclidine): historical and current perspectives.
Chem. 2009, 17, 3456. (Eds: E. Domino). NPP Books: Michigan, 1981, pp. 3146.
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Drug Testing

Review and Analysis

(www.drugtestinganalysis.com) DOI 10.1002/dta.1620

From PCP to MXE: a comprehensive review of

Introduction addictive activity.[8] Despite limitations, the number of potential

Herein we present the rst comprehensive review of non-medically

Arylcyclohexylamines genesis: serendipitous

additional verication. Pharmacological evaluation established ketamine as a short-acting

Table 1. IUPAC chemical nomenclature and common abbreviations

entered Schedule I of the US CSA on 25 October 1978.[64] Sched- Arylcyclohexylalkyoxyamines

scheduled by the US CSA. imine route in Figure 4.

to humans. gic tryptamines and phenethylamines, and the only dissociatives

Figure 5. Research chemical anisylarylcyclohexylamines and aryl-amino-cyclohexan-2-ones.

10255t.htm [7 January 2014]. Der Nervenarzt. 1964, 35, 412.

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