Synthetic Cannabinoid-Related Illnesses and Deaths

Abstract

Use of synthetic cannabinoids (SCs) in the United States is increasing, as are clusters of cases of serious adverse health effects, including death. Though SC intoxication can be difficult to identify, some steps can be taken to respond more quickly to future outbreaks.

Full text

n engl j med 373;2 nejm.org july 9, 2015
PERSPECTIVE
103
the legislation provided no new
resources, no new authority for
postmarketing safety, and little
new flexibility for the agency in
the review process.
Soon after the law’s passage,
the FDA released a proposed de-
cision to reject all eight pending
ingredients, citing multiple gaps
in data, including key safety stud-
ies and reports of adverse events
in countries where relevant prod-
ucts are marketed.
The agency’s proposal provoked
a swift and angry response. In a
press release, the PASS coalition
stated that the agency “demon-
strates clear disregard for in-
creased rates of melanoma and
the public’s demand for latest
sunscreen technology.”
3
The Wall
Stree t Journal editori-
al board stated that
“the agency’s will-
ful culture of con-
trol and delay is the real public-
health menace. . . . The only
solution is to strip the sunscreen
police of all powers over the
stuff.”
4
These attacks missed their
mark. It’s no surprise that the
FDA would act cautiously given
the scientific advice it’s received
and a legal structure that essen-
tially provides it with just one tool:
authorizing extensive marketing
of multiple products and formu-
lations. Understanding the FDA
means recognizing that the frame-
work for over-the-counter prod-
ucts is not designed to promote
innovation, even innovation with
potential public health benefits.
In my view, Congress should
try again and pass legislation es-
tablishing an alternative approval
pathway that combines the flexi-
bility of the new drug pathway
with the ability to simultaneously
approve multiple formulations and
concentrations. The FDA should
be able to negotiate with spon-
sors to get the right data without
years of rulemaking, establish
postmarketing data requirements,
consult with other countries’
regulators to establish consistent
standards where possible, and
move quickly in the event that
safety concerns emerge. Con-
gress should provide additional
resources to facilitate timely
analysis and review. That this
path is viable is evidenced by the
fact that the one approval of a
product with a new sunscreen in-
gredient in the past decade came
through the new drug pathway.
More timely and flexible review
can expand sunscreen options for
consumers and complement other
measures to reduce melanoma
prevalence. Promising steps in-
clude FDA efforts to discourage
use of tanning beds and initia-
tives by the Centers for Disease
Control and Prevention to pro-
mote prevention measures. The
federal government should also
reconsider whether it makes sense
to continue allowing some prod-
ucts to be marketed as sunscreen
without evidence of protection
against cancer. After all, the ulti-
mate goal is to make meaning-
ful progress against this public
health problem.
Disclosure forms provided by the author
are available with the full text of this article
at NEJM.org.
From the Johns Hopkins Bloomberg School
of Public Health, Baltimore.
1. National Cancer Institute. A snapshot
of melanoma (http://www.cancer.gov/
researchandfunding/snapshots/melanoma).
2. Tucker ME. FDA advisory panel calls for
sunscreen safety testing. Medscape Medi-
cal News. September 8, 2014 (http://www
.medscape.com/viewarticle/831359).
3. Public Access to SunScreens Coalition
(PASS). FDA’s announcement on ecamsule
and enzacamene applications demonstrates
clear disregard for increased rates of mela-
noma, public’s demand for latest sunscreen
technology. February 24, 2015 (http://www
.passcoalition.com/index.php/media-info/
173-fda-s-announcement-on-ecamsule-and
-enzacamene-applications-demonstrates
-clear-disregard-for-increased-rates-of
-melanoma-public-s-demand-for-latest
-sunscreen-technology).
4. Washington’s skin cancer hostages: the
FDA is defying Congress and Obama on
better sunscreens. Wall Street Journal.
March 13, 2015 (http://www.wsj.com/articles/
washingtons-skin-cancer-hostages
-1426287044).
DOI: 10.1056/NEJMp1504912
Copyright © 2015 Massachusetts Medical Society.
A Spotlight on Sunscreen Regulation
Synthetic Cannabinoid–Related Illnesses and Deaths
Jordan Trecki, Ph.D., Roy R. Gerona, Ph.D., and Michael D. Schwartz, M.D., M.P.H.
S
ynthetic cannabinoids (SCs)
were first created in the 1980s
as laboratory research tools (lig-
ands) for studying human endo-
cannabinoid receptor systems.
SC-containing products supplied
by illicit manufacturers were then
marketed throughout Europe as
herbal incense, before arriving
in the United States in Novem-
ber 2008. The prevalence and
variety of SCs on the illicit mar-
ket have steadily increased over
the past 6 years, as manufactur-
ers and distributors of SCs and
dealers of SC-containing prod-
ucts have attempted to circumvent
federal, state, and local laws.
An audio interview
with Dr. Sharfstein
is available at NEJM.org

PERSPECTIVE
n engl j med 373;2 nejm.org july 9, 2015
104
Since 2011, through actions on
four separate occasions, the U.S.
Drug Enforcement Administra-
tion (DEA) has placed a total of
15 SCs in Schedule I of the Con-
trolled Substances Act (CSA). In
2012 the Synthetic Drug Abuse
Prevention Act permanently placed
26 synthetic compounds including
10 additional SCs in Schedule I.
States have taken similar actions
to regulate SCs, yet manufactur-
ers continue to rapidly synthesize
new compounds that fall outside
such regulations.
After being shipped to the
United States from foreign chem-
ical suppliers, the psychoactive
substances are typically either
mixed with plant material, dis-
solved in liquid and then applied
to plant material, dissolved in
liquid for use in e-cigarettes, or
dissolved in liquid that users can
ingest or mix with another sub-
stance (such as energy drinks or
tobacco) and consume. SC-con-
taining products are sold in var-
ied packaging, from nondescript
plastic baggies to colorfully la-
beled packets containing intrigu-
ing brand names and claims such
as “legal alternative to marijuana”
and “legal high.”
1,2
The products
are distributed for sale in gas sta-
tions, convenience stores, or head
shops or through Internet vendors.
Despite warnings (“not for hu-
man consumption”) and reassur-
ances (“does not contain [any reg-
ulated] compounds”) on packages,
widespread recreational use of
these products by a broad demo-
graphic, but particularly by
younger and inexperienced users,
has led to multiple clusters of cas-
es of adverse health effects and
deaths.
1,2
As reported in the table,
Synthetic Cannabinoid–Related Illnesses and Deaths
Clusters of Cases of Adverse Health Effects or Severe Toxic Effects and Deaths Associated
with Synthetic Cannabinoid (SC) Product Use.*
Location Date No. of
Cases
No. of Cases
Resulting in
Death Substance Identified
Clusters of illness involving SCs
Casper, WY March 2012 4 0 XLR11†
Portland, OR May–Oct. 2012 6 0 XLR11†
Brunswick, GA Aug.–Sept. 2013 22 0 ADB-PINACA†
Denver, CO Aug.–Sept. 2013 >220 0 ADB-PINACA
Austin, TX May 2014 >20 0 XLR11, AB-FUBINACA‡
Dallas, TX May 2014 >100 0 XLR11, AB-FUBINACA‡
Gainesville, FL May–June 2014 >29 0 AB-CHMINACA†
St. Louis, MO Aug. 2014 3 0 AB-CHMINACA, AB-PINACA
Manchester, NH Aug. 2014 >44 0 AM2201 N-(3-chloropentyl)
isomer, AB-PINACA,
ADB-PINACA, UR-144†
Fort Wayne, IN Aug. 2014 7 0 AB-CHMINACA
Westland, MI Sept. 2014 6 0 AB-PINACA
Baton Rouge, LA Oct. 2014 >120 0 MAB-CHMINACA
Bryan, TX Nov. 2014 >41 2 MAB-CHMINACA†
Beaumont, TX Dec. 2014–Jan. 2015 >62 0 MAB-CHMINACA, AB-PINACA,
ADB-PINACA‡
Salina, KS Dec. 2014–Jan. 2015 3 0 MAB-CHMINACA†
Santa Ana, CA Jan. 2015 >40 0 JWH-122, MAM-2201
Middletown, CT Feb. 2015 11 0 AB-FUBINACA
Austin, TX April 2015 4 0 AB-CHMINACA†
Philadelphia, MS April 2015 6 0 MAB-CHMINACA†
Hampton, VA April 2015 7 0 MAB-CHMINACA†
Hagerstown, MD April 2015 9 0 MAB-CHMINACA†
Jackson, MS April 2015 19 0 MAB-CHMINACA†

n engl j med 373;2 nejm.org july 9, 2015
PERSPECTIVE
105
Synthetic Cannabinoid–Related Illnesses and Deaths
deaths from SC use have ranged
from 13 to 56 years of age (seven
were 13 to 19 years of age; five, 20
to 29; three, 30 to 39; three, 40 to
49; and two, 50 to 56).
A recent study examined the
prevalence and motives for SC
use among patients undergoing
treatment for substance use dis-
(Continued.)
Location Date No. of
Cases
No. of Cases
Resulting in
Death Substance Identified
Additional cases of severe toxic effects involving SCs
Washington County, AR Aug. 2011 1 1 AM2201
Anderson, SC Oct. 2011 1 1 JWH-018
Athens, GA Feb. 2012 1 1 AM2201, JWH-122, JWH-210
Fayetteville, GA March 2012 1 1 AM2201
Benton County, MN Dec. 2012 1 1 UR-144, XLR11
Oakland, CA April 2013 1 0 XLR11
Davenport, IA July 2013 1 1 5F-PB-22
Aurora, CO Aug. 2013 1 1 AB-FUBINACA
Waverly, NE Oct. 2013 1 1 5F-PB-22
Lafayette, LA April 2014 1 1 AB-CHMINACA
Bay Minette, AL April 2014 1 1 AB-CHMINACA
Baton Rouge, LA May 2014 1 1 ADB-FUBINACA
Corvallis, OR May 2014 1 1 AB-CHMINACA†
New Orleans, LA June 2014 1 0 AB-CHMINACA†
Irving, TX June 2014 1 0 AB-CHMINACA†
Atlantic City, NJ June 2014 2 0 AB-FUBINACA, AB-PINACA
Newport Beach, CA July 2014 1 1 AB-CHMINACA
Shreveport, LA July 2014 1 0 AB-CHMINACA†
Austin, TX Aug. 2014 1 1 THJ-2201, AB-PINACA†
Holdrege, NE Oct. 2014 1 0 AB-PINACA†
Austin, TX Oct. 2014 1 1 AB-CHMINACA, AB-PINACA,
ADB-PINACA
MAB-CHMINACA†
Springfield, MO Nov. 2014 1 1 AB-CHMINACA†
Salina, KS Dec. 2014 2 0 MAB-CHMINACA†
Boyle, KY Jan. 2015 1 1 AB-CHMINACA
Killeen, TX Jan. 2015 1 1 AB-CHMINACA, AKB48, XLR11
* SC compounds were identified on the basis of analysis of clinical samples from patients, when available. 5F-PB-22 denotes
1-(5-fluoropentyl)-1H-indole-3-carboxylic acid 8-quinolinyl ester, AB-CHMINACA N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-
(cyclohexylmethyl)-1H-indazole-3-carboxamide, AB-FUBINACA N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-
indazole-3-carboxamide, AB-PINACA N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide, ADB-FUBINACA
N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide, ADB-PINACA N-(1-amino-3,3-dimethyl-
1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide, AKB48 N-(1-adamantyl)-1-pentyl-1H-indazole-3-carboxamide, AM2201
1-(5-fluoropentyl)-3-(1-naphthoyl)indole, AM2201 N-(3-chloropentyl) isomer, (1-(3-chloropentyl)-1H-indol-3-yl)(naphthalen-
1-yl)methanone, JWH-018 1-pentyl-3-(1-naphthoyl)indole, JWH-122 1-pentyl-3-(4-methyl-1-naphthoyl)indole, JWH-210 1-pentyl-
3-(4-ethyl-1-naphthoyl)indole, MAB-CHMINACA N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(cyclohexylmethyl)-1H-indazole-3-
carboxamide, MAM-2201 1-(5-fluoropentyl)-4-methyl-3-(1-naphthoyl)indole, THJ-2201 (1-[5-fluoropentyl]-1H
-indazol-3-yl)(naph-
thalene-1-yl)methanone, UR-144 1-pentyl-3-(2,2,3,3-tetramethycyclopropoyl)indole, and XLR11 1-(5-fluoro-pentyl)-3-(2,2,3,3-tetra-
methylcyclopropoyl)indole.
† Substance identified by the Clinical Toxicology and Environmental Biomonitoring Laboratory, University of California, San Francisco.
‡ Substance identified on the basis of information about local law-enforcement seizures during the same period.

PERSPECTIVE
n engl j med 373;2 nejm.org july 9, 2015
106
order. Some 38% of these pa-
tients reported using an SC, most
commonly by smoking (91%); 27%
also took SCs by other methods,
including using a vaporizer and
e-cigarettes. Cited motives for
use included curiosity or experi-
mentation (91%) and a desire to
feel good or get high (89%), to
relax (71%), and to get high
without risking a positive drug
test (71%).
3
SC use has repeatedly been re-
ported to produce serious adverse
health effects, including but not
limited to excited delirium, acute
kidney injury, seizures, psychosis,
hallucinations, cardiotoxic effects,
coma, and death — with some
users dying before they could
reach an emergency department.
1,2
Unlike opioid drugs such as heroin
and morphine, SCs have no avail-
able antidote, and treatment of
the often unpredictable and severe
adverse health effects is largely
supportive. Moreover, there is no
clear toxidrome that signals the
cause of intoxication in someone
without a history of SC-product
use. Severe signs and symptoms
exhibited in users are also com-
monly seen with many other
classes of recreational stimulant
or hallucinogenic drugs.
Adding to the challenge of
recognizing SC intoxication is
the lack of rapid laboratory tests
to confirm exposure. SCs are not
detected by routine urine im-
munoassay screens for drugs of
abuse, and confirmatory clinical
testing is available only through
sophisticated analysis at reference
or research laboratories. When a
new SC is encountered on the il-
licit market, the compound must
first be identified, through either
testing of products seized by
police or laboratory analysis of
clinical samples from an intoxi-
cated person. After preliminary
identification of a potentially new
compound, an analytical standard
must be synthesized to confirm
the presence of the new SC by re-
peated analysis. If the compound
was previously unknown, collab-
oration between a legitimate
manufacturer of the analytical
standard and the toxicology lab-
oratory analyzing the clinical
samples may identify predicted
metabolites. If these putative me-
tabolites are synthesized as ana-
lytical standards, reanalysis of
biologic samples from patients
in a cluster of SC-associated ill-
ness may provide a means of de-
termining which predicted me-
tabolites are valid targets for
analysis in subsequent cases.
Once both the parent com-
pound and metabolites have been
identified, it takes time for other
toxicology reference laboratories
to obtain the standards and vali-
date their own analytical meth-
ods. Thus, many months may
elapse before confirmatory test-
ing for the new compound is
widely available. By that time,
clandestine illicit laboratories have
moved on to a newer compound.
As a result, cases of SC intoxica-
tion, fatalities from SC misuse,
and outbreaks of severe illness
associated with new or particu-
larly toxic compounds are most
likely underrecognized.
1,2
As the table documents, we
have recently observed an increase
in the incidence of clusters of SC
intoxication resulting in severe ill-
ness and death. (The information
presented here does not represent
all SC-associated cases of severe
toxic effects.) In the past, such
clusters occurred less frequently:
multiple cases of acute kidney
injury in SC users occurred in
Wyoming and Oregon in 2012,
after use of products containing
XLR-11.
4
The following year, two
outbreaks of agitated delirium
linked to the same previously
unknown SC (ADB-PINACA) and
product (“Crazy Clown” or “10X”)
occurred in Brunswick, Georgia,
and Denver
2
; and Gainesville,
Florida, saw a large outbreak in
May 2014, linked to the novel
compound AB-CHMINACA. After
the Florida outbreak, we identified
a trend of a rapidly increasing
number and size of clusters
throughout 2014 and into 2015.
Between mid-March and May
2015, an unprecedented outbreak
resulting from SC use affected at
least 12 states.
5
The Mississippi
State Department of Health re-
ported more than 1200 SC-related
emergency visits and 17 deaths po-
tentially related to SC use during
this period, while the Alabama
Department of Public Health re-
ported more than 1000 such emer-
gency visits and 5 such deaths.
Possible explanations for this
trend include better reporting of
suspected clusters by health care
facilities and local public health
entities, enhanced media atten-
tion to and reporting of recre-
ational-drug-associated clusters of
illness, and improved collabora-
tion between public health and
law-enforcement agencies. Alterna-
tively, the increase may be relat-
ed to the SC compounds them-
selves. Whereas we had at least
some pharmacologic and phar-
macokinetic data on earlier gen-
erations of SC compounds from
their use as experimental can-
nabinoid-receptor ligands, more
recent products contain novel
SC compounds that are rapidly
synthesized and marketed in re-
sponse to regulatory actions. These
compounds often have unknown
receptor-binding affinity and se-
lectivity, which may result in un-
expectedly severe or idiosyncratic
toxicity. Individual pharmacoge-
Synthetic Cannabinoid–Related Illnesses and Deaths

n engl j med 373;2 nejm.org july 9, 2015
PERSPECTIVE
107
Synthetic Cannabinoid–Related Illnesses and Deaths
netic differences among users
may affect the length of time
that the active form of the drug
remains in the body and at what
concentration. Illicit manufac-
turing of SC compounds or SC-
containing products may lead to
the presence of impurities, con-
taminants, or variability in SC
content within products.
Challenges to defining the
scope of the public health threat
posed by SCs include underre-
porting by clinicians and public
health practitioners, limited avail-
ability of laboratory testing to
confirm exposures, delays in the
availability of analytical labora-
tory standards for the newest
compounds, and frequent product
changes. To address these chal-
lenges, clusters of adverse health
effects potentially related to SC-
product use can be reported to
either local poison centers or lo-
cal public health departments.
Cases of severe SC intoxication,
unusual toxic effects, death, or
multiple patients presenting with
SC intoxication clustered in time
and space may reflect the appear-
ance of a novel SC compound or
toxicity of a contaminated or poor-
ly manufactured product; rapid
identification of these events will
allow public health officials to
better support local practitioners.
Collaboration between forensic
and toxicology laboratories and
legitimate suppliers of analytical
standards may result in better
preparation and a more timely
response to future outbreaks. In-
creased recognition and report-
ing by clinicians and public
health personnel may aid feder-
al and state regulatory efforts in
combating this ongoing SC epi-
demic.
The findings and conclusions in this arti-
cle are those of the authors and do not
necessarily represent the views of the Cen-
ters for Disease Control and Prevention, the
Agency for Toxic Substances and Disease
Registry, the Department of Health and
Human Services, the Drug Enforcement
Administration, the Department of Justice,
or any other office of the U.S. government.
Disclosure forms provided by the authors
are available with the full text of this article
at NEJM.org.
From the Office of Diversion Control, Drug
and Chemical Evaluation Section, Drug En-
forcement Administration, Springfield, VA
(J.T.); the Department of Laborator y Medi-
cine, University of California, San Francis-
co, San Francisco (R.R.G.); and the National
Center for Environmental Health, Centers
for Disease Control and Prevention, Atlanta
(M.D.S.).
1. van Amsterdam J, Brunt T, van den Brink
W. The adverse health effects of synthetic
cannabinoids with emphasis on psychosis-
like effects. J Psychopharmacol 2015;29:254-
63.
2. Schwartz MD, Trecki J, Edison LA, Steck
AR, Arnold JK, Gerona RR. A common source
outbreak of severe delirium associated with
exposure to the novel synthetic cannabinoid
ADB-PINACA. J Emerg Med 2015;48:573-80.
3. Bonar EE, Ashrafioun L, Ilgen MA. Syn-
thetic cannabinoid use among patients in
residential substance use disorder treat-
ment: prevalence, motives, and correlates.
Drug Alcohol Depend 2014;143:268-71.
4. Acute kidney injury associated with syn-
thetic cannabinoid use — multiple states,
2012. MMWR Morb Mortal Wkly Rep 2013;
62:93-8.
5. Notes from the field: increase in reported
adverse health effects related to synthetic
cannabinoid use — United States, January–
May 2015. MMWR Morb Mortal Wkly Rep
2015;64:618-9.
DOI: 10.1056NEJMp1505328
Copyright © 2015 Massachusetts Medical Society.
BECOMING A PHYSICIAN
Breaking Up Is Hard to Do
Geoffrey A. Rubin, M.D.
“I
t’s not you — it’s me.”
I blushed in bewilderment
at hearing myself say it. The con-
versation leading up to it had
been jumbled and unintentionally
hurtful to both parties. I had
been totally unprepared. After
20 more minutes and a packet
of tissues, the encounter ended.
It was not productive.
But the breakup aftermath
didn’t involve untagging of Face-
book photos, remorseful late-night
text messages, or venting sessions
with friends. Instead, it meant
the end of faxing recertifications
for the visiting nurse service and
refilling prescriptions: I was end-
ing a relationship not with a girl-
friend but with a patient from
my resident internal medicine
clinic.
Despite all the oversight of
today’s residents — the electronic
fail-safes and hard stops, the hour
logging, the quality-improvement
committees, the personal advisor
meetings — a key aspect of resi-
dency has been largely over-
looked: ending it. In medical
school, we do subinternships to
prepare for the start of clinical
training. As interns, we perform
procedures and run treatment
plans with supervision to solidify
our skills. But we receive little
guidance on leaving residency.
One of the oddest aspects of
concluding residency is the obliga-
tory termination of all our patient
relationships. Just when these re-
lationships are comfortably estab-
lished, most residents at academic
medical centers break ties and
pursue career development —