The n e w e ng l a n d j o u r na l of m e dic i n e
2. Ollech JE, Shen NT, Crawford CV, Ringel Y. Use of probiotics the Food and Drug Administration (FDA) for this
in prevention and treatment of patients with Clostridium diffi
cile infection. Best Pract Res Clin Gastroenterol 2016;30:111-8.
3. Vernaya M, McAdam J, Hampton MD. Effectiveness of probiot
ics in reducing the incidence of Clostridium difficile-associated
diarrhea in elderly patients: a systematic review. JBI Database
System Rev Implement Rep 2017;15:140-64.
4. Allen SJ, Wareham K, Wang D, et al. Lactobacilli and bifido
bacteria in the prevention of antibiotic-associated diarrhoea and
Clostridium difficile diarrhoea in older inpatients (PLACIDE):
a randomised, double-blind, placebo-controlled, multicentre trial.
Lancet 2013;382:1249-57.
5. Golan YDE, Hanson ME, Liao J, et al. Bezlotoxumab (BZO)
decreases recurrence and is associated with a reduction in 30-day
Clostridium difficile infection (CDI)-associated readmissions in
hospitalized patients with CDI. Presented at ASM MICROBE
2016, Boston, June 1620, 2016.
DOI: 10.1056/NEJMc1702531
The editorialist replies: Probiotics were not in
cluded in my editorial because evidence support
ing their use to prevent C. difficile infection seemed
inadequate. Admittedly, there are some controlled
trials that support the use of probiotics,1 but others
show no significant benefit.2 A review of guide
lines for the management of C. difficile infection
from five international societies shows that either
they have not endorsed the use of probiotics for
this purpose or they have failed to address probi
otics in their recommendations.3 To my knowl
edge, none of these agents have been approved by
Zombie Outbreak Caused by Synthetic Cannabinoid
To the Editor: Adams et al. (Jan. 19 issue)1 de
scribe an outbreak of synthetic cannabinoid
AMB-FUBINACA intoxication that was identified
with the use of a new approach that involved pre
dicting and synthesizing analytical standards
of possible cannabinoid analogues before their
emergence in markets.1,2 This method is effective
for detecting new synthetic drugs that have never
been reported. However, since there are numer
ous potential derivatives for every illicit drug,
characterizing them fully in clinical laboratories
is impractical.
All the synthetic cannabinoids that the au
thors mention contain structural motifs of their
raw materials, indole or indazole. Because there
are no indole or indazole rings in common psy
choactive substances such as amphetamines, co
caine, and tetrahydrocannabinol, the presence of
fragment ions of indole and indazole derivatives
1596 n engl j med 376;16nejm.org April 20, 2017
The New England Journal of Medicine
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Copyright 2017 Massachusetts Medical Society. All rights reserved.
indication. Thus, there appears to be a lack of
convincing and consistent support from trials,
C. difficile infection guidelines from five learned
societies, or FDA reviews. Note that this does not
mean that they do not work only that this
recommendation needs better and more consis
tent evidence for support. Also worrisome is the
fact that probiotics is a broad term that in
cludes many different products that may differ
substantially in their results, making product
specificity a likely need.
JohnG. Bartlett, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD
Since publication of his article, the author reports no further
potential conflict of interest.
1. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics
in hospitalized adults prevents Clostridium difficile infection:
a systematic review with meta-regression analysis. Gastroenter
ology 2017 February 9 (Epub ahead of print).
2. Vernaya M, McAdam J, Hampton MD. Effectiveness of probi
otics in reducing the incidence of Clostridium difficile-associated
diarrhea in elderly patients: a systematic review. JBI Database
System Rev Implement Rep 2017;15:140-64.
3. Fehr C, Mensa J. Comparison of current guidelines of five
international societies on Clostridium difficile infection manage
ment. Infect Dis Ther 2016;5:207-30.
DOI: 10.1056/NEJMc1702531
(e.g., C9H6NO+ and C8H5N2O+) might make mass
spectrometry a suitable qualitative screening test
for AMB-FUBINACA and other new synthetic can
nabinoids.3-5 After qualitative screening of spe
cific motif fragment ions in clinical laboratories,
the results could be confirmed in reference labo
ratories by the approach presented by Adams et al.
FengShuo Yang, M.D.
ChaoJu Chen, M.D.
Kaohsiung Medical University Hospital
Kaohsiung, Taiwan
YiChing Lin, M.D.
Kaohsiung Medical University
Kaohsiung, Taiwan
No potential conflict of interest relevant to this letter was re
ported.
1. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M,
Gerona R. Zombie outbreak caused by the synthetic canna
binoid AMB-FUBINACA in New York. N Engl J Med 2017;376:
235-42.
 Correspondence
2. Emery G. New York zombie outbreak shows value of
redicting future designer drugs. Reuters. December 14, 2016
p
(http://uk.reuters.com/article/us-health-chemistry-designer-drugs
-idUKKBN1432WR).
3. Banister SD, Longworth M, Kevin R, et al. Pharmacology of
valinate and tert-leucinate synthetic cannabinoids 5F-AMBICA,
5F-AMB, 5F-ADB, AMB-FUBINACA, MDMB-FUBINACA, MDMB-
CHMICA, and their analogues. ACS Chem Neurosci 2016;7:1241-
54.
4. Akamatsu S, Yoshida M. Fragmentation of synthetic canna
binoids with an isopropyl group or a tert-butyl group ionized by
electron impact and electrospray. J Mass Spectrom 2016;51:28-32.
5. Umebachi R, Saito T, Aoki H, et al. Detection of synthetic
cannabinoids using GC-EI-MS, positive GC-CI-MS, and negative
GC-CI-MS. Int J Legal Med 2017;131:143-52.
DOI: 10.1056/NEJMc1701936
To the Editor: Adams et al. describe the close
collaboration between clinicians and public
agencies to detect the causative agent of a mass
intoxication in New York City. The patients they
reported on had psychomotor slowing, intermit
tent groaning, and a blank stare as signs of de
pression of the central nervous system. This find
ing emphasizes that the so-called Spice drugs are
not harmless herbal blends,1 especially when
very-high-potency compounds are developed by
clandestine chemists to replace banned cannabi
noids.2 As a consequence, many different psycho
active synthetic cannabinoids might appear on
the market,3 and it seems virtually impossible for
a clinician to determine what an individual pa
tient actually ingested. How should the informa
tion provided in this article guide physicians deal
ing with a patient with acute psychiatric symptoms
when intoxication with synthetic cannabinoids is
suspected?
Ion Anghelescu, M.D.
Klinik Dr. Fontheim
Liebenburg, Germany
No potential conflict of interest relevant to this letter was re
ported.
1. Seely KA, Lapoint J, Moran JH, Fattore L. Spice drugs are
more than harmless herbal blends: a review of the pharmacol
ogy and toxicology of synthetic cannabinoids. Prog Neuropsy
chopharmacol Biol Psychiatry 2012;39:234-43.
2. Brents LK, Prather PL. The K2/Spice phenomenon: emer
gence, identification, legislation and metabolic characteriza
tion of synthetic cannabinoids in herbal incense products. Drug
Metab Rev 2014;46:72-85.
3. Langer N, Lindigkeit R, Schiebel HM, Papke U, Ernst L,
Beuerle T. Identification and quantification of synthetic canna
binoids in spice-like herbal mixtures: update of the German
situation for the spring of 2016. Forensic Sci Int 2016;269:31-
41.
DOI: 10.1056/NEJMc1701936
n engl j med 376;16nejm.org April 20, 2017
The New England Journal of Medicine
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Copyright 2017 Massachusetts Medical Society. All rights reserved.
The authors reply: In our article, we describe a
proactive approach for identifying new synthetic
cannabinoids by implementing a surveillance pro
gram. Although this approach was effective in
responding to a cluster of cases of mass intoxica
tion, we recognize the challenges of its imple
mentation in regular clinical laboratories. First,
our approach requires the expertise of a synthetic
organic chemist, not typically available in a clin
ical laboratory. Second, our system relies on ex
tensive collaborative work with various federal
and state agencies.1 Hence, we expect our ap
proach to be most useful in large surveillance
programs and in partnership with regional satel
lite laboratories. It may not be directly applicable
to single patients with suspected intoxication
with a synthetic cannabinoid.
Presumptive screening for specific structural
motifs that are found in synthetic cannabinoids
is an interesting suggestion. Electron ionization
can generate indole or indazole acylium ions
from indole or indazole carboxamides such as
AMB-FUBINACA, which potentially allows for
the screening of this class of synthetic cannabi
noids by means of gas chromatographymass
spectrometry. However, soft-ionization techniques
that are used in liquid chromatographymass
spectrometry do not necessarily generate indole
or indazole acylium ions in adequate amounts
for detection, which limits the potential of this
approach. Presumptive screening for indole or
indazole ions is similarly impractical, since these
functional groups are not unique to synthetic
cannabinoids. Tryptamines such as LSD and psilo
cybin contain an indole moiety, as do some en
dogenous compounds in the blood, such as sero
tonin and tryptophan. Typical blood serotonin
levels are within the range of concentrations at
which indole or indazole carboxamides or their
metabolites have been detected.2,3 Screening for
these groups would potentially lead to false posi
tive results.
Given the variety of chemical classes of syn
thetic cannabinoids, a range of symptoms has
been reported with intoxication. In the patients
we described, severe central nervous system de
pression in the absence of typical signs of syn
thetic cannabinoid intoxication assisted in the
differential diagnosis. However, these clinical ob
servations inform only this specific syndrome of
synthetic cannabinoid intoxication and may not
1597
 The n e w e ng l a n d j o u r na l of m e dic i n e

be applicable to syndromes produced by other Since publication of their article, the authors report no fur
ther potential conflict of interest.
new psychoactive substances.
Roy Gerona, Ph.D. 1. Trecki J, Gerona RR, Schwartz MD. Synthetic cannabinoid
related illnesses and deaths. N Engl J Med 2015;373:103-7.
Axel Adams, B.S. 2. Weiss LA, Abney M, Cook EH Jr, Ober C. Sex-specific ge
University of California, San Francisco netic architecture of whole blood serotonin levels. Am J Hum
San Francisco, CA Genet 2005;76:33-41.
roy.gerona@ucsf.edu 3. Schwartz MD, Trecki J, Edison LA, Steck AR, Arnold JK,
Gerona RR. A common source outbreak of severe delirium
SamuelD. Banister, Ph.D. associated with exposure to the novel synthetic cannabinoid
Stanford University ADB-PINACA. J Emerg Med 2015;48:573-80.
Stanford, CA DOI: 10.1056/NEJMc1701936

Screening for Colorectal Neoplasia

To the Editor: The Clinical Practice article by
Inadomi (Jan. 12 issue)1 did not mention the
potential role of double-contrast barium enema.
Double-contrast barium enema, sometimes re
ferred to as air-contrast barium enema, involves
the study of the whole colon and rectum after air
and barium have been injected transrectally. Mul
tiple radiographs are obtained with the use of
conventional radiographic equipment. Double-
contrast barium enema can detect most cancers
and clinically significant polyps.2
When double-contrast barium enema is com
bined with flexible sigmoidoscopy, the procedure
has a sensitivity similar to that of colonoscopy
for colorectal cancer screening, although the
detection rate of small polyps is lower.3 Flexible
sigmoidoscopy with double-contrast barium
enema should remain an option for colorectal
cancer screening in patients who are at average
risk for colorectal cancer, particularly in third-
world countries where colonoscopy or computed
tomographic colonography is rarely available for
the general population. It is better than doing
nothing.
Jacobo Dib, Jr., M.D.
Hospital de Lidice
Caracas, Venezuela
dib.j@hotmail.com DNA test (FIT combined with a stool DNA test,
No potential conflict of interest relevant to this letter was re
ported.
1. Inadomi JM. Screening for colorectal neoplasia. N Engl J
Med 2017;376:149-56.
2. Levin B, Lieberman DA, McFarland B, et al. Screening and
surveillance for the early detection of colorectal cancer and ad
enomatous polyps, 2008: a joint guideline from the American
Cancer Society, the US Multi-Society Task Force on Colorectal
Cancer, and the American College of Radiology. CA Cancer J Clin
2008;58:130-60.
3. Leung WC, Foo DC, Chan TT, et al. Alternatives to colonos
copy for population-wide colorectal cancer screening. Hong Kong
Med J 2016;22:70-7.
DOI: 10.1056/NEJMc1702535
To the Editor: The article by Inadomi on
colorectal cancer screening considers a healthy,
previously unscreened, 79-year-old woman. For
persons 76 to 85 years of age, the U.S. Preventive
Services Task Force recommends individualized
screening on the basis of the patients health and
screening history. Inadomi appropriately recom
mends shared decision making; however, the mul
tiple screening options could lead to a lengthy
and complex discussion between the patient and
clinician and prompt the clinician to focus on
tests that are the most appropriate for the pa
tient, particularly ones with high sensitivity that,
if negative, could rule out cancer or advanced pre
cancerous lesions. The options of colonoscopy
and annual fecal immunochemical test (FIT) were
suggested, but an elderly person who has previ
ously avoided screening altogether is unlikely to
adhere to annual testing. The multitarget stool
or FIT-DNA) would seem to be a better option
than FIT, because in a single application it is much
more sensitive for colorectal cancer (92% with
FIT-DNA vs. 73.8% with FIT) and advanced pre
cancerous polyps (42% vs. 23.8%)1 and because
this may be the only opportunity for this patient
to benefit from screening.

1598 n engl j med 376;16nejm.org April 20, 2017

The New England Journal of Medicine

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