Modulation of the Immune System in Cannabis Users [3]

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In Reply: Like Dr Fournier and colleagues, we are uncertain
about the possibility of class-specific differences in clinical
outcomes (such as stroke or myocardial infarction) among
antihypertensive drugs. Although debate continues about
their relative efficacies, thiazide diuretics, ␤-blockers,
angiotensin-converting enzyme inhibitors, angiotensin recep-
tor blockers, and long-acting dihydropyridine calcium chan-
nel blockers have been shown to reduce the risk of stroke.
However, given the results of the recently published ALLHAT
trial
1
and the relative costs of the various agents, we believe
that thiazide diuretics remain the agents of first choice in
hypertensive patients for the primary prevention of cardiovas-
cular and cerebrovascular disease. Furthermore, a meta-
regression of 27 antihypertensive drug trials found that the
reductions in stroke (as well as other cardiovascular end
points) from antihypertensive therapy observed in these trials
could be explained by the achieved differences in SBP.
2
Of
note, this meta-regression included the CAPPP trial that
Fournier et al mention.
Drs Lakshminarayan and Anderson are correct in stating that
the NCEP guidelines define only stroke due to carotid artery
disease as a coronary risk equivalent. Patients with ischemic
stroke of other mechanisms may qualify for treatment on the
basis of other risk factors of absolute LDL levels. We believe
that this is consistent with our statement that patients with docu-
mented symptoms related to vascular atherosclerosis are at high
risk of recurrent events and should be considered eligible for
secondary prevention. Consistent with the estimates of Lak-
shminarayan and Anderson, we recently reported that among
119 consecutive patients with anterior circulation stroke or TIA
evaluated in a stroke prevention clinic, 82% had an LDL cho-
lesterol level higher than 100 mg/dL (2.59 mmol/L).
3
In addi-
tion, 74% of patients had hypertension, 23% had diabetes, and
21% had established coronary artery disease. One year later,
only half of patients had LDL cholesterol levels of 100 mg/dL
(2.59 mmol/L) or less,
3
Until better evidence is available, we
believe that symptomatic atherosclerosis in any vascular bed
should be considered a “coronary equivalent” and managed
as such.
In response to Dr Kirshner, 4 randomized trials provide
information on treatment strategies for the secondary preven-
tion of stroke in survivors of TIA or stroke. One evaluated
warfarin vs placebo (and vs aspirin),
4
2 compared aspirin with
placebo,
5-7
and 1 trial compared adjusted-dose warfarin with
low-dose warfarin plus aspirin (this study was not strictly a
“secondary prevention” trial because almost 40% of the
patients enrolled had already experienced a thromboembolic
event).
8
The data from these trials confirm a substantial ben-
efit with adjusted-dose warfarin and a smaller but still statisti-
cally significant benefit with aspirin, as we described. While
these relative benefits are similar to those seen in the trials
of primary prevention for atrial fibrillation discussed above,
the absolute benefit is substantially higher in patients with
prior TIA or stroke given their markedly higher stroke risk at
baseline.
In response to Drs Gebel and Caplan, the Antiplatelet Tri-
alists
9
concluded that the addition of dipyridamole to aspirin
did not provide any significant benefit over aspirin alone. How-
ever, this may have been due to the wide confidence intervals
rather than to the lack of an effect. The authors did note that a
single randomized trial found that the addition of extended-
release dipyridamole to aspirin decreased the risk of death sig-
nificantly. The results of ongoing trials should provide addi-
tional guidance.
Sharon E. Straus, MD, FRCPC
Department of Medicine
University of Toronto
Toronto, Ontario
Finlay A. McAlister, MD, FRCPC
Sumit R. Majumdar, MD, FRCPC
Division of General Internal Medicine
University of Alberta
Edmonton
1. Major outcomes in high-risk hypertensive patients randomized to angiotensin-
converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihy-
pertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA. 2002;288:2981-2997.
2. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure
reduction: a meta-analysis. Lancet. 2001;358:1305-1315.
3. Mouradian MS, Majumdar SR, Senthilselvan A, et al. How well are hyperten-
sion, hyperlipidemia, diabetes, and smoking managed after a stroke or transient
ischemic attack. Stroke. 2002;33:1656-1659.
4. European Atrial Fibrillation Trial Study Group. Secondary prevention in non-
rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lan-
cet. 1993;342:1255-1262.
5. Diener HC, Cunha L, Forbes C, et al. European Secondary Prevention Study 2:
dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neu-
rol Sci. 1996;143:1-13.
6. Koudstaal PF. Anticoagulation for prevention of stroke in patients with non-
rheumatic atrial fibrillation and history of stroke or transient ischemic attack. In:
Warlow C, Van Gijn J, Sandercock P, eds. Stroke Module of the Cochrane Data-
base of Systematic Reviews. Oxford, England: Cochrane Collaboration; 1999.
7. Benavente O, Hart R, Koudstaal P, Laupacis A, McBride R. Antiplatelet therapy
for preventing stroke in patients with nonvalvular atrial fibrillation and no previ-
ous history of stroke or transient ischemic attacks. In: Warlow C, Van Gijn J, Sand-
ercock P, eds. Stroke Module of the Cochrane Database of Systematic Reviews.
Oxford, England: Cochrane Collaboration; 1999.
8. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin ver-
sus low intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial
fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lan-
cet. 1996;348:633-638.
9. Antiplatelet Trialists’ Collaboration. Collaborative meta-analysis of ran-
domised trials of antiplatelet therapy for prevention of death, myocardial infarc-
tion and stroke in high risk patients. BMJ. 2002;324:71-86.
RESEARCH LETTER
Modulation of the Immune System
in Cannabis Users
To the Editor: In vitro studies and experiments in animal
models have found that cannabinoids modulate immune cell
function.
1
However, investigations of immune effects in
human subjects are scarce and contradictory. Gene expres-
sion of cannabinoid receptors in peripheral blood mono-
nuclear cells may be altered among marijuana users.
2
Experimental data in healthy persons have found abnormali-
ties in T lymphocyte and natural killer (NK) cell function,
LETTERS
©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, April 16, 2003—Vol 289, No. 15 1929

but have not confirmed that these alterations might affect
susceptibility to infections.
3
We sought to investigate cell-
mediated immune response and cytokine release in cannabis
users.
Methods. Participants were recruited by word of mouth and
gave written consent to participate in the study, which was ap-
proved by our institutional ethical committee and conducted
in accordance with the Declaration of Helsinki. Volunteers were
deemed healthy after a full medical history and examination.
They were then interviewed about their recent use of illicit drugs,
and their statements were confirmed by urine testing. A psy-
chiatric screening excluded drug abuse or dependence (ex-
cept for cannabis or nicotine) or psychiatric disorders accord-
ing to criteria of the Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition.
A blood sample was obtained between the hours of 8 and
11
AM to determine blood cell count and differential, lympho-
cyte immunophenotyping, lymphocyte proliferative response
to mitogenic stimulation (stimulation index with phytohemo-
agglutinine [SI-PHA] or concanavaline A [SI-ConA]), and lev-
els of interleukin 2 (IL-2), interleukin 10 (IL-10), and trans-
forming growth factor ␤-1 (TGF␤1), as described previously.
4
Comparisons between cannabis exposure categories were
performed using ␹
2
tests or analysis of variance. Multivariate
linear regression models were fitted for each immune param-
eter to analyze the effects of cannabis consumption after
adjusting for sex, as well as consumption of coffee, tobacco,
and alcohol.
Results. According to total cannabis consumption and fre-
quency of use during the previous 6 months, participants were
classified as controls (n=32), occasional users (eventual to
monthly use, n=13) and regular users (weekly to daily use,
n=16). Sex, tobacco smoking, and alcohol consumption were
unequally distributed between groups (T
ABLE).
Cannabis use was associated with a decrease in NK counts,
lymphocyte proliferative response by SI-PHA and SI-ConA, and
levels of IL-2, and an increase in levels of IL-10 and TGF␤1.
No differences were found in counts of total lymphocytes or
CD4, CD8, and CD19 cells (T
ABLE). The significant effect of
cannabis consumption on immune measures persisted after mul-
tivariate analysis controlling for the possible confounding ef-
fects of sex and use of coffee, tobacco, and alcohol. A signifi-
Table. Group Characteristics and Immune Parameters in Controls and Cannabis Users
Characteristic/Parameter
Cannabis Consumption Group
P Value
*
Controls
(n = 32)
Occasional Users
(n = 13)
Regular Users
(n = 16)
Age, mean (SD), y 22 (3) 21 (1) 23 (2) .18
Sex distribution, No (%)
Male 23 (72) 12 (92) 6 (38) .005
Female 9 (28) 1 (8) 10 (62)
Coffee consumption, No (%)
Daily 15 (47) 8 (61) 11 (69) .32
Occasionally/none 17 (53) 5 (39) 5 (31)
Tobacco smoking, No (%)
Daily 4 (13) 2 (15) 4 (26) .03
Weekly 3 (9) 3 (23) 6 (37)
Occasionally/none 25 (78) 8 (62) 6 (37)
Alcohol consumption, No (%)
Daily 0 0 5 (31) .003
Weekly 23 (72) 11 (85) 9 (56)
Occasionally/none 9 (28) 2 (15) 2 (13)
Immune parameters, mean (SD)
Total lymphocytes, cells/µL 1950 (152) 1901 (141) 1862 (176) .23
CD4 T cells, cells/µL 933 (105) 929 (160) 849 (132) .14
CD8 T cells, cells/µL 548 (98) 574 (159) 538 (116) .72
CD19 B cells, cells/µL 182 (61) 142 (45) 158 (76) .13
NK cells, cells/µL 203 (82) 145 (67) 135 (103) .02
SI-PHA, % 96 (15) 97 (25) 57 (27)†‡ ⬍.001
SI-ConA, % 75 (17) 75 (18) 42 (26)†‡ ⬍.001
IL-2, U/mL 10.6 (3.8) 8.6 (5.4) 5.0 (3.4)† ⬍.001
IL-10, pg/mL 903 (191) 1284 (327)§ 1312 (365)† ⬍.001
TGF␤1, pg/mL 660 (172) 1450 (937)§ 1629 (725)† ⬍.001
Abbreviations: IL-2, interleukin 2; IL-10, interleukin 10; SI-ConA, mitogenic stimulation index by concanavaline A; SI-PHA, mitogenic stimulation index by phytohemagglutinin; TGF␤1,
transforming growth factor ␤-1.
*
From ␹
2
test or analysis of variance.
†Significant difference (P⬍.05) between controls and regular users, by analysis of variance post hoc Tukey multiple paired comparisions.
‡Significant difference (P⬍.05) between occasional users and regular users, by analysis of variance post hoc Tukey multiple paired comparisons.
§Significant difference (P⬍.05) between controls and occasional users, by analysis of variance post hoc Tukey multiple paired comparisons.
LETTERS
1930 JAMA, April 16, 2003—Vol 289, No. 15 (Reprinted) ©2003 American Medical Association. All rights reserved.

cant dose-response relationship was found between cannabis
exposure (total life consumption, as the log-transformed num-
ber of cannabis “joints”) and the decrease in counts of total lym-
phocytes, CD4 or NK cells, and IL-2 levels, or the increase in
IL-10 levels.
Comment. Cannabis use was associated with a decrease in
levels of IL-2, a T
H
1-type cytokine related to cell-mediated immu-
nity, and an increase in levels of IL-10, a T
H
2-type cytokine related
to humoral immunity. The decrease of proinflammatory (IL-2)
cytokines and the augment of anti-inflammatory (IL-10 and
TGF␤1) cytokines was associated with a marked reduction in
lymphocyte functionality, and a decrease in the number of NK
cells. The suppression of immediate and innate responses of
the immune system together with the disruption of T
H
1/T
H
2
balance might increase the susceptibility and promote the
progression of infectious diseases and tumors, although the clini-
cal relevance of these findings has not been clearly demon-
strated in humans.
3,5
It also has been suggested that immuno-
modulatory effects of cannabinoids on inflammatory and
autoimmune disorders could lead to new therapeutic inter-
ventions.
6
Roberta Pacifici, PhD
Piergiorgio Zuccaro, PhD
Simona Pichini, PhD
Laboratorio Biochimica Clinica
Istituto Superiore di Sanita´ (ISS)
Rome, Italy
Pere N. Roset, MD, PhD
Sandra Poudevida, PhD
Magı´ Farre´, MD, PhD
Unit of Pharmacology
Institut Municipal d’Investigacio´Me`dica (IMIM)
Autonomous University of Barcelona
Barcelona, Spain
Jordi Segura, PhD
Rafael de la Torre, PharmD, PhD
Unit of Pharmacology
Institut Municipal d’Investigacio´Me`dica (IMIM)
Pompeu Fabra University
Barcelona
Funding/Support: This study was supported in part by Progetto No. 1 “Area Pro-
getto Droga” from Istituto Superiore di Sanita` , Rome, Italy; Generalitat de Catalu-
nya (2001SGR00407); and Fondo de Investigaciones Sanitarias (FIS-00/00777), Spain.
1. Klein TW, Newton C, Friedman H. Cannabinoids receptors and immunity. Im-
munol Today. 1998;19:373-381.
2. Nong L, Newton C, Cheng Q, Friedman H, Roth MD, Klein TW. Altered can-
nabinoid receptor mRNA expression in peripheral blood mononuclear cells from
marijuana smokers. J Neuroimmunol. 2002;127:169-176.
3. Kaslow RA, Blackwelder WC, Ostrow DG, et al. No evidence for a role of al-
cohol or other psychoactive drugs in accelerating immunodeficiency in HIV-1-
positive individuals: a report from the Multicenter AIDS Cohort Study. JAMA. 1989;
261:3424-3429.
4. Pacifici R, Zuccaro P, Herna´ ndez-Lo´ pez, et al. Acute effects of 3,4-
methylenedioxymethamphetamine alone and in combination with ethanol on the
immune system in humans. J Pharmacol Exp Ther. 2001;296:207-215.
5. Roth MD, Baldwin GC, Tashkin DP. Effects of delta-9-tetrahydrocannabinol on
human immune function and host defense. Chem Phys Lipids. 2002;121:229-239.
6. Zurier RB. Prospects for cannabinoids as anti-inflammatory agents. J Cell Bio-
chem. 2003;88:462-466.
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©2003 American Medical Association. All rights reserved. (Reprinted) JAMA, April 16, 2003—Vol 289, No. 15 1931