SPECIAL ARTICLE

Summary of evidence-based guideline: Complementary

and alternative medicine in multiple sclerosis
Report of the Guideline Development Subcommittee of the
American Academy of Neurology

Vijayshree Yadav, MD, ABSTRACT

MCR Objective: To develop evidence-based recommendations for complementary and alternative
Christopher Bever, Jr., medicine (CAM) in multiple sclerosis (MS).
MD, MBA, FAAN
Methods: We searched the literature (1970–March 2011; March 20112September 2013
James Bowen, MD
MEDLINE search), classified articles, and linked recommendations to evidence.
Allen Bowling, MD, PhD
Bianca Weinstock- Results and recommendations: Clinicians might offer oral cannabis extract for spasticity symp-
Guttman, MD toms and pain (excluding central neuropathic pain) (Level A). Clinicians might offer tetrahydro-
Michelle Cameron, MD, cannabinol for spasticity symptoms and pain (excluding central neuropathic pain) (Level B).
PT Clinicians should counsel patients that these agents are probably ineffective for objective
Dennis Bourdette, MD, spasticity (short-term)/tremor (Level B) and possibly effective for spasticity and pain (long-
FAAN term) (Level C). Clinicians might offer Sativex oromucosal cannabinoid spray (nabiximols)
Gary S. Gronseth, MD, for spasticity symptoms, pain, and urinary frequency (Level B). Clinicians should counsel pa-
FAAN tients that these agents are probably ineffective for objective spasticity/urinary incontinence
Pushpa Narayanaswami, (Level B). Clinicians might choose not to offer these agents for tremor (Level C). Clinicians
MBBS, DM, FAAN might counsel patients that magnetic therapy is probably effective for fatigue and probably
ineffective for depression (Level B); fish oil is probably ineffective for relapses, disability,
fatigue, MRI lesions, and quality of life (QOL) (Level B); ginkgo biloba is ineffective for cogni-
Correspondence to tion (Level A) and possibly effective for fatigue (Level C); reflexology is possibly effective for
American Academy of Neurology: paresthesia (Level C); Cari Loder regimen is possibly ineffective for disability, symptoms,
[email protected]
depression, and fatigue (Level C); and bee sting therapy is possibly ineffective for relapses,
disability, fatigue, lesion burden/volume, and health-related QOL (Level C). Cannabinoids
may cause adverse effects. Clinicians should exercise caution regarding standardized vs non-
standardized cannabis extracts and overall CAM quality control/nonregulation. Safety/effi-
cacy of other CAM/CAM interaction with MS disease-modifying therapies is unknown.
Neurology ® 2014;82:1083–1092

GLOSSARY
AAN 5 American Academy of Neurology; AE 5 adverse effect; CAM 5 complementary and alternative medicine; CBD 5
cannabidiol; CI 5 confidence interval; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; EDSS 5
Expanded Disability Status Scale; FDA 5 US Food and Drug Administration; FSS 5 Fatigue Severity Scale; GB 5 ginkgo
biloba; GNDS 5 Guy’s Neurological Disability Scale; HRQOL 5 health-related QOL; MFIS 5 Modified Fatigue Impact Scale;
MS 5 multiple sclerosis; MSIS 5 Multiple Sclerosis Impact Scale; OCE 5 oral cannabis extract; PPMS 5 primary progressive
MS; QOL 5 quality of life; RCT 5 randomized controlled trial; RRMS 5 relapsing-remitting MS; SAE 5 serious adverse effect;
SPMS 5 secondary progressive MS; THC 5 tetrahydrocannabinol; VAS 5 visual analog scale.

Complementary and alternative medicine (CAM) patients with MS,1-10 particularly among those who
therapies are nonconventional therapies used in are female, have higher education levels, and report
addition to or instead of physician-recommended poorer health.1-4,11 This document summarizes
therapies. CAM use is prevalent in 33%–80% of extensive information provided in the complete
Supplemental data
at Neurology.org
From the Department of Neurology (V.Y., M.C., D.B.), Oregon Health & Science University and Department of Neurology (V.Y., M.C., D.B.),
Veterans Affairs Medical Center, Portland; MS Center of Excellence–East (C.B.), VA Maryland Health Care System and Department of Neurology
(C.B.), University of Maryland School of Medicine, Baltimore; Multiple Sclerosis Center (J.B.), Swedish Neuroscience Institute, Seattle, WA;
Multiple Sclerosis Service and Complementary and Alternative Medicine Service (A.B.), Colorado Neurological Institute, Englewood; The Jacobs
Neurological Institute (B.W.-G.), Buffalo, NY; Department of Neurology (G.S.G.), University of Kansas Medical Center, Kansas City, KS; and
Department of Neurology (P.N.), Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA.
Approved by the Guideline Development Subcommittee on January 12, 2013; by the Practice Committee on March 13, 2013; and by the AANI
Board of Directors on December 11, 2013.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2014 American Academy of Neurology 1083

 guideline, available as a data supplement on the conclusions and recommendations. We selected
Neurology® Web site at Neurology.org. Tables e-1 the final level of obligation for compliance with a rec-
through e-3 and appendices e-1 through e-6, cited ommendation (might/may, should, or must) after taking
in the full guideline (data supplement), as well as into consideration the quality of evidence (Level A, B,
references e1–e84, cited in this summary, are or C) and other factors (e.g., limited generalizability of
available at Neurology.org. the studies, safety/side effect concerns, availability of
This guideline addresses the following questions: alternative treatments).
In patients with MS,
Cannabinoids. Cannabinoids are a group of compounds
1. do CAM therapies reduce specific symptoms and with psychoactive properties. Tetrahydrocannabinol
prevent relapses or disability? (THC) and cannabidiol (CBD) are the major cannabi-
2. can CAM use worsen MS or cause serious adverse noids of cannabis. Synthetic cannabinoids are chemically
effects (SAEs)? related to THC. Orally administered cannabinoids
3. can CAM use interfere with MS disease-modifying (cannabis extract, synthetic THC), mucosally delivered
therapies? cannabinoids (cannabis extract oral spray, nabiximols
[trade name Sativex]), and smoked cannabis have all
DESCRIPTION OF THE ANALYTIC PROCESS This
been studied for therapeutic effects in MS.
guideline was developed in accordance with the 2004
American Academy of Neurology (AAN) process Oral cannabinoids (cannabis extract and THC). The search
manual.12 After review of conflict of interest state- identified 9 studies (3 Class I,13-15 2 Class II,16,17 and 4
ments, the AAN selected a panel of experts. A medical Class III18-21).
research librarian helped perform a comprehensive A large Class I study13 (N 5 630; patients with
literature search, and the authors selected articles. relapsing-remitting MS [RRMS], primary progressive
At least 2 authors independently rated each article MS [PPMS], and secondary progressive MS [SPMS];
(AAN therapeutic classification scheme). We linked 15 weeks) found that neither oral cannabis extract
recommendation strength to the evidence quality. (OCE, THC with CBD) nor synthetic THC (Marinol)
With regard to cannabis for pain, we reviewed studies had greater effect than placebo on the primary outcome
evaluating pain associated with spasticity separately measure of spasticity as measured by total Ashworth
from those evaluating pain specified to be of central scale22 change from baseline (mean change 6 SD:
neuropathic origin and made separate recommenda- OCE: 1.24 [6.60], THC: 1.86 [7.95], placebo: 0.92
tions. We performed Bonferroni correction for mul- [6.56], p 5 0.40). However, in this same study,13 sig-
tiple comparisons when necessary. nificantly more patients reported reduced spasticity
symptoms in the treatment groups (secondary out-
ANALYSIS OF EVIDENCE Because studies were comes spasticity/pain: OCE [52/46%], THC [51/
unavailable or, where available, had a high risk of bias, 50%], placebo [37/30%]). Sleep and muscle spasms
were in conflict, or lacked statistical precision, we also improved in the treatment groups.
found the evidence insufficient to support or refute In a second Class I study14 (N 5 249; “stable MS,”
the effectiveness of the following therapies in MS type unspecified; 12 weeks) the proportion of patients
(table 1): acetyl-L-carnitine, acupuncture, biofeed- achieving relief of muscle stiffness was 29.4% in the
back, carnitine, chelation therapy, Chinese medicine, OCE group compared with 15.7% in the placebo group
chiropractic medicine, creatine monohydrate, dental (odds ratio 2.26, 95% confidence interval [CI] CI 1.24–
amalgam replacement, glucosamine sulfate, hippother- 4.13). Secondary outcomes (muscle stiffness and spasms,
apy, hyperbaric oxygen, inosine, linoleic acid, low-dose pain, sleep) also improved in the cannabis group.
naltrexone, massage therapy, mindfulness training, A third Class I study15 (N 5 57; RRMS, SPMS,
music therapy, naturopathic medicine, neural therapy, PPMS), insufficiently powered, found no significant
Padma 28, progressive muscle relaxation therapy, tai difference in objective spasticity (Ashworth scale) or
chi, threonine, transdermal histamine, and yoga. Data patient-reported spasm frequency.
also were insufficient to determine whether any CAM In both adequately powered Class I studies,13,14
therapies worsen MS or interfere with disease-modifying significantly more patients treated with cannabinoids
therapies. reported reduced pain, whereas disability measures
Evidence was available to develop practice recom- and health questionnaire results were not significantly
mendations for use of bee venom therapy, cannabinoids, different between groups. One Class I study13 assessed
ginkgo biloba (GB), lofepramine plus phenylalanine tremor and bladder symptoms and noted no signifi-
with B12 (Cari Loder regimen), low-fat diet with cant difference in outcomes between patients treated
omega-3 supplementation, magnetic therapy, and with cannabinoids and placebo.
reflexology (table 2). This evidence is discussed herein Conclusions. OCE is established as effective for reduc-
and includes only the studies that inform the ing patient-reported spasticity symptoms and pain

1084 Neurology 82 March 25, 2014

Table 1 CAM therapies with insufficient evidence to support specific practice recommendations for their use in multiple sclerosis

CAM intervention Description Evidence MS types studied Adverse effects

Mind2body medicine

Biofeedback Active physiologic monitoring of a body 1 Class IIIe38 MSU

system (e.g., EMG activity). The results of
the monitoring are provided to the patient
in real time.

Music therapy Uses music prescribed in a skilled manner 2 underpowered Class IIIe39,e40 RRMS, PPMS, SPMS
by a music therapist

Mindfulness-based training Mental training by nonjudgmental 1 Class IIIe41 RRMS, SPMS None described
awareness of moment-to-moment
experience by mindfulness exercises
including observation of sensory, affective,
and cognitive domains of perceptible
experience

Hypnosis Induction followed by a series of 1 Class IIIe42 Unspecified None described

suggestions for analgesia and comfort.
Patients practiced the skills by listening to
an audio recording and using a cue to re-
experience hypnotic effects.

Biologically based practices

Padma 28 Ayurvedic mixture of 22 herbse43 with 1 Class IIIe45 Progressive MS, type
presumed immunologic effects on the unclear
suppressor lymphocytes and the
endogenous interferon productione44

Linoleic acid An unsaturated omega-6 fatty acid 2 underpowered Class IIe46,e47 MSU
2 Class IIIe48,e49

Creatine monohydrate A naturally occurring nitrogenous organic 1 underpowered Class IIe50 RRMS, MSU
compound involved in energy metabolism 1 underpowered Class IIIe51
(phosphocreatine)

Acetyl-L-carnitine A naturally occurring compound that is the 1 underpowered Class IIe52 RRMS, SPMS
acetylated form of L-carnitine (synthesized
from lysine and methione)

Inosine Ribosylated precursor of uric acid, which 1 underpowered Class IIe53 RRMS, SPMS 4/16 patients in
raises uric acid levels. Uric acid is a 3 conflicting Class IIIe54-e56 1 Class III study
scavenger of peroxynitrate, a highly developed kidney
reactive compound postulated to cause stonese56
potentially toxic changes in MS plaques,
including nitration of tyrosine residues.

Threonine Naturally occurring amino acid observed to 1 Class IIIe57 Progressive MS, type
increase glycine in rat spinal cord and unspecified
therefore proposed as a treatment of
spasticity

Glucosamine sulfate An amino sugar and a prominent precursor 1 Class Ie58 RRMS
in the biochemical synthesis of
glycosylated proteins and lipids, with
potential immunoregulatory effects

Low-dose naltrexone Long-lasting opiate receptor antagonist; 1 underpowered Class Ie59 All MS subtypes
may intermittently block opiate receptors 1 underpowered Class IIe60
resulting in increased endogenous
production of endorphins and opiate
receptors, promoting psychological well-
being and general health

Transdermal histamine with Histamine is a neurotransmitter 1 Class IIIe61 RRMS and

caffeine progressive MS, type
unspecified

Hyperbaric oxygen therapy 1 Class I noninterpretable due to MS type unspecified

suboptimal control intervention (10%
oxygen with nitrogen) e62

5 underpowered Class IIe63–e67

Manipulative and body-based

practices

Hippotherapy Therapeutic horseback riding where the 3 Class IIIe68-e70; 1 underpowered, 2 RRMS, SPMSe68
subject is described as being passive noninterpretable statistically MS type
evaluating effect on gait, balance, and unspecifiede69
mood All MS subtypese70

Yoga Mind2body approach that has components 4 Class IIIe71-e74; 3 underpowerede71, MS types
of meditation, breathing, and postures e73,e74
evaluating effect on disability, unspecifiede71,e72
spasticity, fatigue, cognition, mood, All MS subtypese73,e74
balance, and walking speed

Continued

Neurology 82 March 25, 2014 1085

 Table 1 Continued

CAM intervention Description Evidence MS types studied Adverse effects

Massage therapy 4 Class III; mood ; self-efficacy ;

e75 e76
MS type
constipatione77; pain, fatigue, balance, unspecifiede75
gait, and spasticitye78 MS all typese76,e77
RRMS, SPMS,
PPMSe78

Chinese acupuncture Procedures involving penetration of the 1 Class IIIe79 evaluating effect on QOL SPMS
skin with needles in order to stimulate in SPMS
certain points on the body

Electroacupuncture Insertion of metallic needles into specific 1 Class III evaluating effect on RRMS
points and stimulating them electrically disability, QOL, and paine80

Progressive muscle relaxation Therapist instructs patients to contract and 1 Class III evaluating effect on pain, RRMS, SPMSe81;
therapy release different muscle groups disability, spasms, fatigue, cognition, RRMS, SPMS,
and depressione81 PPMSe82
1 Class III evaluating QOLe82

Energy medicine

Neural therapy A modified form of acupuncture with local 1 Class IIIe83 evaluating effect on All MS subtypes
anesthetic injections disability

Naturopathic medicine Multimodal therapy including diet, herbs, 1 Class IIIe84 evaluating effect on RRMS
nutritional supplements, homeopathy, QOL, cognition, disability, depression,
physical medicine, and counseling and fatigue

Abbreviations: CAM 5 complementary and alternative medicine; MS 5 multiple sclerosis; MSU 5 MS type unspecified; PPMS 5 primary progressive MS;
QOL 5 quality of life; RRMS 5 relapsing-remitting MS; SPMS 5 secondary progressive MS.
Studies cited using reference list in summary guideline article (appearing in print).

(12–15 weeks; 2 Class I,13,14 1 Class III18). This subjective from baseline: treatment 21.95, placebo 20.9; p 5
benefit is possibly maintained for 1 year (1 Class II17). 0.049) decreased significantly.25 A Class II RCT
THC is probably effective for reducing patient- (N 5 337, all MS types, 15 weeks)26 observed that
reported symptoms of spasticity and pain (15 weeks, tremor did not improve with Sativex.
1 Class I13). This subjective benefit is possibly main- Conclusions. Sativex oromucosal cannabinoid spray is
tained for 1 year (1 Class II17). probably effective for improving subjective spasticity
OCE and THC are probably ineffective for reducing symptoms (6 weeks, 1 Class I23), pain (5 weeks, 1 Class
both objective spasticity measures and MS-related I24), and urinary frequency (10 weeks, 1 Class I25).
tremor symptoms (15 weeks, 1 Class I13). OCE and Sativex oromucosal cannabinoid spray is probably
THC are possibly effective for reducing symptoms and ineffective for reducing objective spasticity measures
objective measures of spasticity over 1 year (1 Class II17). over 6 weeks (1 Class I23) or bladder incontinence
Sativex oromucosal cannabinoid spray. The search iden- episodes over 10 weeks (1 Class I25).
tified 3 Class I,23-25 2 Class II,26,27 and 3 Class III28-30 Sativex oromucosal spray is possibly ineffective for
studies in patients with MS, type unspecified. reducing MS-related tremor over 15 weeks (1 Class II26).
A Class I study, a randomized controlled trial Smoked cannabis. We reviewed 2 Class III studies.31,32
(RCT)23 (N 5 160, 6 weeks), evaluated the effect One Class III crossover study31 (37 patients, RRMS
of Sativex spray (GW Pharmaceuticals, Salisbury, and SPMS, 2 weeks), reported spasticity reduction
UK) delivering THC 2.7 mg and CBD 2.5 mg. Spas- (modified Ashworth scale) in the cannabis group (stan-
ticity visual analog scale (VAS) was the only outcome dardized effect size 2.74, 2.2–3.14). Pain, the secondary
measure on which scores improved significantly after outcome measure, also improved. After cannabis treat-
Bonferroni correction (active 231.2, placebo 28.4, ment, the subjects consistently showed reduced cognitive
difference 222.79, 95% CI 235.52 to 210.07, p 5 performance (Paced Auditory Serial Addition Test).33
0.001). Scores on physician-evaluated spasticity A second Class III study32 (N 5 20, MS type
measures (Ashworth) did not change between groups. unspecified) found that both normal subjects and
A Class I RCT24 (N 5 66, MS type unspecified, 5 patients with MS fared worse on measures of pos-
weeks) in MS-related central neuropathic pain found ture and balance 10 minutes after smoking 1 mari-
that oromucosal cannabinoids were superior for juana cigarette. After Bonferroni correction, the
reducing mean pain intensity (number needed to effect was significant only for patients with MS
treat to reduce pain by 50%: 3.7 [95% CI 2.2– (p 5 0.018).
13]). Another Class I RCT25 (N 5 135, 10 weeks, Conclusions. Data are inadequate to determine the safety
MS type unspecified) did not find improvement in or efficacy of smoked cannabis used for spasticity/pain
the number of incontinence episodes with Sativex. (1 Class III31), balance/posture (1 Class III32), and cog-
However, the daily number of bladder voids (change nition (1 Class III31).

1086 Neurology 82 March 25, 2014

 Table 2 CAM therapies with sufficient evidence to support practice recommendations in multiple sclerosis

Recommendation
CAM intervention Number and class of studies MS types studied Outcome level

Cannabinoids

OCE 2 Class I,13,14 1 Class II,17 RRMS, SPMS, PPMS, Symptoms of spasticity, pain A Effective
1 Class III18 MSU

1 Class I13 RRMS, SPMS, PPMS Signs of spasticity (short-term), tremor (short-term) B Ineffective
17
1 Class II MSU Signs and symptoms of spasticity (long-term) C Effective

2 Class I,13 1 Class II16 RRMS, SPMS, PPMS, Bladder symptoms, urge incontinence U
MSU

Synthetic THC 1 Class I,13 1 Class II17 RRMS, SPMS, PPMS Symptoms of spasticity, pain B Effective
13
1 Class I RRMS, SPMS, PPMS Signs of spasticity (short-term), tremor (short-term) B Ineffective

1 Class II17 MSU Signs and symptoms of spasticity (long-term) C Effective

1 Class I,13 1 Class II,16 RRMS, SPMS, PPMS, Bladder symptoms, urge incontinence, central U
1 Class III19 MSU neuropathic pain

Sativex oromucosal spray 3 Class I,23-25 2 Class II,26,27 MSU Symptoms of spasticity, pain, urinary frequency B Effective
3 Class III28-30

Signs of spasticity, incontinence episodes B Ineffective

Tremor C Ineffective

Anxiety/sleep, cognition, QOL, fatigue U

31,32
Smoked cannabis 2 Class III RRMS, SPMS, MSU Spasticity, pain, balance and posture, cognition U

Other CAM

Ginkgo biloba 2 Class I,e7,e8 2 Class IIe9,e10 RRMS, SPMS, PPMS Fatigue C Effective
Cognitive function A Ineffective

Lofepramine plus 1 Class IIe16 RRMS, SPMS, PPMS Disability, symptoms, depression, fatigue C Ineffective
phenylalanine with B12 (Cari
Loder regimen)

Reflexology 1 Class I,e19 2 Class II,e20,e21 MSU Paresthesia C Effective

1 Class IIIe22

Pain, HRQOL, disability, spasticity, fatigue, cognition, U

bowel/bladder function, depression, anxiety, insomnia

Bee venom 1 Class IIe26 RRMS, SPMS MRI lesion number and volume, relapses, disability, C Ineffective
fatigue, HRQOL

Magnetic therapy 1 Class I,e31 2 Class II,e32,e33 RRMS, SPMS, PPMS Fatigue B Effective
3 Class IIIe34–e36 Depression B Ineffective

Low-fat diet with omega-3 1 Class I,e12 1 Class II,e13 RRMS Relapses, disability, MRI lesions, fatigue, QOL B Ineffective
supplementation 1 Class IIIe14

Abbreviations: CAM 5 complementary and alternative medicine; HRQOL 5 health-related QOL; MS 5 multiple sclerosis; MSU 5 MS type unspecified; OCE 5 oral
cannabis extract; PPMS 5 primary progressive MS; QOL 5 quality of life; RRMS 5 relapsing-remitting MS; SPMS 5 secondary progressive MS; THC 5 tetrahy-
drocannabinol. A 5 established as effective or ineffective; B 5 probably effective or ineffective; C 5 possibly effective or ineffective; U 5 insufficient evidence to
determine effectiveness or ineffectiveness.
Studies cited using reference list in summary guideline article (appearing in print) and e-references for print article (online data supplement).

Cannabinoid practice recommendations. Clinicians might THC is probably ineffective for improving objective
offer OCE to patients with MS to reduce patient- spasticity measures (short-term) or tremor (Level B).
reported symptoms of spasticity and pain (excluding Clinicians might offer Sativex oromucosal canna-
central neuropathic pain) (Level A) and might counsel binoid spray (nabiximols), where available, to reduce
patients that this symptomatic benefit is possibly symptoms of spasticity, pain, or urinary frequency,
maintained for 1 year (Level C), although OCE is although it is probably ineffective for improving
probably ineffective for improving objective spastic- objective spasticity measures or number of urinary
ity measures (short-term) or tremor (Level B). incontinence episodes (Level B).
Clinicians might offer THC to patients with MS to Clinicians might choose not to offer Sativex oro-
reduce patient-reported symptoms of spasticity and pain mucosal cannabinoid spray to reduce MS-related
(excluding central neuropathic pain) (Level B). Clinicians tremor (Level C).
might counsel patients that this symptomatic benefit is Data are inadequate to support or refute use of the
possibly maintained for 1 year (Level C), although following in MS (Level U):

Neurology 82 March 25, 2014 1087

 1. OCE/THC for bladder urge incontinence and have been reported with long-term cannabis expo-
overall symptoms sure.34-36 Development of marijuana addiction is con-
2. Synthetic THC (Marinol) for central neuropathic troversial; however, long-term heavy marijuana use has
pain been associated with tolerance and dependence.37-39
3. Sativex oromucosal cannabinoid spray for overall Evidence is also available, albeit inconsistent, for impair-
bladder symptoms, anxiety symptoms/sleep prob- ments in memory, concentration, and executive func-
lems, cognitive symptoms, quality of life (QOL), tions in chronic cannabis users, although it remains
and fatigue unclear how long these deficits persist after abstinence
4. Smoked cannabis for spasticity, pain, balance/posture, and whether there is permanent neurotoxicity.40,e1-e3 In
and cognition 1 study, patients with MS and prolonged use of “street”
cannabis had cognitive function impairments relative to
Data are inadequate to determine the abuse poten-
patients with MS who did not use cannabis.e4 Patients
tial or effect on psychopathologic symptoms of Sativex
with MS who smoked cannabis regularly had more
cannabinoid spray (Level U).
extensive cognitive abnormalities and were more likely
Clinical context. The cannabinoid studies have lim- to meet criteria for a lifetime DSM-IV psychiatric diag-
itations that physicians and patients must be aware of. nosis.e5 Although not generalizable to medical cannabis,
Most studies were of short duration (6–15 weeks). the associations from these studies of street cannabis
Another limitation was the potential for central side raise concerns. A substudy of the large Class I study
effects to unmask patients to treatment assignment— reviewed here,13 available only in abstract form, reported
a concern with regard to all masked trials involving a significant reduction in verbal learning and memory in
treatments with prominent side effects. It is also patients with MS receiving cannabis extracts vs those
important to recognize that the Ashworth scale used receiving placebo.e6 Several of the reviewed studies as-
for objective measurement may be insensitive to spas- sessed psychopathology and cognition as secondary out-
ticity changes. These factors may contribute to the comes without significant AEs; however, these studies
discordant effects of cannabinoids on subjective and were short-term and inadequately powered to exclude
objective spasticity measures. an effect.15,21,24,28
Adverse effects. Cannabinoids were generally well Clinicians should therefore counsel patients about
tolerated, although some SAEs were reported. Few the potential for psychopathologic/cognitive and other
studies reported deaths in the cannabinoid-treated AEs associated with cannabinoids. Sativex oromucosal
groups (1 due to pneumonia,13 1 to seizure-related cannabinoid spray is not US Food and Drug Adminis-
aspiration pneumonia, and 2 to cancer, presumed tration (FDA) approved and is unavailable in the
unrelated16). Mild/moderate adverse effects (AEs) United States. In the United States, caution should
were common (approximately 50%–80% of subjects) be exercised with regard to extrapolation of results of
and appeared to be equally prevalent in subjects trials of standardized OCEs (which are unavailable
receiving cannabinoids or placebo. No significant lab- commercially) to other nonstandardized, nonregulated
oratory, hematologic, urologic, or cardiac changes, or cannabis extracts (which may be commercially avail-
differences in vital signs, were noted. CNS AEs (e.g., able in states with medical marijuana laws).
dizziness, somnolence, drowsiness, lightheadedness,
memory disturbance, difficulty concentrating) were Ginkgo biloba. We reviewed 4 studies (2 Class I,e7,e8 2
more common in subjects receiving cannabinoids vs Class IIe9,e10). A Class I RCT evaluating cognitive
placebo. Dizziness was most common (15%–50% of function (N 5 39; RRMS, SPMS, PPMS) found that
subjects).13,15,17,20,21,24-26,28,30 Gastrointestinal AEs, subjects taking GB 120 mg twice a day for 12 weeks
including increased appetite, nausea, vomiting, con- had a 4.5-second greater (95% CI 27.6–0.9, p 5
stipation, and dry/sore mouth, occurred in about 0.015, nonsignificant [p , 0.008 significant per
10% of subjects receiving cannabinoids15 and were authors] after Bonferroni correction) improvement in
more common in those receiving cannabinoids than the Stroop Color Word test than those taking
placebo. Other less common AEs included myalgia, placebo.e7 A second Class I study (N 5 121; RRMS,
increased spasticity, seizures (4/137 subjects had seiz- PPMS, SPMS, relapsing-progressive MS; 12 weeks)
ures),23 lower limb weakness, hemorrhagic cystitis, also found no difference in cognition measures with
dehydration, temporary psychosis (1 rated as GB 120-mg administration twice a day compared with
severe),21 hallucinations,24 and oral ulceration.23 placebo, confirming the pilot study results.e8
Because cannabinoids have known psychoactive The Class II study (N 5 22, all MS types) found
properties, their potential for psychopathologic and significantly greater fatigue reduction with GB
neurocognitive AEs is a concern, especially in a patient 240 mg/day for 4 weeks relative to placebo (Modified
population that may be vulnerable due to underlying Fatigue Impact Scale [MFIS]e11 baseline: GB 37.8 6
disorders. Depression and predisposal to psychosis 14.7, placebo 39.8 6 15.1; postintervention: GB

1088 Neurology 82 March 25, 2014

35.5 6 13.9, placebo 42.4 6 15.6; p 5 0.024).e9 A Neurological Disability Scale [GNDS]e17 21.16 [95%
Class II follow-up analysise10 of the data from this CI 22.75 to 0.43], Expanded Disability Status Scale
study did not reveal a difference between the GB [EDSS]e18 20.17 [95% CI 20.39 to 0.05]). There
and placebo groups on visual2spatial memory and was a small improvement in fatigue and symptoms,
attention/concentration. nonsignificant with Bonferroni correction. Depression
GB was well tolerated in all studies. No hemor- did not improve.
rhagic AEs were reported. Conclusion. The Cari Loder regimen is possibly inef-
Conclusions. GB is established as ineffective for fective for reducing MS-related disability, symptoms,
improving cognitive function in MS (12 weeks, 2 depression, or fatigue (all MS subtypes, 1 Class IIe16).
Class Ie7,e8). Lofepramine practice recommendation. Clinicians might
GB is possibly effective over 4 weeks for reducing counsel patients with MS that lofepramine plus
fatigue in MS (1 Class IIe9). L-phenylalanine with vitamin B 12 (Cari Loder reg-

GB practice recommendations. Clinicians might coun-

imen) is possibly ineffective for treating disability, symp-
sel patients with MS that GB is established as ineffec- toms, depression, or fatigue (Level C).
tive for improving cognitive function (Level A). Reflexology. Reflexology involves applying manual
Clinicians might counsel patients with MS that pressure to points on the feet. We evaluated 4 studies
GB is possibly effective for reducing fatigue (Level C). (1 Class I,e19 2 Class II,e20,e21 and 1 Class IIIe22).
Clinical context. GB and other supplements are not The Class I study (underpowered RCT; N 5
FDA regulated. Their quality control may play a role 71; RRMS, SPMS, PPMS) compared 10 weekly
in their effectiveness and AE risk. Moreover, interac- 45-minute sessions of sham reflexology (foot massages)
tions of supplements with other medications, especially with precision reflexology.e19 Both groups showed
disease-modifying therapies for MS, are a clinical reductions in pain (VAS), disability (Roland Morris
concern. Disability Questionnairee23), spasticity (VAS), fatigue
(Multiple Sclerosis Impact Scale [MSIS],e24 Fatigue
Low-fat diet with omega-3 fatty acid supplementation
Severity Scale [FSS], MFIS), and depression (Beck
(omega-3). We reviewed 3 studies (1 Class I,e12 1 Class
Depression Inventorye25). Differences between groups
II,e13 and 1 Class IIIe14). The Class I study (RRMS, were nonsignificant.e19
N 5 92) of omega-3 fatty acids (1,350 mg One Class II RCT (MS type unspecified, N 5 71)
eicosapentaenoic acid and 850 mg docosahexaenoic found significantly greater reductions in paresthesia, uri-
acid daily) revealed no difference in the cumulative nary symptoms, and spasticity (Ashworth Scale) with
number of gadolinium-enhancing MRI lesions at 11 weekly reflexology treatments plus calf massage relative
6 months, relapse rates at 6 and 24 months, disability to calf massage alone.e20 After Bonferroni correction, only
progression, fatigue, or QOL.e12 the difference in paresthesia reduction remained signifi-
The Class II study (1-year underpowered RCT, cant (mean 6 SD difference pre-/posttreatment in trea-
N 5 27, RRMS)e13 evaluated a low-fat diet supple- ted group 21.49 6 2.1, controls 0.16 6 2.1; p 5 0.04).
mented with either omega-3 fatty acid (fish oil) or olive Another Class II RCT (underpowered; SPMS,
oil. There was no significant difference in health- PPMS; N 5 20; 16 weeks) of reflexology compared
related QOL (HRQOL), relapse rates, or disability.e13 with sham treatments did not reveal improvement in
Conclusion. A low-fat diet with fish oil supplemen- the primary outcome of HRQOL (change in MSIS: 17;
tation is probably ineffective for reducing MS-related 95% CI 24.121 to 40.21, p 5 0.112). Secondary
relapse, disability, or MRI lesions, or for improving outcomes of pain, spasticity, sleep, mood, and bowel/
fatigue or QOL (RRMS, 1 Class I).e12 bladder function also did not change.e21
Omega-3 practice recommendation. Clinicians might Conclusions. Reflexology is possibly effective for
counsel patients that a low-fat diet with fish oil sup- reducing MS-associated paresthesia over 11 weeks
plementation is probably ineffective for reducing re- (MS type unspecified, 1 Class IIe20).
lapses, disability, or MRI lesions, or for improving Data are inadequate to support or refute the use of
fatigue or QOL in MS (Level B). reflexology for pain, HRQOL, disability, spasticity,
fatigue, cognition, bowel/bladder function, depres-
Lofepramine. Lofepramine (a tricyclic antidepressant
sion, anxiety, or insomnia in MS.
structurally related to imipramine and desipramine)
Reflexology practice recommendation. Clinicians might
combined with L-phenylalanine and IM vitamin B12 is
counsel patients with MS that reflexology is possibly
known as the Cari Loder regimen.e15 One 24-week Class
effective for reducing paresthesia (Level C).
II RCT (N 5 138, all MS subtypes) compared the
Cari Loder regimen with placebo pills and IM vitamin Bee venom. One Class II crossover studye26 of bee
B12 (1 mg weekly).e16 The primary outcome measures venom (20 stings from live bees 3 times weekly for
of disability did not change significantly (Guy’s 24 weeks) (N 5 26; RRMS, SPMS) found no

Neurology 82 March 25, 2014 1089

 significant effect on the number of new gadolinium- IIIe34) and probably ineffective for reducing depres-
enhancing lesions on MRI, volume of enhancing sion in RRMS over 15 weeks (1 Class Ie31).
lesions, total lesion volume, relapses, disability (EDSS, Data are inadequate to support or refute the effect
Multiple Sclerosis Functional Composite,e27 GNDS), of magnetic therapy on reducing MS-related disabil-
fatigue (Shortened Fatigue Questionnaire,e28 Fatigue ity (1 Class Ie31 with insensitive outcome measure;
Impact Scalee29), or HRQOL (Short Form-36e30). 1 underpowered Class IIe32), bladder control prob-
AEs included tenderness, swelling, and redness at the lems, or spasticity, or on improving cognition, mobil-
sting sites; itching (4 subjects); and flu-like symptoms ity, sensation, or vision (1 underpowered Class II,e32 3
(5 subjects).e26 underpowered/inconsistent Class IIIe34-e36).
Conclusion. Bee sting therapy is possibly ineffective for Magnetic therapy practice recommendation. Clinicians
reducing MS-related relapses, disability, fatigue, total might counsel patients with MS that magnetic ther-
MRI lesion burden, new gadolinium-enhancing lesion apy is probably effective for reducing fatigue (Level B)
volume, or HRQOL (RRMS, SPMS; 1 Class II).e26 and probably ineffective for reducing depression
Bee venom practice recommendation. Clinicians might (Level B).
counsel patients with MS that bee sting therapy is
Other CAM therapies practice recommendation. Clini-
possibly ineffective for reducing relapses, disability,
cians should counsel patients with MS that the safety
fatigue, total MRI lesion burden, new gadolinium-
and efficacy of other reviewed CAM, or the interac-
enhancing lesion volume, or HRQOL (Level C).
tion of CAM with disease-modifying therapies for
Clinical context. Bee stings can be associated with
MS, are unknown Level U).
anaphylactic reaction and possible death.

Magnetic therapy. The search identified 6 studies (1 Class

LIMITATIONS This review has several limitations.
I,e31 2 Class II,e32,e33 and 3 Class IIIe34-e36). Because the search strategy is limited only to MS, some
The Class I 12-week RCT (N 5 41, RRMS) potentially important AEs (e.g., bleeding risk with GB)e37
reported significantly less fatigue (MFIS) with low- of the reviewed therapies noted when they were evaluated
frequency pulsed electromagnetic field therapy (bio- in other diseases were not apparent in the MS popula-
electromagnetic-energy-regulation device, in the form tion. Therapies that have received much press attention
of a metal mat upon which subjects lay for 8 minutes (e.g., dental amalgam removal, transdermal histamine)
twice a day) (active 26.84 6 SE 12.061, placebo have little evidence to support recommendations.
36.67 6 13.253; p 5 0.024). Fatigue, measured by AUTHOR CONTRIBUTIONS
FSS, a secondary outcome measure, also decreased in Vijayshree Yadav: study concept and design, acquisition of data, analysis or
the treated group (FSS mean [SD]: placebo 4.7 [1.6], interpretation of data, drafting/revising the manuscript, critical revision of
treatment 3.5 [1.3], t 5 22.53; p 5 0.016). There the manuscript for important intellectual content, study supervision. Christo-
pher Bever, Jr.: study concept and design, acquisition of the data, analysis and
was no change in depression or disability (EDSS).e31 interpretation of the data, review of the manuscript for important intellectual
However, an EDSS change may not have been de- content. James Bowen: study concept and design, analysis or interpretation of
tected because of the study’s short duration (EDSS data, critical revision of the manuscript for important intellectual content.
Allen Bowling: study concept and design, analysis or interpretation of data,
may be insensitive to change in short-term disability).
critical revision of the manuscript for important intellectual content. Bianca
A Class II underpowered RCTe32 (N 5 30, RRMS/ Weinstock-Guttman: study concept and design, analysis or interpretation of
progressive MS) found no significant change after Bon- data, critical revision of the manuscript for important intellectual content.
ferroni correction in disability (EDSS) or patient- Michelle Cameron: analysis or interpretation of data, critical revision of the
manuscript for important intellectual content. Dennis Bourdette: study con-
reported performance scale related to bladder control, cept and design, acquisition of data, analysis or interpretation of data, critical
cognition, fatigue, mobility, sensation, spasticity, vision, revision of the manuscript for important intellectual content, study supervi-
total performance, or hand function between subjects sion. Gary Gronseth: study concept and design, acquisition of data, analysis
or interpretation of data, drafting/revising the manuscript, critical revision of
wearing wristwatch-size magnetic pulsing devices
the manuscript for important intellectual content, study supervision. Pushpa
(Enermed device) (10–24 hours/day for 2 months) or Narayanaswami: study concept and design, acquisition of data, analysis or
inactive devices. interpretation of data, drafting/revising the manuscript, critical revision of
Another Class II underpowered RCT (N 5 50; the manuscript for important intellectual content, study supervision.

RRMS, SPMS, PPMS) found no significant difference

in fatigue (MFIS, FSS) with low-frequency magnetic STUDY FUNDING
This guideline was developed with financial support from the American
stimulation 3 sessions per week for 8 weeks (intensity Academy of Neurology. None of the authors received reimbursement, hon-
37.5 mT and a sequence of pulses at 4–7 Hz).e33 Mag- oraria, or stipends for their participation in development of this guideline.
netic therapy was generally well tolerated; most studies
reported no AEs.e34,e36 One study reported headache, DISCLOSURE
spasms, and burning sensation.e32 V. Yadav serves as a section editor for Current Neurology and Neuroscience
Reports, served as consultant for Bayer Healthcare Pharmaceutical and
Conclusions. Magnetic therapy is probably effective Biogen Idec, is on the speakers’ bureau of Novartis, and receives research
for reducing fatigue in RRMS (1 Class I,e31 1 Class support from the McDougall Foundation, National Multiple Sclerosis

1090 Neurology 82 March 25, 2014

Society (NMSS) Foundation, Nancy Davis Center Without Walls Foun- 2. Schwartz CE, Laitin E, Brotman S, LaRocca N. Utilization
dation, and Biogen Idec. C. Bever received travel funding from the of unconventional treatments by persons with MS: is it alter-
American Academy of Neurology (unrelated to this guideline), the Uni- native or complementary? Neurology 1999;52:626–629.
versity of Maryland School of Medicine, and the Department of Veterans
3. Marrie RA, Hadjmichael O, Vollmer T. Predictors of
Affairs; has a patent held or pending for use of hematogenous stem cells
alternative medicine use by multiple sclerosis patients.
in neuronal replacement therapy and gene delivery; has received funding
for merit grants from the US Department of Veterans Affairs and a pilot Mult Scler 2003;9:461–466.
grant from the NMSS; and has received license fee payments and royalty 4. Nayak S, Matheis RJ, Schoenberger NE, Shiflett SC. Use
payments (or has contractual rights for receipt of future royalty payments) of unconventional therapies by individuals with multiple
related to the patent disclosed above. Dr. Bever’s spouse has received sclerosis. Clin Rehab 2003;17:181–191.
publishing royalties from Ambulatory Medicine, Barker et al. J. Bowen 5. Stuifbergen AK, Harrison TC. Complementary and alter-
reports no relevant disclosures. A. Bowling has received funding for travel native therapy use in persons with multiple sclerosis.
and honoraria from the Consortium of Multiple Sclerosis Centers, the Rehab Nurs 2003;28:141–147.
NMSS, the Multiple Sclerosis Foundation, ProCE, the Center for Dis-
6. Apel A, Greim B, Zettl UK. How frequently do patients
ability Services, and the Mandell Center for MS; has received research
with multiple sclerosis use complementary and alterna-
support from Biogen Idec and Novartis; has consulted for Questcor; and
serves on the speakers’ bureaus of Acorda, Bayer, Biogen Idec, EMD Serono, tive medicine? Complement Therapies Med 2005;13:
Genzyme, Novartis, Pfizer, and Teva Neurosciences. B. Weinstock-Guttman 258–263.
has served on speakers’ bureaus and as a consultant for Biogen Idec, Teva 7. Apel A, Greim B, Konig N, Zettl UK. Frequency of current
Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme, Sanofi, Mylan, utilisation of complementary and alternative medicine by pa-
and Acorda; and has received grant/research support from the agencies listed tients with multiple sclerosis. J Neurol 2005;253:1331–1336.
above as well as from Questcor and Shire. M. Cameron has received research 8. Yadav V, Shinto L, Morris C. Use and self reported benefit
support from the US Department of Veterans Affairs, the NMSS, the Collins
of complementary and alternative (CAM) therapies among
Foundation, Acorda Therapeutics, and the Multiple Sclerosis International
multiple sclerosis patients. Int J MS Care 2006;8:5–10.
Federation and funding for travel and honoraria from the Consortium of
9. Schwarz S, Knorr C, Geiger H. Complementary and alternative
Multiple Sclerosis Centers. D. Bourdette has received speaker honoraria and
consulting fees from Biogen Idec and Teva Neurosciences, consulting fees medicine for multiple sclerosis. Mult Scler 2008;14:1113–1119.
from Elan Pharmaceuticals, speaker honoraria from Genzyme, and research 10. Leong EM, Semple SJ, Angley M, Siebert W, Petkov J,
grants from the US Department of Veterans Affairs, National Institutes of McKinnon RA. Complementary and alternative medicines
Health, and NMSS. G. Gronseth and P. Narayanaswami report no relevant and dietary interventions in multiple sclerosis: what is
disclosures. Go to Neurology.org for full disclosures. being used in South Australia and why? Complement Ther
Med 2009;17:216–223.
DISCLAIMER 11. Shinto L, Yadav V, Morris C. Demographic and health-
This statement is provided as an educational service of the American related factors associated with complementary and alterna-
Academy of Neurology. It is based on an assessment of current scientific tive medicine (CAM) use in multiple sclerosis. Mult Scler
and clinical information. It is not intended to include all possible proper 2006;12:94–100.
methods of care for a particular neurologic problem or all legitimate cri- 12. AAN (American Academy of Neurology). Clinical Practice
teria for choosing to use a specific procedure. Neither is it intended to
Guideline Process Manual, St Paul, MN: The American
exclude any reasonable alternative methodologies. The AAN recognizes that
Academy of Neurology; 2004.
specific patient care decisions are the prerogative of the patient and
13. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treat-
the physician caring for the patient, based on all of the circumstances
involved. The clinical context section is made available in order to ment of spasticity and other symptoms related to multiple
place the evidence-based guideline(s) into perspective with current sclerosis (CAMS study): multicentre randomised placebo-
practice habits and challenges. Formal practice recommendations are controlled trial. Lancet 2003;362:1517–1526.
not intended to replace clinical judgment. 14. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG;
for MUSEC Research Group. Multiple Sclerosis and
CONFLICT OF INTEREST Extract of Cannabis: results of the MUSEC trial.
The American Academy of Neurology is committed to producing indepen- J Neurol Neurosurg Psychiatry 2012;83:1125–1132.
dent, critical and truthful clinical practice guidelines (CPGs). Significant ef- 15. Vaney C, Heinzel-Gutenbrenner M, Jobin P, et al. Effi-
forts are made to minimize the potential for conflicts of interest to influence cacy, safety and tolerability of an orally administered can-
the recommendations of this CPG. To the extent possible, the AAN keeps nabis extract in the treatment of spasticity in patients with
separate those who have a financial stake in the success or failure of the prod- multiple sclerosis: a randomized, double-blind, placebo-
ucts appraised in the CPGs and the developers of the guidelines. Conflict of controlled, crossover study. Mult Scler 2004;10:417–424.
interest forms were obtained from all authors and reviewed by an oversight
16. Freeman RM, Adekanmi O, Waterfield MR, et al. The effect
committee prior to project initiation. AAN limits the participation of authors
of cannabis on urge incontinence in patients with multiple
with substantial conflicts of interest. The AAN forbids commercial participa-
tion in, or funding of, guideline projects. Drafts of the guideline have been
sclerosis: a multicentre, randomised placebo-controlled trial
reviewed by at least 3 AAN committees, a network of neurologists, Neurology (CAMS-LUTS). Int Urogynecol J Pelvic Floor Dysfunct
peer reviewers and representatives from related fields. The AAN Guideline 2006;17:636–641.
Author Conflict of Interest Policy can be viewed at www.aan.com. For 17. Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids
complete information on this process, access the 2004 AAN process in multiple sclerosis (CAMS) study: safety and efficacy
manual.12 data for 12 months follow up. J Neurol Neurosurg Psy-
chiatry 2005;76:1664–1669.
Received August 21, 2013. Accepted in final form December 4, 2013. 18. Ungerleider JT, Andrysiak T, Fairbanks L, Ellison GW,
Myers LW. Delta-9-THC in the treatment of spasticity asso-
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1092 Neurology 82 March 25, 2014

 Summary of evidence-based guideline: Complementary and alternative medicine in
multiple sclerosis: Report of the Guideline Development Subcommittee of the American
Academy of Neurology
Vijayshree Yadav, Christopher Bever, Jr, James Bowen, et al.
Neurology 2014;82;1083-1092
DOI 10.1212/WNL.0000000000000250

This information is current as of March 24, 2014

Updated Information & including high resolution figures, can be found at:
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Supplementary Material Supplementary material can be found at:

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http://n.neurology.org/content/suppl/2014/03/22/82.12.1083.DC2
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