Jcant 2(3-4) online.pdf

Cannabis in Multiple Sclerosis: Women's Health Concerns SUMMARY. Women's health has received greater attention with the
recognition of significant differences in disease expression and drug ac-
tion in men and women. Multiple sclerosis is a neurological disorder
with important gender differences. MS patients have employed cannabis
to treat a number of symptoms associated with the disease including
spasticity, pain, tremor, fatigue, and autonomic dysfunction. The scien-
tific literature includes supportive case reports, single-patient (N-of-1)
trials and randomized clinical trials. Large-scale clinical trials are under-
way to answer questions concerning the efficacy and safety of cannabis
in patients with MS. While these studies will answer important questions
concerning the actions of cannabinoids on the nervous system, addi-
tional studies in female MS patients will be needed to address issues such
as gender-specific actions on symptoms such as pain and autonomic dys-
function along with studies in menopausal and post-menopausal women.
Since the drug-drug interactions have been reported with cannabinoids,
the effects of cannabis on the actions of other centrally-acting drugs
should be explored. [Article copies available for a fee from The Haworth
Document Delivery Service: 1-800-HAWORTH. E-mail address: <getinfo@
haworthpressinc.com> Website:
2002 by
The Haworth Press, Inc. All rights reserved.]

KEYWORDS. Multiple sclerosis, cannabis, cannabinoids, spasticity,
women's medicine
Denis J. Petro, MD, 1550 Clarendon Boulevard, Suite 510, Arlington, VA 22209-2783 [Haworth co-indexing entry note]: "Cannabis in Multiple Sclerosis: Women's Health Concerns." Petro, Denis J. Co-published simultaneously in Journal of Cannabis Therapeutics (The Haworth Integrative HealingPress, an imprint of The Haworth Press, Inc.) Vol. 2, No. 3/4, 2002, pp. 161-175; and: Women and Cannabis:Medicine, Science, and Sociology (ed: Ethan Russo, Melanie Dreher, and Mary Lynn Mathre) The HaworthIntegrative Healing Press, an imprint of The Haworth Press, Inc., 2002, pp. 161-175. Single or multiple copiesof this article are available for a fee from The Haworth Document Delivery Service [1-800-HAWORTH, 9:00a.m. - 5:00 p.m. (EST). E-mail address: getinfo@haworthpressinc.com].
 2002 by The Haworth Press, Inc. All rights reserved.
Women and Cannabis: Medicine, Science, and Sociology Women's health issues have received attention as gender differences in dis- ease expression and drug action are discovered. A gender-based approach rec-ognizes the fundamental physiologic differences between men and women.
The areas of difference between men and women in the nervous system are ex-tensive including anatomy, cell numbers, neurotransmitter systems, responseto hormones, sensation threshold and disease frequencies. Gender and multi-ple sclerosis (MS) has been the subject of several excellent reviews (Olek andKhoury 2000; Coyle 2000). Specific disorders such as migraine headache, de-pression and motor neuron disease also show clear gender preferences.
Multiple sclerosis is a disorder with important gender-associated differ- ences in expression. Cannabis also interacts with the endocrine and immunesystems of males and females with distinctions. As therapeutic cannabis useamong MS patients has increased over the past generation, a review of the sub-ject with attention to women's health concerns is warranted.
Multiple sclerosis is the most common cause of chronic neurological dis- ability in young adults (Rusk and Plum 1998), and is more likely seen inwomen and in those who grew up in northern latitudes. In a summary of 30 in-cidence/prevalence studies, the cumulative female-to-male ratio was 1.77:1.00(Irizarry 1997). With 350,000 MS patients in the United States, the number offemale MS patients is approximately 225,000. Gender is clearly a determinantof susceptibility to MS. The increased female incidence in MS is similar toother autoimmune diseases with onset of symptoms in adulthood such as my-asthenia gravis, Hashimoto's thyroiditis, Sjögren's syndrome and systemiclupus erythematosus. The female preponderance in MS lessens in those inwhom presentation occurs later in life. MS attacks are less frequent duringpregnancy while the postpartum period is one of higher risk (Whitaker 1998).
While the postpartum increase in risk for MS attacks may discourage child-bearing, women who have borne a child fare better in the long term than thosewomen who have not (Runmarker and Anderson 1995). Interestingly, the oc-currence of a first pregnancy may lead to some permanent change in immunestatus.
Recognizing that current MS treatment is less than optimal, the use of can- nabis offers an opportunity to demonstrate the therapeutic potential of canna-binoids on a number of neurological symptoms. In a survey of health care in471 people with MS in the United Kingdom, use of cannabis was acknowl-edged by 8% (Somerset et al. 2001). Extrapolating to the 60,000 MS patients inthe UK provides an estimate of 4,800 MS patients who employ cannabis in theUK and 28,000 in the United States. In a publication commenting on the use ofcannabis in South Africa, James (1994) reported the experiences of a femaleMS patient (p. 369): Denis J. Petro A few years ago I had started to eat small quantities of marijuana . . theeffects were immediate and remarkable. Control of bladder functioningwhich was a humiliating problem is restored to normal and has been aliberating influence in my life-style. I can now go out shopping, to thetheater, etc., without anticipation of dread and panic. Painful and disturb-ing attacks of spasticity are relieved and now restful patterns of sleep areensured where previously sleep was disrupted by urinary frequency orpain and discomfort not least I can laugh and giggle, have marvelous sexand forget that I have this awful, incurable, intractable disease.
The challenge for physicians is to evaluate patient observations using scien- tific methodology. Many authors have described individual patient experi-ences of therapeutic use of cannabis to treat symptoms of MS (Grinspoon andBakalar 1997; Brown 1998; Iversen 2000). Additional support has been pro-vided by single-patient clinical trials (N-of-1) and prospective double-blindplacebo-controlled studies.
TREATMENT OPTIONS: ACUTE EPISODES,
DISEASE MODIFICATION AND SYMPTOM MANAGEMENT
Management of an acute episode of demyelination in MS is sometimes achieved to a limited extent with corticosteroids. Disease modification is diffi-cult to assess because MS is a chronic, unpredictable disorder in which the bur-den of white matter involvement is highly variable and the clinical response todrug treatment is modest. Five drugs have been approved by regulatory author-ities to modify the clinical course of MS. Avonex® (interferon-beta-1a),Betaseron® (interferon-beta-1b), Copaxone® (glatiramer acetate/copolymer 1),and Rebif® (interferon beta 1a) have demonstrated efficacy in relapsing-remit-ting MS and may slow the course of secondary progressive MS. Novantrone®(mitoxantrone) is approved for secondary progressive and progressive relaps-ing MS. Immunosuppressants such as corticosteroids, methotrexate, andcyclophosphamide have been used to alter the natural history of MS with somesuccess.
CANNABIS IN ACUTE TREATMENT AND DISEASE
While patients may claim that cannabis can alter the natural history of MS, no clinical trials have been conducted in either acute treatment or disease mod-ification. Data from animal research supports cannabinoids as a potentialdisease modifying treatment for MS. The immune-mediated disease, experi- Women and Cannabis: Medicine, Science, and Sociology mental autoimmune encephalomyelitis (EAE), is considered the laboratorymodel of MS. In a study in the Lewis rat and guinea pig, Lyman and colleagues(1989) demonstrated that the oral administration of ∆-9-tetrahydrocannabinol(THC) was effective in the prevention and suppression of EAE. The authorssuggested that ∆-9-THC might prove to be a new and relatively innocuousagent for the treatment of immune-mediated diseases such as MS. Since∆-9-THC is the cannabinoid associated with negative psychotropic actions, in-vestigators used other cannabinoids to assess actions in EAE. Wirguin and col-leagues (1994) studied the effect of ∆-8-THC on EAE in the rat. Orallyadministered ∆-8 THC significantly reduced the incidence and severity of neu-rological deficit while parenteral administration was not effective. The differ-ence can be explained on first-pass metabolism in the liver, which produces theactive metabolite. Additional support for beneficial effects of cannabinoids inEAE was reported by Achiron and co-investigators (2000) using a syntheticnon-psychotropic cannabinoid, dexanabinol (HU-211). The authors suggestedthat dexanabinol may provide an alternate treatment of acute exacerbations ofMS. Finally, Guzman, Sanchez and Galve-Roperh (2001) reviewed the experi-mental evidence showing the protective effects of cannabinoids from toxic in-sults such a glutamatergic over-stimulation, ischemia and oxidative damage.
The authors described the potential of cannabinoids to downregulate inflam-matory cytokine production.
If cannabinoid drugs are to be used in acute treatment of MS or in disease modification, then studies in female patients will be needed. These studies in-volve assessment of drug effects on fertility, pregnancy and in nursing moth-ers. Since inclusion of women in early clinical trials is usually insufficient toidentify gender-based differences in response, animal models are used toidentify potential pharmacologic and toxicological effects (Christian 2001).
Unfortunately, current animal models do not consistently demonstrate gen-der-based differences seen in humans. The cannabinoid ∆-9-THC is marketedin the United States as Marinol® and information concerning use in women isprovided in the Physicians' Desk Reference (2002). Marinol is included inCategory C (FDA designation for drugs with animal data showing harm to thefetus with no controlled human studies). The drug labeling states that Marinolshould be used only if the potential benefit justifies the potential risk to the fetus.
Likewise, its use in nursing mothers is not recommended since Marinol is con-centrated in and secreted in human breast milk and is absorbed by the nursingbaby.
Drug interaction studies would be needed to investigate the potential for significant interactions with drugs commonly used by women. Because canna-binoids are highly bound to plasma proteins and might displace other pro-tein-bound drugs, dosage adjustment for other highly protein-bound drugsmay be needed. In addition, drugs metabolized by hepatic mixed-function Denis J. Petro oxidase enzymes may be inhibited by cannabinoids (Benowitz and Jones1977). In the PDR drug interaction section for Marinol, specific precautionsare included regarding potential interactions with a number of drugs includingsympathomimetic agents, antihistamines, tricyclic antidepressants, muscle re-laxants, barbiturates and theophylline. Other drugs which may be important infemale patients include birth control drugs, hormones administered to treatsymptoms associated with menopause, steroids, and drugs used in the treat-ment of osteoporosis.
The effects of inhaled cannabis on fetal development have been studied extensively. In a study of six one-year-old infants exposed daily to cannabisprenatally and through breastfeeding, no malformations were found in canna-bis-exposed infants (Tennes et al. 1985). A prospective study of the effects ofprenatal exposure to cigarettes and cannabis on growth from birth to adoles-cence found no significant effects on growth measures at birth although asmaller head circumference observed at all ages reached statistical signifi-cance among the adolescents born to heavy marijuana users (Fried et al. 1999).
Finally, the relationship between maternal use of cannabis and pregnancy out-come was investigated in a study of 12,000 women in the UK (Fergusson et al.
2002). Five percent of mothers reported smoking cannabis before and/or dur-ing pregnancy. The use of cannabis during pregnancy was not associated withincreased risk of perinatal mortality or morbidity. The babies of women whoused cannabis weekly before and during pregnancy were lighter than those ofnon-users and had shorter birth lengths and smaller head circumferences. Thefindings of this study are consistent with earlier studies that have found an ab-sence of statistical association between cannabis use and antenatal or perinatalmorbidity and mortality. The reduced birth weight seen with regular or heavycannabis use suggests that to optimize fetal growth and minimize the risk of anadverse pregnancy outcome, pregnant women should limit cannabis use dur-ing pregnancy. In female patients during the reproductive years, fertility andpregnancy are usually not affected by MS. While MS activity seems to de-crease during pregnancy, exacerbation rates increase in the first 6 monthspostpartum (Birk and Rudick 1986). Since cannabinoids are secreted in humanbreast milk and absorbed by the nursing baby, cannabis use while breast-feed-ing should be avoided.
Special studies of cannabis in menopausal and post-menopausal women have been conducted. Mendelson and colleagues (1985) studied LH levels inmenopausal women after marijuana smoking and found no significant differ-ence in LH levels when compared to values for healthy menopausal women. Ina study of the acute effects of marijuana smoking in post-menopausal women,Benedikt and colleagues (1986) noted statistically significant increases inpulse rate, intoxication levels and the confusion component of the Profile ofMood States Questionnaire (POMS). The finding of neuropsychological per- Women and Cannabis: Medicine, Science, and Sociology formance impairment in post-menopausal women is not unlike the findings inmoderate cannabis users (Pope et al. 2001) and in heavy cannabis users(Solowij et al. 2002). The degree of impairment in memory and attention arenot surprising in chronic heavy users. Pope (2002) presents the consensusopinion that some cognitive deficits persist for hours or days after acute intoxi-cation with cannabis has subsided. Since cognitive impairment is associatedwith MS, the potential for significant adverse effect on memory and attentionin MS patients using therapeutic cannabis should be a subject of future clinicalresearch.
CANNABIS IN SYMPTOM MANAGEMENT
Manifestations of MS are protean and depend on the location of persistent central nervous system lesions. Since MS lesions have a predilection for certainanatomic locations, recognizable clinical syndromes are common in MS. Sur-veys of symptoms in MS have been carried out with the most common symp-toms including fatigue, balance impairment, muscle disturbances (weakness,stiffness, pain and spasm), and bowel and bladder impairment (Compston1997). In chronic MS, signs and symptoms of motor dysfunction are found in atleast 75 percent of patients (Miller 2000) with sensory impairment noted in 50percent. Cerebellar abnormalities (ataxia, tremor, nystagmus or dysarthria) arefound in at least a third of MS patients. Autonomic symptoms including bowel,bladder or sexual dysfunction are found in at least 50 percent of patients.
A survey of cannabis-using MS patients in the USA and UK by Consroe and colleagues (1997) reported improvements after cannabis use in spasticity,chronic pain, acute paroxysmal phenomena, tremor, emotional dysfunction,anorexia/weight loss, fatigue, diplopia, sexual dysfunction, bowel and bladderdysfunction, vision dimness, dysfunction of walking and balance, and memoryloss (descending rank order). While the authors of this study discuss the poten-tial shortcomings of the survey design, this report suggests that cannabis maysignificantly relieve signs and symptoms of MS such as spasticity and painalong with a number of other complaints.
IMPAIRED MOBILITY: SPASTICITY
In the 19th century, O'Shaughnessy (1842) used hemp extract in treating muscle spasms associated with tetanus and rabies. Reynolds (1890) reportedusing cannabis to treat muscle spasms, as well as for epilepsy, migraine, andother indications. While medicinal cannabis use continued in the years afterthe work of O'Shaughnessy and Reynolds, little was published concerningcannabis and spasticity until the 1970s. A survey of 10 spinal-cord injured Denis J. Petro males was published in 1974 in which 5 patients reported reduced spasticity, 3patients noted no effect and 2 patients did not have significant spasticity (Dunnand Davis 1974).
The use of cannabis to treat spasticity associated with MS has been reported by a number of investigators over the subsequent interval. Petro (1980) re-ported one patient with MS who used cannabis to treat nocturnal leg fatigueand spasms associated with spasticity. Petro and Ellenberger (1981) conducteda double-blind clinical trial that demonstrated statistically significant reduc-tion in spasticity following the oral administration of ∆-9-THC in doses of 5and 10 mg. Investigators have confirmed the observation using ∆-9-THC(Hanigan et al. 1985; Ungerleider et al. 1988; Maurer et al. 1990), cannabis(Meinck et al. 1989) and nabilone (Martyn et al. 1995). Additional preclinicalsupport for the benefit from cannabis in spasticity was provided by the reportof Baker and colleagues (2000). In this study, cannabinoid receptor agonismimproved tremor and spasticity in mice with chronic relapsing experimentalallergic encephalomyelitis (CREAE) and indicated that the endogenous canna-binoid system may be active in control of spasticity and tremor. Further sup-port for cannabinoid receptor involvement was provided in an animal study inwhich cannabinoid receptor (CB1) changes were found in regions of the brain involved in the control of motor symptoms (Berrendero et al. 2001). The roleof the endocannabinoid system in spasticity was demonstrated in CREAEmice in a further study, which manipulated tone using cannabinoid receptoragonists and antagonists (Baker et al. 2001).
Since a considerable body of scientific evidence supports the efficacy of cannabinoids in spasticity, review articles (Gracies et al. 1997; Consroe 1999)and medical texts (Compston 1999; Compston 2001) include cannabis as atreatment option in spasticity. In Brain's Diseases of the Nervous System Elev-enth Edition (Compston 2001), among the treatments for spasticity associatedwith MS, cannabinoids are listed along with baclofen, dantrium, benzo-diazepines and tizanidine.
Gender issues are involved in MS-associated spasticity. Since females are more likely to experience demyelination at an earlier age than males, the bur-den of white matter disease over time may be greater in females. The earlierappearance of symptoms in females is somewhat counterbalanced by a greaterprevalence of spinal MS seen in males and occurring later in life. The late oc-curring form of MS often involves progressive spinal lesions presenting withspasticity and pain.
Tremor in MS is treated with beta-blockers, anticonvulsants or, in rare cases, stereotactic procedures. Experimental evidence for benefit from canna- Women and Cannabis: Medicine, Science, and Sociology bis is provided in a preclinical study by Baker and colleagues (2000) in whichtreatment with a CB1 antagonist resulted in increased forelimb tremor. Since isolation of tremor from spasticity may be difficult in experimental animals,interpretation of such evidence may be questioned. In the survey of patientswith MS by Consroe and associates (1997), 90% of subjects with tremor re-ported improvement after cannabis. In a study of 8 MS patients with tremorand ataxia, oral THC was effective in 2 of 8 subjects with both subjective andobjective improvement (Clifford 1983).
Nystagmus is an eye movement abnormality often associated with MS. In an N-of-1 clinical trial, a 52-year-old man with MS and pendular nystagmuswas studied in the United Kingdom over 3 months before and after cannabis inthe form of cigarettes, nabilone and cannabis oil-containing capsules (Schon etal. 1998). The investigators demonstrated improved visual acuity and suppres-sion of the patient's pendular nystagmus after inhaled cannabis and were ableto correlate the therapeutic effect with acute changes in serum cannabinoidlevels. Nabilone and orally administered cannabis oil capsules had no effect.
Because of the anatomical relationships involved in eye movement control, theauthors suggest an effect at the level of the dorsal pontine tegmentum. In sup-port of action at the level of the deep brain stem is the benefit seen with cannabisin intractable hiccups (Gilson and Busalacchi 1998) and evidence supportingcannabinoid analgesic actions mediated in the rostral ventromedial medulla(Meng et al. 1998). Responding to the report of benefit in nystagmus associ-ated with MS, Dell'Osso (2000) reported an individual with congenital nystag-mus whose oscillations dampened after smoking cannabis. Dell'Osso commentedthat while he had seen similar reports from patients, cannabis research is dis-couraged in the United States.
The complex integration of sensory and motor function required for pos- tural regulation is impaired in many patients with MS. Impairment of postureis most disabling for patients, distressing for caregivers, and frustrating forphysicians. Lesions of spinal, cerebral and cerebellar pathways result in loss ofbalance. In a study of 10 MS patients, inhaled cannabis caused increasedpostural tracking error both in MS patients and in normal control subjects(Greenberg et al. 1994). The authors admitted in their publication that dynamicposturography "is not a measure of spasticity." Some authors have reported in-correctly that this study is a negative study in spasticity. Since cerebellar dys- Denis J. Petro function is a common finding in MS seen in a third to 80 percent of patients,one can anticipate that many MS patients with both motor and cerebellarsymptoms may find improved spasticity and impaired balance. Cannabinoidsshould be used with caution in patients with the combination of corticospinal(spasticity) and cerebellar (balance) deficits.
Fatigue is one of the most frequently reported symptoms in MS and is clearly distinct from fatigue experienced in an otherwise healthy individual.
The mechanism for fatigue in MS is unknown. No differences have been foundin the level of MS-associated fatigue between men and women. Clinical trialshave demonstrated that amantadine may be beneficial; however, the support-ing evidence is weak (Branas et al. 2000). In a single-blind trial of modafinil inpatients with MS (Rammohan et al. 2002), fatigue scores were improved dur-ing treatment (200 mg/day). In the only study addressing the effect of cannabison fatigue, Consroe (1997) reported survey data which showed from 60 to 70%of subjects reported cannabis reduced fatigue states (tiredness, leg weakness).
No controlled clinical trials of cannabinoids have investigated this condition.
Because of the nature of MS as a disruption of transmission of nerve impulses, paroxysmal manifestations are commonly seen including tonicbrainstem attacks, trigeminal neuralgia, and spasticity. Anticonvulsants andantidepressants are commonly used in MS pain syndromes, with some benefit.
Cannabinoids have not been studied extensively in MS-associated pain. Inother pain models, cannabinoids have demonstrated efficacy comparable topotent analgesics, such as the opioids (Campbell et al. 2001). Gender differ-ences can affect pain via biological differences in the nociceptive and percep-tual systems. In humans, women are, in general, more sensitive to painfulstimuli when compared to men (LeResche 2001). The prevalence of pain syn-dromes in female patients with MS has not been studied.
Bladder impairment in MS is seen in up to 80% of patients at some time dur- ing the course of the disease and can vary from slight inconvenience to poten-tially life-threatening when renal function is compromised. The complexinteraction between bladder detrussor and sphincter function is disrupted with Women and Cannabis: Medicine, Science, and Sociology spinal cord lesions in MS. Drugs used in the treatment of spasticity such asbaclofen and diazepam are effective in treating bladder symptoms in many MSpatients by inhibiting the urethral sphincter. MS patients, as the example of thefemale patient from South Africa described earlier (James, 1994), report im-provements in bladder function after cannabinoid use. Based on the observa-tions of improved urinary tract function, an open-label pilot study of cannabisbased medicinal extract (CBME) has been reported by Brady and colleagues(2001). In this study sublingual CBME improved lower urinary tract functionin 10 patients with advanced MS and refractory urinary tract dysfunction over8 weeks of treatment.
Treatment of sexual dysfunction in male MS patients includes a range of options including pharmacological treatments such as sildenafil (Viagra®),papaverine or phentolamine. No treatment other than local administration ofartificial lubrication is available for treatment of sexual dysfunction in fe-males. In the Consroe survey of cannabis effects on MS signs and symptoms(1997), 51 subjects reported sexual dysfunction with 62.7% claiming improve-ment in sexual function after cannabis. No analysis by gender was reported.
Based on previously reported survey data, the clinical study of cannabis as atreatment of sexual dysfunction in MS appears warranted.
Neurologists in practice in the 1970s noted two distinct patient groups using therapeutic cannabis. Military personnel injured in Vietnam claimed that can-nabis was helpful in controlling symptoms associated with traumatic spinal in-jury. Female patients described beneficial effects from cannabis in treatingspasticity, migraine headache or menstrual pain. These observations led to anumber of small clinical trials supporting the claims of individual patients. Be-cause of regulatory hurdles in conducting clinical research with cannabis, thetotal number of patients treated with cannabinoid drugs remains low.
Fortunately, interest in the subject has increased with the initiation of sev- eral large-scale cannabis studies in MS in the United Kingdom. The NationalInstitute of Clinical Excellence (NICE), the UK regulatory authority, will as-sess the results of clinical trials scheduled be completed by the end of 2002.
Over the years, many patients have asked questions concerning the efficacy and safety of cannabis as a therapeutic agent. While cannabis remains as a pro-hibited drug in the United States, ∆-9-THC is marketed as Marinol® withoutobjection. One can contrast a potential package insert for cannabis with that for Denis J. Petro the antispastic drug, Lioresal® Intrathecal. With the use of Lioresal via a spinalpump, the drug labeling states that in clinical trials "13 deaths occurringamong the 438 patients treated with Lioresal Intrathecal in premarketingstudies." Interestingly, two MS patients died suddenly within 2 weeks of drugadministration. Imagine the regulatory reaction if a single patient would die af-ter cannabis use. A potential risk associated with cannabis is secondary to theinhalation of cannabis containing smoke. The evidence of significant healthrisk associated with cigarette smoking is overwhelming. While many patientsavoid inhalation risks by using oral cannabis, the rapid action of an inhaled for-mulation is effective with symptoms such as flexor spasms or tonic brainstemattacks. One study noted an elevated risk of myocardial infarction (4.8 timesbaseline) in the 60 minutes after cannabis inhalation (Mittleman et al. 2001).
While cannabis was considered a rare trigger of acute myocardial infarction,risk elevation was associated with obesity, current cigarette smoking and malegender.
Additional safety concerns associated with cannabis use in MS include the negative effects of cannabis on balance and cognition. While these negative ef-fects may limit the potential usefulness of cannabis as a treatment of chronicsymptoms in MS, many MS patients may yet benefit from cannabis.
While the interest in cannabis as a therapeutic agent for MS is high, many unanswered scientific questions remain including: 1. How does cannabis compare with current standard treatments for MS 2. Can alternative delivery systems be developed to provide rapid onset of action with greater safety when compared to inhaled cannabis? 3. Can specific cannabinoids be used more effectively to stimulate or block cannabinoid system receptor activity? 4. Can the immune-modulating actions of cannabis be used to alter the nat- ural history of MS? 5. Can the long-term risks and benefits of cannabis be quantified to deter- mine a useful risk/benefit ratio in treating the life-long disability in MS? Evidence in support of cannabis treatment for spasticity associated with MS includes animal studies and a small number of clinical trials using cannabinoiddrugs. Clinical reports of benefit in tremor and nystagmus have been publishedin MS patients. Potential other signs and symptoms in MS, which may be im-proved with cannabis, include fatigue, pain, bladder disturbances and sexualdysfunction. Women are twice as likely as men to develop MS. Gender spe- Women and Cannabis: Medicine, Science, and Sociology cific concerns in female patients include use of cannabis during pregnancy,potential effects on the fetus, and risks associated with breast-feeding. Large-scale clinical trials may provide some answers concerning the potential of can-nabis in treatment of MS.
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MONISTAT DERM™ CREAM CRÈME MONISTAT DERM™ Fluconazole Capsule 150 mg Miconazole Nitrate Cream USP 2% Capsule de Fluconazole 150 mg Crème de nitrate de miconazole à 2 % USP IMPORTANT : VEUILLEZ LIRE ATTENTIVEMENT IMPORTANT PLEASE READ La présente notice est la partie III d'une « monographie de produit » en trois parties This leaflet is part III of a three-part "Product Monograph" published when

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Lithium-ion batteries – The bubble bursts Stuttgart, October 2012 Consolidation in the lithium-ion battery (LiB) market is inevitable – Stakeholders need to revise their strategies The large-format lithium-ion cell market will face overcapacity and price wars: - Demand is lower than expected - A lot of capacity has been built up – but new equipment to be installed will be