SUMMARY. Women’s health has received greater attention with the rec- ognition of significant differences in disease expression and drug action in men and women. Multiple sclerosis is a neurological disorder with impor- tant 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 scientific literature in- cludes supportive case reports, single-patient (N-of-1) trials and random- ized clinical trials. Large-scale clinical trials are underway 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, additional studies in female MS patients will be needed to address issues such as gender-specific ac- tions on symptoms such as pain and autonomic dysfunction 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: <[email protected] haworthpressinc.com> Website:
2002 by The Haworth Press, Inc. All rightsKEYWORDS. 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 Haworth Inte-grative Healing Press, an imprint of The Haworth Press, Inc., 2002, pp. 161-175. Single or multiple copies of thisarticle are available for a fee from The Haworth Document Delivery Service [1-800-HAWORTH, 9:00 a.m. - 5:00p.m. (EST). E-mail address: [email protected]].
2002 by The Haworth Press, Inc. All rights reserved. Women and Cannabis: Medicine, Science, and SociologyINTRODUCTION
Women’s health issues have received attention as gender differences in dis-
ease expression and drug action are discovered. A gender-based approach recog-nizes the fundamental physiologic differences between men and women. Theareas of difference between men and women in the nervous system are extensiveincluding anatomy, cell numbers, neurotransmitter systems, response to hor-mones, sensation threshold and disease frequencies. Gender and multiple sclero-sis (MS) has been the subject of several excellent reviews (Olek and Khoury2000; Coyle 2000). Specific disorders such as migraine headache, depression andmotor neuron disease also show clear gender preferences.
Multiple sclerosis is a disorder with important gender-associated differences
in expression. Cannabis also interacts with the endocrine and immune systems ofmales and females with distinctions. As therapeutic cannabis use among MS pa-tients has increased over the past generation, a review of the subject with atten-tion to women’s health concerns is warranted.
Multiple sclerosis is the most common cause of chronic neurological disabil-
ity in young adults (Rusk and Plum 1998), and is more likely seen in women andin those who grew up in northern latitudes. In a summary of 30 incidence/preva-lence 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 of female MS patientsis approximately 225,000. Gender is clearly a determinant of susceptibility toMS. The increased female incidence in MS is similar to other autoimmune dis-eases with onset of symptoms in adulthood such as myasthenia gravis,Hashimoto’s thyroiditis, Sjögren’s syndrome and systemic lupus erythematosus. The female preponderance in MS lessens in those in whom presentation occurslater in life. MS attacks are less frequent during pregnancy while the postpartumperiod is one of higher risk (Whitaker 1998). While the postpartum increase inrisk for MS attacks may discourage childbearing, women who have borne a childfare better in the long term than those women who have not (Runmarker and An-derson 1995). Interestingly, the occurrence of a first pregnancy may lead to somepermanent change in immune status.
Recognizing that current MS treatment is less than optimal, the use of canna-
bis offers an opportunity to demonstrate the therapeutic potential of cannabinoidson a number of neurological symptoms. In a survey of health care in 471 peoplewith MS in the United Kingdom, use of cannabis was acknowledged by 8%(Somerset et al. 2001). Extrapolating to the 60,000 MS patients in the UK pro-vides an estimate of 4,800 MS patients who employ cannabis in the UK and28,000 in the United States. In a publication commenting on the use of cannabisin South Africa, James (1994) reported the experiences of a female MS patient (p. 369):
A few years ago I had started to eat small quantities of marijuana . . . the ef-fects were immediate and remarkable. Control of bladder functioningwhich was a humiliating problem is restored to normal and has been a liber-ating influence in my life-style. I can now go out shopping, to the theater,etc., without anticipation of dread and panic. Painful and disturbing attacksof spasticity are relieved and now restful patterns of sleep are ensuredwhere previously sleep was disrupted by urinary frequency or pain and dis-comfort not least I can laugh and giggle, have marvelous sex and forget thatI 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 experiencesof therapeutic use of cannabis to treat symptoms of MS (Grinspoon and Bakalar1997; Brown 1998; Iversen 2000). Additional support has been provided by sin-gle-patient clinical trials (N-of-1) and prospective double-blind placebo-con-trolled 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 difficultto assess because MS is a chronic, unpredictable disorder in which the burden ofwhite matter involvement is highly variable and the clinical response to drugtreatment is modest. Five drugs have been approved by regulatory authorities tomodify the clinical course of MS. Avonex® (interferon-beta-1a), Betaseron® (in-terferon-beta-1b), Copaxone® (glatiramer acetate/copolymer 1), and Rebif® (in-terferon beta 1a) have demonstrated efficacy in relapsing-remitting MS and mayslow the course of secondary progressive MS. Novantrone® (mitoxantrone) isapproved
cyclophosphamide have been used to alter the natural history of MS with somesuccess. CANNABIS IN ACUTE TREATMENT AND DISEASE MODIFICATION
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 modifica-tion. Data from animal research supports cannabinoids as a potential diseasemodifying treatment for MS. The immune-mediated disease, experimental auto-immune encephalomyelitis (EAE), is considered the laboratory model of MS. In
Women and Cannabis: Medicine, Science, and Sociology
a study in the Lewis rat and guinea pig, Lyman and colleagues (1989) demon-strated that the oral administration of ∆-9-tetrahydrocannabinol (THC) was ef-fective in the prevention and suppression of EAE. The authors suggested that∆-9-THC might prove to be a new and relatively innocuous agent for the treat-ment of immune-mediated diseases such as MS. Since ∆-9-THC is thecannabinoid associated with negative psychotropic actions, investigators usedother cannabinoids to assess actions in EAE. Wirguin and colleagues (1994)studied the effect of ∆-8-THC on EAE in the rat. Orally administered ∆-8 THCsignificantly reduced the incidence and severity of neurological deficit whileparenteral administration was not effective. The difference can be explained onfirst-pass metabolism in the liver, which produces the active metabolite. Addi-tional support for beneficial effects of cannabinoids in EAE was reported byAchiron and co-investigators (2000) using a synthetic non-psychotropiccannabinoid, dexanabinol (HU-211). The authors suggested that dexanabinolmay provide an alternate treatment of acute exacerbations of MS. Finally,Guzman, Sanchez and Galve-Roperh (2001) reviewed the experimental evidenceshowing the protective effects of cannabinoids from toxic insults such aglutamatergic over-stimulation, ischemia and oxidative damage. The authors de-scribed the potential of cannabinoids to downregulate inflammatory cytokineproduction.
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 mothers. Since inclusion of women in early clinical trials is usually insufficient to identifygender-based differences in response, animal models are used to identify poten-tial pharmacologic and toxicological effects (Christian 2001). Unfortunately,current animal models do not consistently demonstrate gender-based differencesseen in humans. The cannabinoid ∆-9-THC is marketed in the United States asMarinol® and information concerning use in women is provided in the Physi-cians’ Desk Reference (2002). Marinol is included in Category C (FDA designa-tion for drugs with animal data showing harm to the fetus with no controlledhuman studies). The drug labeling states that Marinol should be used only if the po-tential benefit justifies the potential risk to the fetus. Likewise, its use in nursingmothers is not recommended since Marinol is concentrated in and secreted in hu-man breast milk and is absorbed by the nursing baby.
Drug interaction studies would be needed to investigate the potential for sig-
nificant interactions with drugs commonly used by women. Because canna-binoids are highly bound to plasma proteins and might displace otherprotein-bound drugs, dosage adjustment for other highly protein-bound drugsmay be needed. In addition, drugs metabolized by hepatic mixed-functionoxidase enzymes may be inhibited by cannabinoids (Benowitz and Jones 1977). In the PDR drug interaction section for Marinol, specific precautions are in-
cluded regarding potential interactions with a number of drugs includingsympathomimetic agents, antihistamines, tricyclic antidepressants, muscle relax-ants, barbiturates and theophylline. Other drugs which may be important in fe-male patients include birth control drugs, hormones administered to treatsymptoms associated with menopause, steroids, and drugs used in the treatmentof 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 cannabis pre-natally and through breastfeeding, no malformations were found in cannabis-ex-posed infants (Tennes et al. 1985). A prospective study of the effects of prenatalexposure to cigarettes and cannabis on growth from birth to adolescence foundno significant effects on growth measures at birth although a smaller head cir-cumference observed at all ages reached statistical significance among the ado-lescents born to heavy marijuana users (Fried et al. 1999). Finally, therelationship between maternal use of cannabis and pregnancy outcome was in-vestigated in a study of 12,000 women in the UK (Fergusson et al. 2002). Fivepercent of mothers reported smoking cannabis before and/or during pregnancy. The use of cannabis during pregnancy was not associated with increased risk ofperinatal mortality or morbidity. The babies of women who used cannabisweekly before and during pregnancy were lighter than those of non-users and hadshorter birth lengths and smaller head circumferences. The findings of this studyare consistent with earlier studies that have found an absence of statistical associ-ation between cannabis use and antenatal or perinatal morbidity and mortality. The reduced birth weight seen with regular or heavy cannabis use suggests that tooptimize fetal growth and minimize the risk of an adverse pregnancy outcome,pregnant women should limit cannabis use during pregnancy. In female patientsduring the reproductive years, fertility and pregnancy are usually not affected byMS. While MS activity seems to decrease during pregnancy, exacerbation ratesincrease in the first 6 months postpartum (Birk and Rudick 1986). Sincecannabinoids are secreted in human breast milk and absorbed by the nursingbaby, cannabis use while breast-feeding should be avoided.
Special studies of cannabis in menopausal and post-menopausal women have
been conducted. Mendelson and colleagues (1985) studied LH levels in meno-pausal women after marijuana smoking and found no significant difference in LHlevels when compared to values for healthy menopausal women. In a study of theacute effects of marijuana smoking in post-menopausal women, Benedikt andcolleagues (1986) noted statistically significant increases in pulse rate, intoxica-tion levels and the confusion component of the Profile of Mood States Question-naire (POMS). The finding of neuropsychological performance impairment inpost-menopausal women is not unlike the findings in moderate cannabis users(Pope et al. 2001) and in heavy cannabis users (Solowij et al. 2002). The degreeof impairment in memory and attention are not surprising in chronic heavy users. Women and Cannabis: Medicine, Science, and Sociology
Pope (2002) presents the consensus opinion that some cognitive deficits persistfor hours or days after acute intoxication with cannabis has subsided. Since cog-nitive impairment is associated with MS, the potential for significant adverse ef-fect on memory and attention in MS patients using therapeutic cannabis shouldbe a subject of future clinical research. CANNABIS IN SYMPTOM MANAGEMENT
Manifestations of MS are protean and depend on the location of persistent cen-
tral nervous system lesions. Since MS lesions have a predilection for certain ana-tomic locations, recognizable clinical syndromes are common in MS. Surveys ofsymptoms in MS have been carried out with the most common symptoms includ-ing fatigue, balance impairment, muscle disturbances (weakness, stiffness, painand spasm), and bowel and bladder impairment (Compston 1997). In chronic MS,signs and symptoms of motor dysfunction are found in at least 75 percent of pa-tients (Miller 2000) with sensory impairment noted in 50 percent. Cerebellar ab-normalities (ataxia, tremor, nystagmus or dysarthria) are found in at least a third ofMS patients. Autonomic symptoms including bowel, bladder or sexual dysfunctionare 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, an-orexia/weight loss, fatigue, diplopia, sexual dysfunction, bowel and bladder dys-function, vision dimness, dysfunction of walking and balance, and memory loss(descending rank order). While the authors of this study discuss the potentialshortcomings of the survey design, this report suggests that cannabis may signifi-cantly relieve signs and symptoms of MS such as spasticity and pain along with anumber of other complaints. IMPAIRED MOBILITY: SPASTICITY
In the 19th century, O’Shaughnessy (1842) used hemp extract in treating mus-
cle spasms associated with tetanus and rabies. Reynolds (1890) reported usingcannabis to treat muscle spasms, as well as for epilepsy, migraine, and other indi-cations. While medicinal cannabis use continued in the years after the work ofO’Shaughnessy and Reynolds, little was published concerning cannabis andspasticity until the 1970s. A survey of 10 spinal-cord injured males was pub-lished in 1974 in which 5 patients reported reduced spasticity, 3 patients noted noeffect and 2 patients did not have significant spasticity (Dunn and 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) reported
one patient with MS who used cannabis to treat nocturnal leg fatigue and spasmsassociated with spasticity. Petro and Ellenberger (1981) conducted a dou-ble-blind clinical trial that demonstrated statistically significant reduction inspasticity following the oral administration of ∆-9-THC in doses of 5 and 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 preclinical support for the benefitfrom cannabis in spasticity was provided by the report of Baker and colleagues(2000). In this study, cannabinoid receptor agonism improved tremor andspasticity in mice with chronic relapsing experimental allergic encephalomyelitis(CREAE) and indicated that the endogenous cannabinoid system may be active incontrol of spasticity and tremor. Further support for cannabinoid receptor in-volvement was provided in an animal study in which cannabinoid receptor (CB1)
changes were found in regions of the brain involved in the control of motor symp-toms (Berrendero et al. 2001). The role of the endocannabinoid system inspasticity was demonstrated in CREAE mice in a further study, which manipu-lated tone using cannabinoid receptor agonists 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 a treat-ment option in spasticity. In Brain’s Diseases of the Nervous System EleventhEdition (Compston 2001), among the treatments for spasticity associated withMS, cannabinoids are listed along with baclofen, dantrium, benzodiazepines andtizanidine.
Gender issues are involved in MS-associated spasticity. Since females are
more likely to experience demyelination at an earlier age than males, the burdenof white matter disease over time may be greater in females. The earlier appear-ance of symptoms in females is somewhat counterbalanced by a greater preva-lence of spinal MS seen in males and occurring later in life. The late occurringform of MS often involves progressive spinal lesions presenting with spasticityand pain. TREMOR
Tremor in MS is treated with beta-blockers, anticonvulsants or, in rare cases,
stereotactic procedures. Experimental evidence for benefit from cannabis is pro-vided in a preclinical study by Baker and colleagues (2000) in which treatmentwith a CB1 antagonist resulted in increased forelimb tremor. Since isolation of
tremor from spasticity may be difficult in experimental animals, interpretation ofsuch evidence may be questioned. In the survey of patients with MS by Consroeand associates (1997), 90% of subjects with tremor reported improvement after
Women and Cannabis: Medicine, Science, and Sociology
cannabis. In a study of 8 MS patients with tremor and ataxia, oral THC was effec-tive in 2 of 8 subjects with both subjective and objective improvement (Clifford1983). NYSTAGMUS
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 nystagmus wasstudied in the United Kingdom over 3 months before and after cannabis in theform of cigarettes, nabilone and cannabis oil-containing capsules (Schon et al. 1998). The investigators demonstrated improved visual acuity and suppressionof the patient’s pendular nystagmus after inhaled cannabis and were able to cor-relate the therapeutic effect with acute changes in serum cannabinoid levels. Nabilone and orally administered cannabis oil capsules had no effect. Because ofthe anatomical relationships involved in eye movement control, the authors sug-gest an effect at the level of the dorsal pontine tegmentum. In support of action atthe level of the deep brain stem is the benefit seen with cannabis in intractable hic-cups (Gilson and Busalacchi 1998) and evidence supporting cannabinoid analge-sic actions mediated in the rostral ventromedial medulla (Meng et al. 1998). Responding to the report of benefit in nystagmus associated with MS, Dell’Osso(2000) reported an individual with congenital nystagmus whose oscillationsdampened after smoking cannabis. Dell’Osso commented that while he had seensimilar reports from patients, cannabis research is discouraged in the UnitedStates. POSTURAL REGULATION
The complex integration of sensory and motor function required for postural
regulation is impaired in many patients with MS. Impairment of posture is mostdisabling for patients, distressing for caregivers, and frustrating for physicians. Lesions of spinal, cerebral and cerebellar pathways result in loss of balance. In astudy of 10 MS patients, inhaled cannabis caused increased postural tracking er-ror both in MS patients and in normal control subjects (Greenberg et al. 1994). The authors admitted in their publication that dynamic posturography “is not ameasure of spasticity.” Some authors have reported incorrectly that this study is anegative study in spasticity. Since cerebellar dysfunction is a common finding inMS seen in a third to 80 percent of patients, one can anticipate that many MS pa-tients with both motor and cerebellar symptoms may find improved spasticityand impaired balance. Cannabinoids should be used with caution in patients withthe combination of corticospinal (spasticity) and cerebellar (balance) deficits. FATIGUE
Fatigue is one of the most frequently reported symptoms in MS and is clearly
distinct from fatigue experienced in an otherwise healthy individual. The mecha-nism for fatigue in MS is unknown. No differences have been found in the levelof MS-associated fatigue between men and women. Clinical trials have demon-strated that amantadine may be beneficial; however, the supporting evidence isweak (Branas et al. 2000). In a single-blind trial of modafinil in patients with MS(Rammohan et al. 2002), fatigue scores were improved during treatment (200mg/day). In the only study addressing the effect of cannabis on fatigue, Consroe(1997) reported survey data which showed from 60 to 70% of subjects reportedcannabis reduced fatigue states (tiredness, leg weakness). No controlled clinicaltrials of cannabinoids have investigated this condition. PAIN
Because of the nature of MS as a disruption of transmission of nerve impulses,
paroxysmal manifestations are commonly seen including tonic brainstem at-tacks, trigeminal neuralgia, and spasticity. Anticonvulsants and antidepressantsare commonly used in MS pain syndromes, with some benefit. Cannabinoidshave not been studied extensively in MS-associated pain. In other pain models,cannabinoids have demonstrated efficacy comparable to potent analgesics, suchas the opioids (Campbell et al. 2001). Gender differences can affect pain via bio-logical differences in the nociceptive and perceptual systems. In humans, womenare, in general, more sensitive to painful stimuli when compared to men(LeResche 2001). The prevalence of pain syndromes in female patients with MShas not been studied. BLADDER DYSFUNCTION
Bladder impairment in MS is seen in up to 80% of patients at some time during
the course of the disease and can vary from slight inconvenience to potentiallylife-threatening when renal function is compromised. The complex interactionbetween bladder detrussor and sphincter function is disrupted with spinal cord le-sions in MS. Drugs used in the treatment of spasticity such as baclofen and diaze-pam are effective in treating bladder symptoms in many MS patients byinhibiting the urethral sphincter. MS patients, as the example of the female pa-tient from South Africa described earlier (James, 1994), report improvements inbladder function after cannabinoid use. Based on the observations of improvedurinary tract function, an open-label pilot study of cannabis based medicinal ex-tract (CBME) has been reported by Brady and colleagues (2001). In this study
Women and Cannabis: Medicine, Science, and Sociology
sublingual CBME improved lower urinary tract function in 10 patients with ad-vanced MS and refractory urinary tract dysfunction over 8 weeks of treatment. SEXUAL DYSFUNCTION
Treatment of sexual dysfunction in male MS patients includes a range of op-
tions including pharmacological treatments such as sildenafil (Viagra®),papaverine or phentolamine. No treatment other than local administration of arti-ficial lubrication is available for treatment of sexual dysfunction in females. Inthe Consroe survey of cannabis effects on MS signs and symptoms (1997), 51subjects reported sexual dysfunction with 62.7% claiming improvement in sex-ual function after cannabis. No analysis by gender was reported. Based on previ-ously reported survey data, the clinical study of cannabis as a treatment of sexualdysfunction in MS appears warranted. DISCUSSION
Neurologists in practice in the 1970s noted two distinct patient groups using
therapeutic cannabis. Military personnel injured in Vietnam claimed that canna-bis was helpful in controlling symptoms associated with traumatic spinal injury. Female patients described beneficial effects from cannabis in treating spasticity,migraine headache or menstrual pain. These observations led to a number ofsmall clinical trials supporting the claims of individual patients. Because of regu-latory hurdles in conducting clinical research with cannabis, the total number ofpatients treated with cannabinoid drugs remains low.
Fortunately, interest in the subject has increased with the initiation of several
large-scale cannabis studies in MS in the United Kingdom. The National Instituteof Clinical Excellence (NICE), the UK regulatory authority, will assess the re-sults 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® without ob-jection. One can contrast a potential package insert for cannabis with that for theantispastic drug, Lioresal® Intrathecal. With the use of Lioresal via a spinalpump, the drug labeling states that in clinical trials “13 deaths occurring amongthe 438 patients treated with Lioresal Intrathecal in premarketing studies.” In-terestingly, two MS patients died suddenly within 2 weeks of drug administra-tion. Imagine the regulatory reaction if a single patient would die after cannabisuse. A potential risk associated with cannabis is secondary to the inhalation ofcannabis containing smoke. The evidence of significant health risk associatedwith cigarette smoking is overwhelming. While many patients avoid inhalation
risks by using oral cannabis, the rapid action of an inhaled formulation is effec-tive with symptoms such as flexor spasms or tonic brainstem attacks. One studynoted an elevated risk of myocardial infarction (4.8 times baseline) in the 60 min-utes after cannabis inhalation (Mittleman et al. 2001). While cannabis was con-sidered a rare trigger of acute myocardial infarction, risk elevation wasassociated with obesity, current cigarette smoking and male gender.
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 un-
answered 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 ac-
tion with greater safety when compared to inhaled cannabis?
3. Can specific cannabinoids be used more effectively to stimulate or block
4. Can the immune-modulating actions of cannabis be used to alter the natu-
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 published inMS patients. Potential other signs and symptoms in MS, which may be improvedwith cannabis, include fatigue, pain, bladder disturbances and sexual dysfunc-tion. Women are twice as likely as men to develop MS. Gender specific concernsin female patients include use of cannabis during pregnancy, potential effects onthe fetus, and risks associated with breast-feeding. Large-scale clinical trials mayprovide some answers concerning the potential of cannabis in treatment of MS. Women and Cannabis: Medicine, Science, and Sociology
Achiron, A., S. Miron, V. Lavie, R. Margalit, and A. Biegon. 2000. Dexanabinol
(HU-211) effect on experimental autoimmune encephalomyelitis: implications for thetreatment of acute relapses of multiple sclerosis. J Neuroimmunol 102(1):26-31.
Baker, D., G. Pryce, J.L. Croxford, P. Brown, R.G. Pertwee, J.W. Huffman, and L.
Layward. 2000. Cannabinoids control spasticity and tremor in a multiple sclerosismodel. Nature 404:84-7.
Baker, D., G. Pryce, J.L. Croxford, P. Brown, R.G. Pertwee, A. Makriyannis, A.
Khanolkar, L. Layward, F. Fezza, T. Bisogno, and V. Di Marzo. 2001. Endo-cannabinoids control spasticity in a multiple sclerosis model. FASEB J 15(2):300-2.
Benedikt, R.A., P. Cristofaro, J.H. Mendelson, and N.K. Mello. 1986. Effects of acute
marijuana smoking in post-menopausal women. Psychopharmacol 90:14-7.
Benowitz, N.L., and R.T. Jones. 1977. Effect of delta-9-tetrahydrocannabinol on drug
distribution and metabolism: antipyrine, pentobarbital and ethanol. Clin PharmacolTher 22(3):259-68.
Berrendero, F., A. Sanchez, A. Cabranes, C. Puerta, J.A. Ramos, A. Garcia-Merino, and J.
Fernandez-Ruiz. 2001. Changes in cannabinoid CB receptors in striatal and cortical
regions of rats with experimental allergic encephalomyelitis, an animal model of mul-tiple sclerosis. Synapse 41:195-202.
Birk, K., and R. Rudick. 1986. Pregnancy and multiple sclerosis. Arch Neurol 43:719-26. Brady, C.M., R. DasGupta, O.J. Wiseman, K.J. Berkley, and C.J. Fowler. 2001. Acute
and chronic effects of cannabis-based medicinal extract on refractory lower urinarytract dysfunction in patients with advanced multiple sclerosis–early results. Congressof the IACM Abstracts, p. 9.
Branas, P., R. Jordan, A. Fry-Smith, A. Burls, and C. Hyde. 2000. Treatment for fatigue in
multiple sclerosis: A rapid and systematic review. Health Technol Assess 4(27):1-61.
Brown, D.T. 1998. The therapeutic potential for cannabis and its derivatives. Cannabis:The Genus Cannabis. Amsterdam: Harwood Academic.
Cambell, F.A., M.R. Tramer, D. Carroll, D.J.M. Reynolds, R.A. Moore, and H.J.
McQuay. 2001. Are cannabinoids an effective and safe treatment option in the man-agement of pain? A qualitative systematic review. Brit Med J 323:13-16.
Christian, M.S. 2001. Introduction/overview: gender-based differences in pharmacologic
and toxicologic responses. Int J Toxicol 20(3):145-8.
Clifford, D.B. 1983. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol
Compston, A. 1999. Treatment and management of multiple sclerosis. McAlpine’s Multi-ple Sclerosis. New York: Churchill Livingstone.
Compston, A. 2001. Multiple sclerosis and other demyelinating diseases. Brain’s Dis-eases of the Nervous System. New York: Oxford University Press.
Consroe, P. 1999. Clinical and experimental reports of marijuana and cannabinoids in
spastic disorders. Marijuana and Medicine. Totowa, NJ: Humana Press.
Consroe, P., R. Musty, J. Rein, W. Tillery, and R. Pertwee. 1997. The perceived effects of
smoked cannabis on patients with multiple sclerosis. Eur Neurol 38:44-8.
Coyle, P.K. 2000. Women’s Issues Multiple Sclerosis: Diagnosis, Medical Management,and Rehabilitation New York: Demos Medical Publishing.
Dell’Osso, L.F. 2000. Suppression of pendular nystagmus by smoking cannabis in a pa-
tient with multiple sclerosis. Neurology 54(11):2190-1.
Dunn, M., and R. Davis. 1974. The perceived effects of marijuana on spinal cord injured
Fergusson, D.M., L.J. Horwood, and K. Northstone. 2002. Maternal use of cannabis and
pregnancy outcome. Brit J Obstet Gyn 109(1):21-7.
Fried, P.A., B. Watkinson, and R. Gray. 1999. Growth from birth to early adolescence in
offspring prenatally exposed to cigarettes and marijuana. Neurotoxicol Teratol21(5):513-25.
Gilson, I., and M. Busalacchi. 1998. Marijuana for intractable hiccups. Lancet 351:267. Gracies, J.M., P. Nance, E. Elovic, J. McGuire, and D.M. Simpson. 1997. Traditional
pharmacological treatments for spasticity. Part II: General and regional treatments. Muscle & Nerve 20 Suppl 6:S92-S120.
Greenberg, H.S., S.A.S. Werness, J.E. Pugh, R.O. Andrus, D.J. Anderson, and E.F. Dom-
ino. 1994. Short-term effects of smoking marijuana on balance in patients with multi-ple sclerosis and normal volunteers. Clin Pharmacol Ther 55:324-8.
Grinspoon, L., and J.B. Bakalar. 1997. Common medical uses: multiple sclerosis. Mari-juana, the Forbidden Medicine. Rev. and exp. Ed. New Haven: Yale University Press.
Guzman, M., C. Sanchez, and I. Galve-Roperh. 2001. Control of the cell survival/death
decision by cannabinoids. J Mol Med 78:613-25.
Hanigan, W.C., R. Destree, and X.T. Truong. 1985. The effect of ∆-9-THC on human
spasticity. Clin Pharmacol Ther 35:198.
Iversen, L.L. 2000. The Science of Marijuana. New York: Oxford University Press. Irizarry, M.C. 1997. Multiple sclerosis. Neurologic Disorders in Women. Boston:
James, T. 1994. The baby and the bathwater. S Afr Med J 84(6):369. LeResche, L. 2001. Gender, cultural, and environmental aspects of pain. Bonica’s Man-agement of Pain 3rd Edition Philadelphia: Lippincott Williams & Wilkins.
Lyman, W.D., J.R. Sonett, C.F. Brosnan, R. Elkin, and M.B. Bornstein. 1989. Delta-9
tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalo-myelitis. J Neuroimmunol 23:73-81.
Martyn, C.N., L.S. Illis, and J. Thom. 1995. Nabilone in the treatment of multiple sclero-
Maurer, M., V. Henn, A. Dittrich, and A. Hoffmann. 1990. Delta-9 tetrahydrocannabinol
shows antispastic and analgesic effects in a single case, double-blind trial. Eur ArchPsych Clin Neurosci 240(1):1-4.
Meinck, H.M., P.W. Schonle, and B. Conrad. 1990. Effect of cannabinoids on spasticity
and ataxia in multiple sclerosis. J Neurol 236(2):120-2.
Mendelson, J.H., P. Cristofaro, J. Ellingboe, R. Benedikt and N.K. Mello. 1985. Acute ef-
fects of marijuana on luteinizing hormone in menopausal women. PharmacolBiochem Behav 23:765-8.
Meng, I.D., B.H. Manning, W.J. Martin, and H.L. Fields. 1998. An analgesia circuit acti-
vated by cannabinoids. Nature 395:381-3. Women and Cannabis: Medicine, Science, and Sociology
Mittleman, M.A., R.A. Lewis, M. Maclure, J.B. Sherwood, and J.E. Muller. 2001. Trig-
gering myocardial infarction by marijuana. Circulation 103(23):2805-9.
Olek, M.J., and S.J. Khoury. 2000. Multiple Sclerosis. Women and Health. San Diego:
O’Shaughnessy, W.B. 1842. On the preparation of the Indian hemp or ganjah (Cannabisindica): the effects on the animal system in health, and their utility in the treatment oftetanus and other convulsive diseases. Trans Med Phys Soc Bombay 8:421-61.
Petro, D.J. 1980. Marijuana as a therapeutic agent for muscle spasm or spasticity.
Petro, D.J. and C. Ellenberger. 1981. Treatment of human spasticity with ∆-9-tetra-
hydrocannabinol. J Clin Pharmacol 21:413S-416S. Physicians’ Desk Reference 56th Edition. 2002. Montvale, NJ: Medical Economics. Pope, H.G. 2002. Cannabis, cognition, and residual confounding. J Amer Med Assoc
Pope, H.G., A.J. Gruber, J.I. Hudson, M.A. Huestis, and D. Yurgelun-Todd. 2001.
Neuropsychological performance in long-term cannabis users. Arch Gen Psychiatry58:909-15.
Rammohan, K.W., J.H. Rosenberg, D.J. Lynn, A.M. Blumenfeld, C.P. Pollak, and H.N.
Nagaraja. 2002. Efficacy and safety of modafinil (Provigil®) for the treatment of fa-tigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry72(2):179-83.
Reynolds, J.R. 1890. On the therapeutic uses and toxic effects of Cannabis indica. Lancet
Runmarker, B. and O. Anderson. 1995. Pregnancy is associated with a lower risk of onset
and a better prognosis in multiple sclerosis. Brain 118:253-61.
Rusk, A. and F. Plum. 1998. Neurologic Health and Disorders. In Textbook of Women’sHealth Philadelphia: Lippincott-Raven.
Schon, F., P.E. Hart, T.L. Hodgson, A.L.M. Pambakian, M. Ruprah, E.M. Williamson,
and C. Kennard. 1999. Suppression of pendular nystagmus by smoking cannabis in apatient with multiple sclerosis. Neurology 53(9):2209-10.
Solowij, N., R.S. Stephens, R.A. Roffman, T. Babor, R. Kadden, M. Miller, K.
Christiansen, B. McRee, and J. Vendetti. 2002. Cognitive functioning of long-termheavy cannabis users seeking treatment. J Amer Med Assoc 287(9):1123-31.
Somerset, M., R. Campbell, D.J. Sharp and T.J. Peters. 2001. What do people with MS
want and expect from health-care services? Health Expectations 4:29-37.
Tennes, K., N. Avitable, C. Blackard, C. Boyles, B. Hassoun, L. Holmes and M Kreye.
1985. Marijuana, prenatal and postnatal exposure in the human. In: Pinkert, T.M., ed. Current research on the consequences of maternal drug abuse. NIDA Res Monogr59:48-60.
Ungerleider, J.T., T. Andyrsiak, L. Fairbanks, G.W. Ellison, and L.W. Myers. 1988.
Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Phar-macological Issues in Alcohol and Substance Abuse 7(1):39-50.
Whitaker, J., 1998. Effects of pregnancy and delivery on disease activity in multiple scle-
rosis. N Engl J Med 339:339-40.
Wirguin, I., R. Mechoulam, A. Breuer, E. Schezen, J. Weidenfeld, and T. Brenner. 1994.
Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacology 28:209-14.
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Abstract Die Effektivität osteopathischer Behandlungen bei autonomen somatoformen Störungen Gesa Diedrichsen Somatoforme autonome Störungen sind gekennzeichnet durch Symptome eines vegetativ innervierten Organs. Das Ziel dieser Arbeit ist es herauszufinden, ob es Studien gibt, die sich mit auseinandersetzen, deren Validität zu bewerten und eine Aussage zum derzeitigen Forschungssta