Jump to Main Content

Cannabis and Amyotrophic Lateral Sclerosis: Hypothetical and Practical Applications,
and a Call for Clinical Trials


American Journal of Hospice & Palliative Care
Published online May 3, 2010

Gregory T. Carter, MD, MS1, Mary E. Abood, PhD2, Sunil K. Aggarwal, PhD3, Michael D. Weiss, MD1,4,5


Significant advances have increased our understanding of the molecular mechanisms of amyotrophic lateral sclerosis (ALS), yet this has not translated into any greatly effective therapies. It appears that a number of abnormal physiological processes occur simultaneously in this devastating disease. Ideally, a multidrug regimen, including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (including tumor necrosis factor alpha [TNF-a] inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent would be required to comprehensively address the known pathophysiology of ALS. Remarkably, cannabis appears to have activity in all of those areas.

Preclinical data indicate that cannabis has powerful antioxidative, anti-inflammatory, and neuroprotective effects.In the G93ASOD1 ALS mouse, this has translated to prolonged neuronal cell survival, delayed onset, and slower progression of the disease. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. With respect to the treatment of ALS, from both a disease modifying and symptom management viewpoint, clinical trials with cannabis are the next logical step. Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease. Keywords: cannabis, endocannabinoids, amyotrophic lateral sclerosis, clinical trials, motor neuron disease.


Amyotrophic lateral sclerosis (ALS), with an incident rate of 5 to 7 per 100 000 population, is the most common form of adult motor neuron disease.1 Amyotrophic lateral sclerosis is a rapidly progressive neuromuscular disease that destroys both upper and lower motor neurons, resulting in weakness, spasticity, and ultimately death from respiratory failure. The vast majority of ALS cases are acquired and occur sporadically. Emerging evidence suggests that increased oxidative stress from free radical toxicity and/or excessive glutamate activity is what leads to motor neuron cell death in the brain and spinal cord.2-5 Inherited forms of the disease, which occur in approximately 5% to 10% of all patients with ALS, are largely because of mutations in the superoxide dismutase gene, presumably producing a marked increase in oxidative stress. Presentations of familial ALS have more variability than in sporadic ALS and are mutation specific with the most aggressive form because of the A4V mutation.5 Recent results have established that ALS also involves other nonneuronal cells including astroglia and microglia.6,7 Other putative mechanisms involved in motor neuron degeneration in ALS include mitochondrial dysfunction, neuroinflammation, growth factor deficiency, and glutamate excitotoxicity.2,3 Significant advances have been made regarding our understanding of the molecular mechanisms of ALS.8-12

However, this has not yet translated into an effective therapeutic treatments. To date, the only food and drug administration- (FDA)approved therapy available for ALS is the antiglutamatergicagent Riluzole, which has limited therapeutic efficacy.10 Given this perspective, there remains an ongoing search for novel therapeutic approaches. There is increasing evidence that cannabinoids and manipulation of the endocannabinoid system may have beneficial disease-modifying potential in ALS.13-21

Moreover, the clinical effects of cannabis, the principal cannabinoid-producing botanical agent, have been reported to be useful in managing the symptomatology in ALS, as well as many other neurodegenerative disorders.22-34 Thus, significant efforts are now being directed at evaluating the role of the endocannabinoid system in the pathophysiology of ALS.

In addition, there is an emerging body of science that points to a role of exogenous cannabinoids in both clinical symptom management and a positive disease-modifying effect.13-21

The Physiology and Pharmacology of Cannabinoids

Prior to the last decade, there was little known about the specific pharmacological and molecular effects of cannabis. However, important advances have taken place recently, which have greatly increased the understanding of the receptors and ligands composing the endogenous cannabinoid system.35-54

Research has shown that 2 major cannabinoid receptor subtypes exist, including the cannabinoid receptor, type 1 (CB1) subtype, which is predominantly expressed in the brain, and the cannabinoid receptor, type 2 (CB2) subtype, which is primarily found on the cells of the immune system.35,49,50 A variety of ligands for these receptors based on the cannabinoid structure have been synthesized and studied.Experiments performed with several types of neural cells that endogenously express the CB1 receptor suggest that activation of protein kinases may be responsible for some of the cellular responses elicited by these receptors.51

The discovery of the endocannabinoids, that is, endogenous metabolites capable of activating the cannabinoid receptors, and the understanding of the molecular mechanisms leading to their biosynthesis, release, and inactivation, have created a new area in research on the pharmaceutical applications of cannabinoid-based medicines.52

The characterization of endocannabinoids such as anandamide and the detection of widespread cannabinoid receptors in the brain and peripheral tissues suggest that the cannabinoid system represents a previously unrecognized ubiquitous network in the nervous system. Cannabinoid receptors are G protein-coupled, 7-segment transmembrane proteins, similar to the receptors of other neurotransmitters such as dopamine, serotonin, and norepinephrine. 51,52 Dense receptor concentrations are found in the cerebellum, basal ganglia, and hippocampus, likely accounting for the effect of exogenously administered cannabinoids on motor tone and coordination as well as mood state.53-55 Low concentrations are found in the brain stem, accounting for the low potential for lethal overdose with cannabinoid-based medicines. 56-59 A growing number of strategies for separating sought-after therapeutic effects of cannabinoid receptor agonists from the unwanted consequences of CB1 receptor activation are emerging. Recently, ligands have been developed that are potent and selective agonists for CB1 and CB2 receptors, as well as potent CB1—selective antagonists and inhibitors of endocannabinoid uptake or metabolism.60 In addition, varieties of cannabis are known to contain a mix of partial cannabinoid agonists and antagonists, which can be rationally used.

This knowledge may lead to the design of synthetic cannabinoid agonists and antagonists as well as cannabis strains with high therapeutic potential. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids that cannabinoids play an important role in the regulation of the immune system.

Recent studies show that cannabinoids downregulate cytokine and chemokine production, both mechanisms that suppress inflammatory responses.61-64 Manipulation of endocannabinoids (ie, via the use of exogenous cannabis) has great potential treatment viability against inflammatory disorders, including the inflammation seen in the central nervous system (CNS) of the patients with ALS.

The potential use of cannabinoids as a novel class of anti-inflammatory agents may become one of the predominant indications, as that includes not only neuromodulation but pain as well.65,66 Indeed, any number of inflammatory processes that are at least partially triggered by activated T cells or other cellular immune components could be treated with cannabis and other cannabinoid-basedmedicines.

Cannabinoids are chemically classified as terpenes. These are lipid-soluble hydrocarbons that function as major biosynthetic cellular messengers in many forms of life. Terpenes are widespread in plants and most species of animals as well, including humans. Any compound that resembles the basic terpenes structure, yet may be modified chemically via oxidation or other processes, is termed a terpenoid. Many hormones, including estrogens, are terpenoids, and share the same basic organic chemical structure as cannabinoids.53,54 All terpenes are organic, readily penetrate the highly lipophilic CNS.

Interestingly, tamoxifen, which is an antagonist of the estrogen receptor in breast tissue, is terpenoid and chemically resembles cannabinoids. Tamoxifen’s primary use is as a FDA-approved drug for the treatment of breast cancer.67-69 However, phase II clinical trials of tamoxifen in ALS have now demonstrated preliminary efficacy and safety.68 A phase 2B study demonstrated increased survival after 2 years in patients with ALS taking higher doses of tamoxifen, with no effect seen in 2 lower dose groups.68 The 3 higher dose groups experienced a 4- to 6-month prolongation of survival over a 24-month trial, with no significant side effects observed.68 Interestingly, glutamate uptake in cultured retinal cells is inhibited by tamoxifen, thus this mechanism may be part of a possible beneficial effectin ALS.67 The chemical similarity between cannabinoids and tamoxifen points to a possible shared mechanism of action for neural protection.69

The cannabis plant is a remarkably complex plant, with several phenotypes, each containing over 400 distinct chemical moieties.70-73 Approximately 70 of these are chemically unique and classified as cannabinoids.70-73 Delta-9 tetrahydrocannabinol (THC) and delta-8 THC appear to produce the majority of the psychoactive effects of cannabis.74,75 Delta-9 THC, the active ingredient in dronabinol (Marinol), is the most abundant cannabinoid in the plant, which historically led researchers to erroneously hypothesize that it was the main source of the drug’s impact.

It is now known that other major plant cannabinoids, including cannabidiol and cannabinol, modify the pharmacology of THC and have distinct effects of their own. Cannabidiol is the second most prevalent of cannabis’s active ingredients and may produce most of its therapeutic effects.

Cannabidiol becomes THC as the plant matures and this THC over time breaks down into cannabinol. Up to 40% of the cannabis resin in some strains is cannabidiol.72 The amount varies according to plant. Some varieties of Cannabis sativa have been found to have no cannabidiol.72 Cannabidiol breaks down to cannabinol as the plant matures. Much less is known about cannabinol, although it appears to have distinct pharmacological properties that are quite different from cannabidiol. Cannabinol has significant anticonvulsant, sedative, and other pharmacological activities likely to interact with the effects of THC.75-78 Cannabinol may induce sleep and may provide some protection against seizures for epileptics.78

Hypothetical Applications Preclinical Studies of the Endocannabinoid System in ALS

The primary murine model for human ALS is the G93A-SOD1 mutant mouse, which is genetically engineered to replicate familial ALS.4 There is strong evidence in the G93A-SOD1 mouse model of ALS that the endocannabinoid system is involved, both directly and indirectly, in the pathophysiology of the disease. Several recent studies have highlighted this. Rossi et al17 investigated both excitatory and inhibitory synaptic transmission in the striatum of symptomatic G93A-SOD1 ALS mice, along with the sensitivity of these synapses to CB1 receptor stimulation. They reported a reduced frequency of glutamate-mediated spontaneous excitatory postsynaptic currents and increased frequency of GABA-mediated spontaneous inhibitory postsynaptic currents in recordings from striatal neurons in ALS mice. This is likely due to some presynapticdefects in transmitter release. The sensitivity of CB1 receptors in controlling both glutamate and GABA transmission was potentiated in ALS mice.

This provides good evidence that adaptations of the endocannabinoid system might be involved in the pathophysiology of ALS. This is not inconsistent with current theories on pathophysiological mechanisms of ALS, which still remain largely a pathophysiologic enigma.79-83 Bilsland et al18 showed that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delayed disease progression.

Furthermore, genetic ablation of the fatty acid amide hydrolase(FAAH) enzyme, which results in raised levels of the endocannabinoid anandamide by preventing its breakdown, prevented the appearance of disease signs in90-day-old SOD1G93A mice. Surprisingly, elevation of cannabinoid levels with either WIN55,212-2 or FAAH ablation had no effect on life span. Ablation of the CB1 receptor, in contrast, had no effect on disease onset in SOD1G93A mice but significantly extended life span.

Together, these results indicate that cannabinoids havesignificant neuroprotective and disease-modifying effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor-based mechanisms.

It is now known that during active neurodegeneration from disease or trauma in the CNS, the concentration of tumor necrosis factor alpha (TNF-a) rises well above normal levels during the inflammatory response. Addition of exogenous TNF-a, both in vitro and in vivo, to neurons has been shown to significantly potentiate glutamatergic excitotoxicity.

Thus, the discovery of drug targets reducing excess TNF-a expression may help protect neurons after injury. Zhao et al84 investigated the neuroprotective role of the CB1 receptor after TNF-a exposure in the presence or absence of CB1 agonists. They demonstrated that CB1 activation blocks the TNF-ainduced increase in inflammation, thus protecting the neurons from damage. Thus, neuroprotective strategies which increase CB1 activity may help to reduce damage to motor neurons in ALS that are mediated by CNS inflammation. Additionally, CB2 receptors are dramatically upregulated in inflamed neural tissues associated with CNS disorders, including ALS.85 In G93A-SOD1 mutant mice, endogenous cannabinoids are elevated in spinal cords of symptomatic mice.21

Furthermore, treatment with nonselective cannabinoid partial agonists prior to, or on, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms. Shoemaker et al14 demonstrated that messenger RNA (mRNA) levels, receptor binding, and function of CB2, but not CB1, receptors are dramatically and selectively upregulated in spinal cords of G93A-SOD1 mice in a temporal pattern paralleling disease progression.

Daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increased the survival interval after disease onset by 56%.14 Disease-Modifying Treatment of ALS Clinical trials for ALS have been largely based on preclinical work using the G93A-SOD1 mouse.

Unfortunately, translation of therapeutic success in mice to humans has proven quite difficult and a cure for ALS is not yet known. Many factors have been implicated in explaining the predominantly negative results of numerous randomized clinical trials in ALS, including methodological problems in the use of animal-drug screening, the lack of assessment of pharmacokinetic profile of the drugs, and methodological pitfalls of clinical trials in patients with ALS. Riluzole is currently the only agent approved by the FDA for the treatment of ALS.10 This drug inhibits the presynaptic release of glutamate and reduces neuronal damage in experimental models of ALS. Four controlled trials of a total of 974 riluzole-treated and 503 placebo-treated patients showed that it prolonged survival opposed to placebo, although the benefit was fairly modest.10 Because oxidative stress is one of the proposed pathogenic factors in ALS, antioxidants have been extensively tested, including vitamin E, vitamin C, coenzyme Q, B-carotene, N-acetylcysteine, and creatine, an amino acid naturally found in skeletal.11

To date, trials of neurotrophic factors,antioxidants, glutamate antagonists, and creatine have all failed to show any significant benefit in humans, although most had significant benefit shown in mice.11 It is currently felt that a cocktail approach may be the ideal treatment strategy, including glutamate antagonists, antioxidants, and neurotrophic factors.68

Recently, the kynurenine pathway (KP) has emerged as a potential target for ALS treatment. 8 The KP is a major route for the metabolism of tryptophan,generating neuroactive intermediates in the process. These catabolites include the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN), and theneuroprotective NMDA receptor antagonist, kynurenic acid (KYNA). These catabolites appear to play a key role in the communication between the nervous and immune systems and also in modulating cell proliferation and tissue function. Targeting the KP, hence, could offer a new therapeutic option to improve ALS treatment, and several drugs that block the KP are already under investigation.

Although other potential neuroprotective agents have been evaluated in randomized clinical trials, none have shown unequivocal benefit for the treatment of ALS.

Thus, there remains an enormous need for more trials to test other putative disease-modifying therapies.

As the effectiveness of such drugs can only be definitively established by large, costly, phase III randomized controlled studies, it is imperative that researchers target compounds that have potential benefit based on demonstrated pharmacological and physiological mechanisms. There remains the possibility that ALS could represent a state of clinical endocannabinoid deficiency (CED).28,31 The endocannabinoid anandamide demonstrates dopamineblocking and anti-inflammatory effects and is also tonically active in the periaqueductal gray matter.81 Endocannabinoids also modulate glutamatergic neurotransmission indirectly via NMDA receptors, and these pathways can be modulated to produce a clinical effect, such as reduction in motor tone, seizure threshold, and perception of pain and mood state.82-93 These clinical, biochemical, and pathophysiological patterns could reflect an underlying abnormality in the endocannabinoid system in ALS that could be potentially treated with exogenous cannabinoids, that is, via clinical use of cannabis or some derivative thereof.

Practical Applications Symptom Management in ALS

As discussed previously, animal studies strongly suggest that the endocannabinoid system is implicated in the pathophysiology of ALS, either directly as part of the underlying disease mechanisms, or indirectly, inasmuch as this system plays a role in the homeostatic functioning of the neuromuscular system.

Irrespective, it is clear that cannabinoids are able to slow down the progression of ALS in mice, likely by acting as an antioxidant, among other mechanisms.15-18 In addition to the neuroprotective effect, patients report that cannabis helps in treating symptoms of the disease, including alleviating pain and muscle spasms, improving appetite, diminishing depression,and helping to manage sialorrhea (excessive drooling) by drying up saliva in the mouth.24

Indeed, in a large survey it was noted that patients with ALS who were able to obtain cannabis found it preferable to prescription medication in managing their symptoms. However, this study also noted that the biggest reason patients with ALS were not using cannabis was their inability to obtain it, due to legal or financial reasons or lack of safe access.24,26 There are many other clinical problems faced by patients with ALS that could be helped by cannabis.

The majority of patients with ALS experience significant pain.24 The pain is largely due to immobility, which can cause adhesive capsulitis, mechanical back pain, pressure areas on the skin, and more rarely, neuropathic pain.24,31 Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering.94-98

Treatment of pain, therefore, should be recognized as an important aspect of palliative care in ALS.

A recent Cochrane review of the evidence for the efficacy of drug therapy in relieving pain in ALS revealed no randomized or quasi-randomized controlled trials showing significant benefit. Despite the major pain problems encountered by patients with ALS, there are no clear guidelines and few randomized clinical trials about how to manage pain in ALS.

However, as noted previously, the cannabinoids have been shown to produce an antiinflammatory effect by inhibiting the production and action of TNF and other acute phase cytokines.35 Additionally, cannabis may reduce pain sensation, likely through a brain stem circuit that also contributes to the p ain- suppressing effects of morphine.99 Cannabinoids produce analgesia by modulating rostral ventromedial medulla neuronal activity in a manner similar to, but pharmacologically distinct from, that of morphine. 100,101 This analgesic effect is also exerted by some endogenous cannabinoids (anandamide) and synthetic cannabinoids(methanandamide) and may be prevented by the use of selective antagonists.102-104

Thus, cannabinoids are centrally acting analgesics with a different mechanism of action than opioids, although the analgesia produced by cannabinoids and opioids may involve similar pathways at the brain stem level.103-105

There are now multiple, well-controlled clinical studies using cannabis to treat pain, showing ample evidence of analgesic efficacy.106 A recent systematic review and metaanalysis of double-blind randomized controlled trials that compared any cannabis preparation to placebo among participants with chronic pain showed a total of 18 completed trials.The studies indicate that cannabis is moderately efficacious for the treatment of chronic pain.106 In the setting of ALS, the medications should be titrated to the point of comfort.

Concomitant use of narcotics may also be beneficial because, as noted above, the opioid receptor system is distinct from the cannabinoid system. In that regard, the antiemetic effect of cannabis may help with the nausea sometimes associated with narcotic medications. In addition to pain, spasticity is also a major problem for patients with ALS. Spasticity in ALS is induced both at the motor cortex and at the spinal cord level through the loss of motor neuron inhibition.107-110 Cannabis has an inhibitory effect via augmentation of g-amino-butyric acid (GABA) pathways in the CNS.111 This produces motor neuron inhibition at spinal levels in mice.

Several past studies have suggested that cannabinoid therapy provide at least a subjective reduction of spasticity, although virtually all of the studies have been done in patients with multiple sclerosis (MS).29,112 A survey study has shown that patients with ALS do subjectively report that cannabis helps alleviate symptoms of spasticity.24 In addition to pain and spasticity, there are other pharmacological effects of cannabis that may be useful for patients with ALS. Patients with ALS and bulbar symptoms also usually have difficulty controlling and swallowing the saliva that is normally present in the oral cavity.113 Cannabis is a potent antisalivatory compound that swiftly dries the oral cavity and upper airway, potentially reducing the risk of aspiration pneumonia and increasing patient comfort.22,24 Cannabis also increases appetite and may help prevent ‘‘ALS cachexia,’’ a phenomenon experienced by some patients where weight loss occurs in excess of that caused by muscle atrophy and reduced caloric intake.114-116 In addition to improving appetite, cannabis appears to also help with mood state and sleep. Patients with ALS previously have reported that cannabis is at least moderately effective at reducing symptoms of pain, spasticity, drooling, appetite loss, and depression.24

Cannabinoids will vaporize at temperatures in the range of 200_F and can be inhaled via a hot mist.117-119 This delivers the cannabinoids rapidly, allowing for ease of titration and letting patients with ALS having severe dysarthria rapid access to the drug’s effects. Vaporizing also helps dry up oral secretions.24 Cannabis may also be ingested orally or through a feeding tube, although absorption is much slower. Cannabis can be titrated to desired effect, with individual, patient-specific dosing.120-122 In terms of clinical trials for disease-modifying effects, dosing paradigm would be more complex. Fortunately, the low toxicity of cannabis would allow for trail and error. Based on the available studies, a typical dosing range for clinical effects would likely be 1 to 2 g/d of cannabis, with an average THC content of 20% by weight.122

A Call for Clinical Trials

In terms of symptoms management, cannabis is a substance with many pharmacological properties that are directly applicable to the clinical care of patients with ALS. These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, sleep induction, and mood elevation.24 From a pharmacological perspective, cannabis is remarkably safe with realistically no possibility of overdose or frank physical addiction.

There is a valid, logical, scientifically grounded rationale to support the use of cannabis in the pharmacological management of ALS. Indeed, cannabis, as a single compound, could potentially replace and provide the benefits of multiple standard medications, including analgesics, antispasmodics, anxiolytics, antidepressants, appetite stimulants, and agents used to dry the mouth (typically anticholinergic medications).There is ample clinical evidence to warrant the empiric use of cannabis to manage the symptoms of ALS.

From an experimental, disease-modifying perspective, it is not likely that a single mechanism agent would treat all of the abnormal physiological processes occurring simultaneously in this devastating disease.123-127 Thus, some experts are now advocating for a combination drug approach to slowing the progression of ALS.80

Based on what is known about the pathophysiology of ALS, a multidrug regimen would include glutamate antagonists, antioxidants, a CNS anti-inflammatory agent, a microglial cell modulators, including TNF-a inhibitors, an antiapoptotic agent, 1 or more neurotrophic growth factors and a mitochondrial function-enhancing agent.127,128

Remarkably, cannabinoids appear to have at least some activity in all of those categories.129-131

Moreover, there is a particularly strong, growing, body of preclinical data indicating that cannabis has powerful antioxidative, anti-inflammatory, and protective neuromodulatory effects.132-135 In the G93ASOD1 ALS mouse, this has translated to prolonged neuronal cell survival.15,16,18,43

There is an overwhelming amount of preclinical and clinical evidence to warrant initiating a multicenter randomized,double-blind, placebo-controlled trial of cannabis as a disease-modifying compound in ALS. Secondary outcome measures could include clinical management, with end points such as pain scores, quality-of-life measures, and so on. Developing a multicenter clinical research trial using cannabis would pose many unique barriers that would have to be overcome.

Inasmuch as there is no commercial manufacturer of cannabis, the study would have to be funded either by the federal government or privately.

Presumably, there would be no industry funding. Obtaining the trial drug would require the investigators to gain access to a large, reliable supply of cannabis that is legal for medical research. At present, the only source of cannabis that can be legally used in research in the United States is through the National Institute on Drug Abuse (NIDA). National Institute on Drug Abuse provides low-potency material and makes the cannabis available only to projects it approves. National Institute on Drug Abuse supplies cannabis with a THC content, by weight, of 2% to 4% typically, although it has supplied cannabis with an 8% by weight THC content on occasion. 136,137 The average THC content of cannabis at randomly surveyed medical cooperatives in California is approximately 15% to 20%.26,117,121

Thus, an independent source of cannabis would be needed to ensure a consistently high cannabinoid content that may be strong enough to possibly alter the disease progression. An independent cannabis source would also allow investigators to avoid NIDA’s arbitrary and lengthy review process that it mandates before providing any cannabis for research. Historically, NIDA has derailed clinical trial plans by refusing to supply cannabis, even after the research protocols were approved by the FDA.117

Nonetheless, it is possible, with coordinated effort, to effectively do doubleblind, randomized, placebo-controlled clinical trials with cannabis. 138-141 To properly evaluate both subjective and objective effects, cannabinoid blood levels should be followed as well, to further ensure adequate data for a dose_response curve.

Clinical trials with cannabis would also address the issue of single versus multiple drug clinical trials. Arguable, multiple drug trials would increase the chances of success but also exponentially increase the difficulty of completing the trial and analyzing the data. Cannabis, as a single agent, in essence provides the advantages of a multiple drug trial due to its multiple mechanisms of action.

Cannabis is a unique compound that possesses significant internal therapeutic synergy.

The search for the underlying cause of ALS continues.142,143 With respect to treatment, from both a symptom management and disease modifying viewpoint, the logical next step, based on the available science, would be clinical trials with cannabis. Although not expected to be necessarily curative, it is not unreasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.

Declaration of Conflicting Interests

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.


The authors received no financial support for the research and/or authorship of this article.

American Journal of Hospice & Palliative Care, published online May 3rd 2010

To have a copy for your own Library, please read and download the paper here:

Cannabis and ALS, PDF Document


1. Qureshi M, Schoenfeld DA, Paliwal Y, Shui A, Cudkowicz ME.

The natural history of ALS is changing: improved survival. Amyotroph

Lateral Scler. 2009;10(5-6):324-331.

2. Miller RG, Jackson CE, Kasarskis EJ, et al. Quality Standards subcommittee

of the American Academy of Neurology. Practice parameter

update: the care of the patient with amyotrophic lateral

sclerosis: multidisciplinary care, symptom management, and cognitive/

behavioral impairment (an evidence-based review): report

of the Quality Standards Subcommittee of the American Academy

of Neurology. Neurology. 2009;73(15):1227-1233.

3. Miller RG, Jackson CE, Kasarskis EJ, et al. Quality Standards Subcommittee

of the American Academy of Neurology. Practice parameter

update: the care of the patient with amyotrophic lateral

sclerosis: drug, nutritional, and respiratory therapies (an

evidence-based review): report of the Quality Standards Subcommittee

of the American Academy of Neurology. Neurology.


4. Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in

mice that express a human Cu/Zn superoxide dismutase mutation.

Science. 1994;264:1772-1775.

5. Weiss MD, Ravits JM, Schuman N, Carter GT. A 4V superoxide

dismutase mutation in apparently sporadic ALS resembling neuralgic

amyotrophy. Amyotroph Lateral Scler. 2006;7(1):61-63.

6. Suzuki M, Klein S, Wetzel EA, et al. Acute glial activation by

stab injuries does not lead to overt damage or motor neuron

degeneration in the G93A mutant SOD1 rat model of amyotrophic

lateral sclerosis. Exp Neurol. 2010;221(2):346-352.

7. Boille´e S, Vande Velde C, Cleveland DW. ALS: a disease of

motor neurons and their nonneuronal neighbors. Neuron. 2006;


8. Chen Y, Meininger V, Guillemin GJ. Recent advances in the

treatment of amyotrophic lateral sclerosis. Emphasis on kynurenine

pathway inhibitors. Cent Nerv Syst Agents Med Chem.


9. Van Damme P, Robberecht W. Recent advances in motor neuron

disease. Curr Opin Neurol. 2009;22(5):486-492.

10. Miller RG, Mitchell JD, Lyon M, Moore DH. Riluzole for amyotrophic

lateral sclerosis (ALS)/motor neuron disease (MND).

Cochrane Database Syst Rev. 2007;24(1):CD001447.

11. Distad BJ, Meekins GD, Liou LL, Weiss MD, Carter GT,

Miller RG. Drug therapy in amyotrophic lateral sclerosis. Phys

Med Rehabil Clin N Am. 2008;19(3):633-651.

12. Distad BJ, Weiss MD. Neurotrophic factors in neuromuscular disease.

Phys Med Rehabil Clin N Am. 2005;16(4):999-1014.

13. Kim K, Moore DH, Makriyannis A, Abood ME. AM1241, a cannabinoid

CB2 receptor selective compound, delays disease progression

in a mouse model of amyotrophic lateral sclerosis. Eur

J Pharmacol. 2006;542(1-3):100-105.

14. Shoemaker JL, Seely KA, Reed RL, Crow JP, Prather PL. The

CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic

mouse model of amyotrophic lateral sclerosis when initiated

at symptom onset. J Neurochem. 2007;101(1):87-98.

15. Raman C, McAllister SD, Rizvi G, Patel SG, Moore DH,

Abood ME. Amyotrophic lateral sclerosis: delayed disease progression

in mice by treatment with a cannabinoid. Amyotroph Lateral

Scler Other Motor Neuron Disord. 2004;5(1):33-39.

16. Weydt P, Hong S, Witting A, Mo¨ ller T, Stella N, Kliot M. Cannabinol

delays symptom onset in SOD1 (G93A) transgenic mice

without affecting survival. Amyotroph Lateral Scler Other Motor

Neuron Disord. 2005;6(3):182-184.

17. Rossi S, De Chiara V, Musella A, et al. Abnormal sensitivity of

cannabinoid CB1 receptors in the striatum of mice with experimental

amyotrophic lateral sclerosis. Amyotroph Lateral Scler.


18. Bilsland LG, Dick JR, Pryce G, et al. Increasing cannabinoid levels

by pharmacological and genetic manipulation delay disease

progression in SOD1 mice. FASEB J. 2006;20(7):1003-1005.

19. Bilsland LG, Greensmith L. The endocannabinoid system in

amyotrophic lateral sclerosis. Curr Pharm Des. 2008;14(23):


20. Zhao P, Ignacio S, Beattie EC, Abood ME. Altered presymptomatic

AMPA and cannabinoid receptor trafficking in motor neurons

of ALS model mice: implications for excitotoxicity. Eur J

Neurosci. 2008;27(3):572-579.

21. Witting A, Weydt P, Hong S, Kliot M, Moller T, Stella N. Endocannabinoids

accumulate in spinal cord of SOD1 transgenic mice.

J Neurochem. 2004;89(6):1555-1557.

22. Carter GT, Rosen BS. Marijuana in the management of amyotrophic

lateral sclerosis. Am J Hosp Palliat Care. 2001;18(4):


23. Gelinas D, Miller RG, Abood ME. A pilot study of safety and tolerability

of Delta 9-THC (Marinol) treatment for ALS. Amyotroph

Lateral Scler Other Motor Neuron Disord. 2002;3(suppl 1):23.

24. Amtmann D, Weydt P, Johnson KL, Jensen MP, Carter GT. Survey

of cannabis use in patients with amyotrophic lateral sclerosis.

Am J Hosp Palliat Care. 2004;21:95-104.

25. Carter GT, Weydt P. Cannabis: old medicine with new promise

for neurological disorders. Curr Opin Investig Drugs. 2002;


26. Aggarwal SK, Carter GT, Sullivan MD, ZumBrunnen C,

Morrill R, Mayer JD. Medicinal use of cannabis in the United

States: historical perspectives, current trends, and future directions.

J Opioid Manag. 2009;5(3):153-168.

27. Aggarwal SK, Carter GT, Sullivan MD, ZumBrunnen C,

Morrill R, Mayer JD. Characteristics of patients with chronic pain

accessing treatment with medical cannabis in Washington State.

J Opioid Manag. 2009;5(5):257-286.

28. Russo EB. Clinical endocannabinoid deficiency (CECD): can this

concept explain therapeutic benefits of cannabis in migraine,

fibromyalgia, irritable bowel syndrome and other treatmentresistant

conditions? Neuro Endocrinol Lett. 2008;29(2):192-200.

29. Lakhan SE, Rowland M. Whole plant cannabis extracts in the

treatment of spasticity in multiple sclerosis: a systematic review.

BMC Neurol. 2010;9:59-61.

30. Adams IB, Martin BR. Cannabis: pharmacology and toxicology

in animals and humans. Addiction. 1996;91(11):1585-1614.

31. Romero J, Orgado JM. Cannabinoids and neurodegenerative diseases.

CNS Neurol Disord Drug Targets. 2009;8(6):440-450.

32. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol.

Delta9 tetrahydrocannabinol are neuroprotective antioxidants.

Proc Natl Acad Sci U S A. 1998;95(14):8268-8273.

33. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R,

Axelrod J. Neuroprotective antioxidants from marijuana. Ann N

Y Acad Sci. 2000;899:274-282.

34. Nagayama T, Sinor AD, Simon RP, et al. Cannabinoids and neuroprotection

in global and focal cerebral ischemia and in neuronal

cultures. J Neurosci. 1999;19(8):2987-2995.

35. Abood ME. Molecular biology of cannabinoid receptors. Handb

Exp Pharmacol. 2005;168:81-115.

36. McAllister SD, Hurst DP, Barnett-Norris J, Lynch D, Reggio PH,

Abood ME. Structural mimicry in class A G protein-coupled

receptor rotamer toggle switches: the importance of the

F3.36(201)/W6.48(357) interaction in cannabinoid CB1 receptor

activation. J Biol Chem. 2004;279(46):48024-48037.

37. McAllister SD, Chan C, Taft RJ, et al. Cannabinoids selectively

inhibit proliferation and induce death of cultured human glioblastoma

multiforme cells. J Neurooncol. 2005;74(1):31-40.

38. Kapur A, Samaniego P, Thakur GA, Makriyannis A, Abood ME.

Mapping the structural requirements in the CB1 cannabinoid

receptor transmembrane helix II for signal transduction. J Pharmacol

Exp Ther. 2008;325(1):341-348.

39. Gehani NC, Nalwalk JW, Razdan RK, et al. Significance of cannabinoid

CB1 receptors in improgan antinociception. J Pain.


40. Anavi-Goffer S, Fleischer D, Hurst DP, et al. Helix 8 Leu in the

CB1 cannabinoid receptor contributes to selective signal transduction

mechanisms. J Biol Chem. 2007;282(34):25100-25113.

41. McAllister SD, Rizvi G, Anavi-Goffer S, et al. An aromatic

microdomain at the cannabinoid CB(1) receptor constitutes an

agonist/inverse agonist binding region. J Med Chem. 2003;


42. McAllister SD, Tao Q, Barnett-Norris J, et al. A critical role for a

tyrosine residue in the cannabinoid receptors for ligand recognition.

Biochem Pharmacol. 2002;63(12):2121-2136.

43. Abood ME, Rizvi G, Sallapudi N, McAllister SD. Activation of

the CB1 cannabinoid receptor protects cultured mouse spinal neurons

against excitotoxicity. Neurosci Lett. 2001;309(3):197-201.

44. Panikashvili D, Simeonidou C, Ben Shabat S, et al. An endogenous

cannabinoid (2 AG) is neuroprotective after brain injury.

Nature. 2001;413(6855):527-531.

45. Chen Y, Buck J. Cannabinoids protect cells from oxidative cell

death: a receptor independent mechanism. J Pharmacol Exp Ther.


46. Eshhar N, Striem S, Biegon A. HU 211, a non psychotropic cannabinoid,

rescues cortical neurones from excitatory amino acid

toxicity in culture. Neuroreport. 1993;5(3):237-240.

47. Guzman M, Sanchez C, Galve-Roperth I. Control of the cell survival/

death decision by cannabinoids.JMolMed. 2001;78:613-625.

48. Maenpaa H, Mannerstrom M, Toimela T, Salminen L,

Saransaari P, Tahti H. Glutamate uptake is inhibited by tamoxifen

and toremifene in cultured retinal pigment epithelial cells. Pharmacol

Toxicol. 2002;91(3):116-122.

49. Klein TW, Lane B, Newton CA, Friedman H. The cannabinoid

system and cytokine network. Proc Soc Exp Biol Med. 2000;


50. Pertwee RG. Cannabinoid receptor ligands: clinical and neuropharmacological

considerations, relevant to future drug discovery

and development. Expert Opin Investig Drugs. 2000;9(7):


51. De Laurentiis A, Ferna´ndez Solari J, Mohn C, Zorrilla

Zubilete M, Rettori V. Endocannabinoid system participates in

neuroendocrine control of homeostasis. Neuro immuno modulation.


52. Di Marzo V, Bisogno T, De Petrocellis L. Endocannabinoids: new

targets for drug development. Curr Pharm Des. 2000;6(13):


53. Gonza´lez S, Bisogno T, Wenger T, et al. Sex steroid influence on

cannabinoid CB(1) receptor mRNA and endocannabinoid levels

in the anterior pituitary gland. Biochem Biophys Res Commun.


54. Lo´pez HH, Webb SA, Nash S. Cannabinoid receptor antagonism

increases female sexual motivation. Pharmacol Biochem Behav.


55. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M.

Cannabinoids as novel anti-inflammatory drugs. Future Med

Chem. 2009;1(7):1333-1349.

56. Mouslech Z, Valla V. Endocannabinoid system: an overview of

its potential in current medical practice. Neuro Endocrinol Lett.


57. Wegener N, Koch M. Neurobiology and systems physiology of

the endocannabinoid system. Pharmacopsychiatry. 2009;

42(suppl 1):S79-S86.

58. De Petrocellis L, Di Marzo V. An introduction to the endocannabinoid

system: from the early to the latest concepts. Best Pract

Res Clin Endocrinol Metab. 2009;23(1):1-15.

59. Goodfellow CE, Glass M. Anandamide receptor signal transduction.

Vitam Horm. 2009;81:79-110.

60. Pertwee RG. Ligands that target cannabinoid receptors in the

brain: from THC to anandamide and beyond. Addict Biol. 2008;


61. Cencioni MT, Chiurchiu` V, Catanzaro G, et al. Anandamide suppresses

proliferation and cytokine release from primary human

T-lymphocytes mainly via CB2 receptors. PLoS One.


62. Pasquariello N, Catanzaro G, Marzano V, et al. Characterization

of the endocannabinoid system in human neuronal cells and proteomic

analysis of anandamide-induced apoptosis. J Biol Chem.

2009 23;284(43):29413-29426.

63. Pandey R, Mousawy K, Nagarkatti M, Nagarkatti P. Endocannabinoids

and immune regulation. Pharmacol Res. 2009;60(2):


64. Parolaro D, Massi P, Rubino T, Monti E. Endocannabinoids in the

immune system and cancer. Prostaglandins Leukot Essent Fatty

Acids. 2002;66(2-3):319-332.

65. Mato S, Alberdi E, Ledent C, Watanabe M, Matute C. CB1 cannabinoid

receptor-dependent and -independent inhibition of

depolarization-induced calcium influx in oligodendrocytes. Glia.


66. Anand P, Whiteside G, Fowler CJ, Hohmann AG. Targeting CB2

receptors and the endocannabinoid system for the treatment of

pain. Brain Res Rev. 2009;60(1):255-266.

67. Maenpaa H, Mannerstrom M, Toimela T, Salminen L,

Saransaari P, Tahti H. Glutamate uptake is inhibited by tamoxifen

and toremifene in cultured retinal pigment epithelial cells. Pharmacol

Toxicol. 2002;91(3):116-122.

68. Traynor BJ, Bruijn L, Conwit R, et al. Neuroprotective agents for

clinical trials in ALS: a systematic assessment. Neurology. 2006;


69. Lee ES, Yin Z, Milatovic D, Jiang H, Aschner M. Estrogen and

tamoxifen protect against Mn-induced toxicity in rat cortical primary

cultures of neurons and astrocytes. Toxicol Sci. 2009;


70. Gerra G, Zaimovic A, Gerra ML, et al. Pharmacology and toxicology

of Cannabis derivatives and endocannabinoid agonists.

Recent Pat CNS Drug Discov. 2010;5(1):46-52.

71. Fischedick JT, Glas R, Hazekamp A, Verpoorte R. A qualitative

and quantitative HPTLC densitometry method for the analysis of

cannabinoids in Cannabis sativa L. Phytochem Anal. 2009;20(5):


72. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Nonpsychotropic

plant cannabinoids: new therapeutic opportunities

from an ancient herb. Trends Pharmacol Sci. 2009;30(10):


73. Turcotte D, Le Dorze JA, Esfahani F, Frost E, Gomori A,

Namaka M. Examining the roles of cannabinoids in pain and other

therapeutic indications: a review. Expert Opin Pharmacother.


74. Akinshola BE, Chakrabarti A, Onaivi ES. In vitro and in

vivo action of cannabinoids. Neurochem Res. 1999;24(10):


75. Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and

metabolism of delta 1 tetrahydrocannabinol and other cannabinoids

with emphasis on man. Pharmacol Rev. 1986;38(1):21-43.

76. Borrelli F, Aviello G, Romano B, et al. Cannabidiol, a safe and

non-psychotropic ingredient of the marijuana plant Cannabis

sativa, is protective in a murine model of colitis. J Mol Med.


77. Zanelati TV, Biojone C, Moreira FA, Guimara˜es FS, Joca SR.

Antidepressant-like effects of cannabidiol in mice: possible involvement

of 5-HT1A receptors. Br J Pharmacol. 2010;159(1):122-128.

78. Jones NA, Hill AJ, Smith I, et al. Cannabidiol displays antiepileptiform

and antiseizure properties in vitro and in vivo. J Pharmacol

Exp Ther. 2010;332(2):569-577.

79. Krivickas LS, Carter GT. Amyotrophic lateral sclerosis. J Spinal

Cord Med. 2002;25(4):274-276.

80. Weiss MD, Weydt P, Carter GT. Current pharmacological management

of amyotrophic lateral sclerosis and a role for rational

polypharmacy. Expert Opin Pharmacother. 2004;5(4):735-746.

81. Maccarrone M, Finazzi-Agro A. The endocannabinoid system,anandamide

and the regulation of mammalian cell apoptosis. Cell

Death Differ. 2003;10:946-955.

82. Burgess RW, Cox GA, Seburn KL. Neuromuscular disease models

and analysis. Methods Mol Biol. 2010;602:347-393.

83. Weiss MD, Carter GT. The state of the science of all motor neuron

diseases. Phys Med Rehabil Clin N Am. 2008;19(3):xix-xx.

84. Zhao P, Leonoudakis D, Abood ME, Beattie EC. Cannabinoid

receptor activation reduces TNFalpha-induced surface localization

of AMPAR-type glutamate receptors and excitotoxicity. Neuropharmacology.


85. Yiangou Y, Facer P, Durrenberger P, et al. COX-2, CB2 and

P2X7-immunoreactivities are increased in activated microglial

cells/macrophages of multiple sclerosis and amyotrophic lateral

sclerosis spinal cord. BMC Neurol. 2006;6:12.

86. Kapur A, Zhao P, Sharir H, et al. Atypical responsiveness of the

orphan receptor GPR55 to cannabinoid ligands. J Biol Chem.


87. Zhao P, Leonoudakis D, Abood ME, Beattie EC. Cannabinoid

receptor activation reduces TNFalpha-induced surface localization

of AMPAR-type glutamate receptors and excitotoxicity. Neuropharmacology.


88. Zhang M, Adler MW, Abood ME, Ganea D, Jallo J, Tuma RF.

CB2 receptor activation attenuates microcirculatory dysfunction

during cerebral ischemic/reperfusion injury. Microvasc Res.


89. Wallace MJ, Martin BR, DeLorenzo RJ. Evidence for a physiological

role of endocannabinoids in the modulation of seizure

threshold and severity. Eur J Pharmacol. 2002;452:295-301.

90. Wallace MJ, Blair RE, Falenski KW, Martin BR, DeLorenzo RJ.

The endogenous cannabinoid system regulates seizure frequency

and duration in a model of temporal lobe epilepsy. J Pharmacol

Exp Ther. 2003;307:129-137.

91. Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic

potential of cannabis. Lancet Neurology. 2003;2:291-298.

92. Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain

injury: therapeutic implications. Trends Mol Med. 2002;8:58-61.

93. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce

hyperalgesia and inflammation via interaction with peripheral

CB1 receptors. Pain. 1998;75:111-119.

94. Abresch RT, Seyden NK, Wineinger MA. Quality of life: issues

for persons with neuromuscular diseases. Phys Med Rehabil Clin

N Am. 1998;9(1):233-248.

95. Mayadev AS, Weiss MD, Distad BJ, Krivickas LS, Carter GT. The

amyotrophic lateral sclerosis center: a model of multidisciplinary

management. Phys Med Rehabil Clin N Am. 2008;19(3):619-631.

96. Carter GT, Butler LM, Abresch RT, Ugalde VO. Expanding the

role of hospice in the care of amyotrophic lateral sclerosis. Am

J Hosp Palliat Med. 1999;16(6):707-710.

97. Brettschneider J, Kurent J, Ludolph A, Mitchell JD. Drug therapy

for pain in amyotrophic lateral sclerosis or motor neuron disease.

Cochrane Database Syst Rev. 2008;(3):CD005226.

98. Bromberg MB. Quality of life in amyotrophic lateral sclerosis.

Phys Med Rehabil Clin N Am. 2008;19(3):591-605.

99. Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit

activated by cannabinoids. Nature. 1998;395(6700):381-383.

100. Zeltser R, Seltzer Z, Eisen A, Feigenbaum JJ, Mechoulam R.

Suppression of neuropathic pain behavior in rats by a nonpsychotropic

synthetic cannabinoid with NMDA receptorblocking

properties. Pain. 1991;47(1):95-103.

101. Elikottil J, Gupta P, Gupta K. The analgesic potential of cannabinoids.

J Opioid Manag. 2009;5(6):341-357.

102. Karst M, Wippermann S. Cannabinoids against pain. Efficacy

and strategies to reduce psychoactivity: a clinical perspective.

Expert Opin Investig Drugs. 2009;18(2):125-133.

103. Thomas BF, Adams IB, Mascarella SW, Martin BR, Razdan RK.

Structure activity analysis of anandamide analogs: Relationship to

a cannabinoid pharmacophore. J MedChem. 1996;39(2):471-497.

104. Agurell S, Halldin M, Lindgren JE, et al. Pharmacokinetics and

metabolism of delta 1 tetrahydrocannabinol and other cannabinoids

with emphasis on man. Pharmacol Rev. 1986;38(1):21-43.

105. Johansson E, Halldin MM, Agurell S, Hollister LE,

Gillespie HK. Terminal elimination plasma half life of delta 1

tetrahydrocannabinol (delta 1 THC) in heavy users of marijuana.

Eur J Clin Pharmacol. 1989;37(3):273-277.

106. Martı´n-Sa´nchez E, Furukawa TA, Taylor J, Martin JL. Systematic

review and meta-analysis of cannabis treatment for chronic

pain. Pain Med. 2009;10(8):1353-1368.

107. Richardson JD. Cannabinoids modulate pain by multiple

mechanisms of action. J Pain. 2000;1(1):1-20.

108. Meinck HM, Schonle PW, Conrad B. Effects of cannabinoids on

spasticity and ataxia in multiple sclerosis. J Neurol. 1989;


109. Greenberg HS, Weiness AS, Pugh JE. Short term effects of

smoking marijuana on balance in patients with multiple sclerosis

and normal volunteers. Clin Pharmacol Ther. 1994;55:324-328.

110. Fitzgerald PB, Williams S, Daskalakis ZJ. A transcranial magnetic

stimulation study of the effects of cannabis use on motor

cortical inhibition and excitability. Neuropsychopharmacology.


111. Lichtman AH, Martin BR. Spinal and supraspinal components of

cannabinoid-induced antinociception. J Pharmacol Exp Ther.


112. Collin C, Davies P, Mutiboko IK, Ratcliffe S. Sativex Spasticity

in MS Study Group. Randomized controlled trial of cannabisbased

medicine in spasticity caused by multiple sclerosis. Eur

J Neurol. 2007;14(3):290-296.

113. Carter GT, Johnson ER, Bonekat HW, Lieberman JS.

Laryngeal diversion in the treatment of intractable aspiration

in motor neuron disease. Arch Phys Med Rehabil. 1992;


114. Rosenfeld J, Ellis A. Nutrition and dietary supplements in motor

neuron disease. Phys Med Rehabil Clin N Am. 2008;19(3):


115. Greenberg I, Kuehnle J, Mendelson JH, Bernstein JG. Effects of

marijuana use on body weight and caloric intake in humans. Psycho

pharmacol. 1976;49:79-84.

116. Nelson K, Walsh D, Deeter P, Sheehan F. A phase II study of

delta-9-tetrahydrocannabinol for appetite stimulation in

cancer-associated anorexia. J Palliat Care. 1994;10(1):14-18.

117. Gieringer DH, Rosenthal E, Carter GT. Marijuana medical

handbook: practical guide to the therapeutic uses of marijuana.

Oakland, CA: Quick American Press; 2008:39-109.

118. Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME,

Benowitz NL. Vaporization as a smokeless cannabis delivery

system: a pilot study. Clin Pharmacol Ther. 2007;82(5):


119. Pomahacova B, Van der Kooy F, Verpoorte R. Cannabis smoke

condensate III: the cannabinoid content of vaporised Cannabis

sativa. Inhal Toxicol. 2009;21(13):1108-1112.

120. Carter GT, Ugalde VO. Medical marijuana: Emerging applications

for the management of neurological disorders. Phys Med

Rehabil Clin N Am. 2004;15(4):943-954.

121. Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal

cannabis: rational guidelines for dosing. IDrugs. 2004;7(5):


122. Aggarwal SK, Kyashna-Tocha M, Carter GT. Dosing Medical

Marijuana: Rational Guidelines on Trial in Washington State.

MedGenMed. 2007;9(3):52-53.

123. Kirk R. Clinical trials in CNS–SMi’s eighth annual conference.

IDrugs. 2010;13(2):66-69.

124. Al-Shamahi A, Kirkham K, Hookes L. Society for Neuroscience

- 39th Annual Meeting. Part 1 – Novel therapies for the treatment

of CNS disorders and pain. IDrugs. 2009;12(12):731-733.

125. Al-Shamahi A, Kirkham K, Hookes L. Society for Neuroscience

- 39th Annual Meeting. Part 2 – Novel therapies for neurodegenerative

disorders and other CNS diseases. IDrugs. 2009;12(12):


126. Macauley D, Al-Shamahi A. Society for Neuroscience—38th

Annual Meeting—Data for therapeutics for CNS diseases and

disorders. IDrugs. 2009;12(1):17-19.

127. Gwinn K, Corriveau RA, Mitsumoto H, et al, for ALS Research

Group. Amyotrophic lateral sclerosis: an emerging era of collaborative

gene discovery. PLoS One. 2007;2(12):e1254.

128. Weydt P, Weiss MD, Moller T, Carter GT. Neuroinflammation

as a therapeutic target in amyotrophic lateral sclerosis. Curr

Opin Investig Drugs. 2002;3(12):1720-1724.

129. Robson P. Human studies of cannabinoids and medicinal cannabis.

Handb Exp Pharmacol. 2005;168:719-756.

130. McCarberg BH, Barkin RL. The future of cannabinoids as

analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic

overview. Am J Ther. 2007;14(5):475-483.

131. Gerra G, Zaimovic A, Gerra ML, et al. Pharmacology and toxicology

of Cannabis derivatives and endocannabinoid agonists.

Recent Pat CNS Drug Discov. 2010;5(1):46-52.

132. Barchet TM, Amiji MM. Challenges and opportunities in CNS

delivery of therapeutics for neurodegenerative diseases. Expert

Opin Drug Deliv. 2009;6(3):211-225.

133. Kanehisa M. Representation and analysis of molecular networks

involving diseases and drugs. Genome Inform. 2009;23(1):


134. Mechoulam R. Discovery of endocannabinoids and some random

thoughts on their possible roles in neuroprotection and

aggression. Prostaglandins Leukot Essent Fatty Acids. 2002;


135. Gerdeman GL, Lovinger DM. Emerging roles for endocannabinoids

in long-term synaptic plasticity. Br J Pharmacol. 2003;


136. Russo EB. History of cannabis and its preparations in saga, science,

and sobriquet. Chem Biodivers. 2007;4(8):1614-1648.

137. El Sohly MA, Wachtel SR, de Wit H. Cannabis versus THC:

response to Russo and McPartland. Psycho pharmacol. 2003;


138. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIVassociated

sensory neuropathy: a randomized placebo-controlled

trial. Neurology. 2007;68(7):515-521.

139. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized,

placebo-controlled, crossover trial of cannabis cigarettes in neuropathic

pain. J Pain. 2008;9(6):506-521.

140. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis

for neuropathic pain in HIV: a randomized, crossover clinical

trial. Neuropsychopharmacol. 2009;34(3):672-680.

141. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled

trial of cannabis-based medicine in central pain in multiple

sclerosis. Neurology. 2005;65(6):812-819.

142. Benatar M, Kurent J, Moore DH. Treatment for familial amyotrophic

lateral sclerosis/motor neuron disease. Cochrane Database

Syst Rev. 2009;1:CD006153.

143. Valdmanis PN, Daoud H, Dion PA, Rouleau GA. Recent

advances in the genetics of amyotrophic lateral sclerosis. Curr

Neurol Neurosci Rep. 2009;9(3):198-205.

American Journal of Hospice & Palliative Care, published online May 3rd 2010

To have a copy for your own Library, please read and download the paper here: Cannabis and ALS, PDF Document