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Medical marijuana in neurology Expert Review of Neurotherapeutics Downloaded from informahealthcare.com by Korea University on 12/27/14 For personal use only.

Expert Rev. Neurother. 14(12), 1453–1465 (2014)

Selim R Benbadis*1, Juan Sanchez-Ramos1, Ali Bozorg1, Melissa Giarratano1, Kavita Kalidas1, Lara Katzin1, Derrick Robertson1, Tuan Vu1, Amanda Smith2 and Theresa Zesiewicz1 1 Department of Neurology, University of South Florida, Tampa, FL, USA 2 USF Health Byrd Alzheimer’s Institute, Tampa, FL 33613, USA *Author for correspondence: [email protected]

Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are D9-tetrahydrocannabinol, which possesses psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy, migraine and weight loss. Data are also limited in regards to adverse events and safety. Common nonspecific adverse events are similar to those of other CNS ‘depressants’ and include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even with recreational use. There is a concern about psychological dependence, but physical dependence is less well documented. Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will likely expand. KEYWORDS: CBD • epilepsy • headaches • marijuana • multiple sclerosis • neurology

Cannabis preparations have been used as medications since the 19th century in Europe and much longer as a traditional medicine in other cultures. In 1999, the Institute of Medicine published a comprehensive review of the literature [1] and concluded that although there are risks, medical cannabis may be helpful for nausea and vomiting, weight loss, pain, anxiety, glaucoma, spasticity, multiple sclerosis (MS), seizures and movement disorders. The American Academy of Neurology (AAN) recently published a position statement [2] and concluded that medical marijuana is ‘probably effective’ for some symptoms of MS (spasticity, central pain, painful spasms and urinary dysfunction), ‘probably ineffective’ for levodopa-induced dyskinesias of Parkinson’s disease, and of ‘unknown efficacy’ in non-chorea symptoms of Huntington’s disease, Tourette’s syndrome (TS), cervical dystonia and epilepsy. Unfortunately, quality clinical research on cannabis preparations has been limited by the legal status of marijuana. Legal restrictions on the use of marijuana were formalized in 1970 when the Controlled Substance Act included marijuana in the list of Schedule I drugs. Substances in this informahealthcare.com

10.1586/14737175.2014.985209

group have been deemed by the US FDA and Drug Enforcement Administration (DEA) to have ‘no currently accepted medical use in the USA, a lack of accepted safety for use under medical supervision and a high potential for abuse’. Schedule I drugs include heroin, LSD, methaqualone (Quaalude) and 3,4-methylenedioxymethamphetamine (MDMA or ‘Ecstasy’) among others. The situation in regards to marijuana legalization is continuously evolving as the issue is being addressed by the legislation in each state. Currently, 23 states and the District of Columbia have enacted laws that allow people to use marijuana as a medication with a doctor’s recommendation. Four of those states have also legalized marijuana for recreational use in adults. Marijuana is still illegal under federal law, but the Justice Department is not challenging state laws as long as they do not violate other federal enforcement priorities, such as selling to minors or trafficking the drug with gangs and cartels. Marijuana is still a DEA Schedule I drug, but given the above, its potential role for medical use is a timely topic. Here

 2014 Informa UK Ltd

ISSN 1473-7175

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CB1 receptor response (% of maximum)

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Concentration-response curve

Full agonist (HU-210) Partial agonist (THC) Antagonist (rimonabant) Inverse agonist (CBD) Agonist + antagonist ? Agonist + inverse agonist

50

25

0

–25 Log (ligand concentration)

Figure 1. Concentration–response curves of cannabinoid compounds on the CB1 receptor. The full agonist is the compound HU-210, which is a synthetic cannabinoid; the partial agonists are THC, which is a cannabinoid found in cannabis, and anandamide, which is an endocannabinoid found in humans; the antagonist is rimonabant, a synthetic cannabinoid studied for weight control; and the inverse antagonist is CBD, which has no direct CB1 activity but is postulated to be an example of an inverse agonists. It is unknown what exact combination of agonists, antagonists and inverse agonists is in cannabis and the result of this combination. CB1: Cannabinoid-1; CBD: Cannabidiol; HU-210: 3-(1,1´- dimethylheptyl)-6aR, 7, 10, 10aR-tetrahydro-1-hydroxy-6, 6-dimethyl-6Hdibenzo[b, d]pyran-9-methanol; THC: D9-tetrahydrocannabinol. Permission obtained from John Wiley and Sons.

the authors will review the potential utility of cannabinoids for treatment of neurologic diseases. Basic pharmacology

Marijuana describes preparations derived from the dried leaves and flowers of the Cannabis plant. Synthetic cannabinoids are pharmaceutical agents that are approved as prescription drugs in several countries. These include dronabinol (Marinol) and nabilone (Cesamet), two oral agents that are FDA approved for use in the USA. Nabiximols (SativexTM ) is an oromucosal spray prepared from the extracts of the Cannabis plant, legalized in several other countries but not in the USA [3,4]. The genus Cannabis includes two species that produce useful amounts of psychoactive cannabinoids: Cannabis sativa and C. indica. A third strain, C. ruderalis, has few psychoactive properties. Cannabis contains many compounds; it is postulated that the C. sativa plant contains over 400 compounds, approximately 60 of which are active [5–7]. The active compounds are collectively known as cannabinoids, and their potency is variable depending on the species and extraction process. There are three compounds that have been isolated and identified as the most potent: D9-tetrahydrocannabinol (THC), cannabidiol (CBD) and cannibinol. In the 1960s, THC was established as the cannabinoid primarily responsible for the psychoactive properties of 1454

marijuana and the one responsible for most, though not all, of the pharmacologic effects of cannabis [3,4,8,9]. Cannabis is one of the first plants to have been used medicinally, and the therapeutic properties of marijuana have been known for over 5000 years [7]. However, only recently has its mechanism of action become understood better. In the 1990s, two types of cannabinoid receptors were identified: the cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors. CB1 receptors are located primarily throughout the CNS and, to a lesser extent, in the peripheral tissue [3,4,8,9]. The CB1 receptors are spread throughout the brain and are found in high densities in the neuron terminals of the basal ganglia, cerebellum, hippocampus, neocortex, hypothalamus and limbic cortex. The periaqueductal gray, dorsal horn and immune cells also contain CB1 receptors, but to a lesser extent. A number of neurotransmitters are affected by CB1, including acetylcholine, norepinephrine, dopamine, serotonin, GABA, glutamate and D-aspartate [5]. These interactions account for many of marijuana’s effects on pleasure, memory, thought, concentration, sensory and time perception, and coordination. The CB2 receptors are present mainly on immune cells and peripheral tissues and can have inflammatory, immunosuppressive and antinociceptive activities [5,10]. The definitive pharmacologic actions of CB2 receptor binding have yet to be determined, but recently, CB2 receptors were identified in microglia [3]. As mentioned previously, there are multiple cannabinoid compounds in medical cannabis, with varying effects on the receptors (FIGURE 1) [3]. THC is the most potent of the compounds and is considered a partial agonist at the CB1 receptor. CBD is non-psychotropic and its mechanism of action is not completely understood [3,4]. It is thought that CBD may be an inverse agonist since it has been found to, in fact, counteract the psychotropic activity of THC [8,9]. Anandamide is one of several endogenous cannabinoids that have been identified and widely studied [5,10]. These neurotransmitters, known collectively as endocannabinoids, are synthesized on demand to act on the CB receptors and then, in turn, are hydrolyzed as needed to maintain homeostasis. Cannabis preparations are available in a number of dosage forms, all with vastly different concentrations of the various cannabinoid compounds. Cannabis can be administered in many ways. The plant material can be smoked in cigarettes or pipes, inhaled through a vaporizer, extracts can be applied topically as oils or balms and various formulations can be ingested in food or drinks. The systemic bioavailability of THC and CBD depends on the concentration within the product as well as the dosage form [3]. After inhalation, both THC and CBD are absorbed rapidly (within minutes). Bioavailability ranges from 10 to 45% and depends on how much is lost by heat or by exhalation [3,4,11]. Vaporizing cannabis is becoming increasingly popular as it allows for rapid absorption with minimal combustible byproducts and can be inhaled without generating smoke. Oral absorption of the cannabinoids, on the other hand, results in a lower bioavailability (5–20%) due to gastric degradation and extensive first-pass effect. The peak effect may Expert Rev. Neurother. 14(12), (2014)

Medical marijuana in neurology

also be significantly delayed (~1–3 h), resulting in difficulty with appropriate dosing, and self-dosing by patients [3,4]. THC and CBD are extremely lipophilic compounds; they ultimately accumulate in the adipose tissue and are mainly metabolized in the liver [4,11].

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Epilepsy

The potential role of marijuana as a treatment for epilepsy was brought to the forefront in August 2013 by a TV special report on a child with Dravet syndrome, a severe epilepsy of childhood. Charlotte, the subject in this report, had failed conventional treatments, was deteriorating, and had a dramatic response to oral administration of an oil prepared from a strain of cannabis that was high in CBD and low in THC (the cannabis strain became known as Charlotte’s Web). Other similar reports have followed, and patients and families now routinely inquire about the possible use of marijuana for treatment. Evidence in humans

Only two small double-blinded, placebo-controlled studies of cannabinoids in epilepsy have been published. In both studies, daily oral CBD was used as an adjunct to antiepileptic drugs. One study demonstrated a beneficial effect in seven out of eight patients [12], while the other showed no improvement in 12 patients [13]. A Cochrane database review concluded that no reliable conclusions could be drawn regarding the efficacy of cannabinoids as a treatment for epilepsy, and could only conclude that a short-term dose of 200–300 mg daily of CBD was safe [14]. Animal studies

The anticonvulsant profiles of cannabis-derived botanical drug substances rich in cannabidivarin and containing CBD were found to have significant anticonvulsant effects in models of acute seizures such as the pentylenetetrazole, audiogenic seizure and pilocarpine-induced convulsions [15]. CBD was also found effective in the penicillin model, where it decreased the proportion of the most severe tonic–clonic seizures and seizure-related mortality [16]. In mice, CBD prevented tonic convulsions caused by a convulsant current and by convulsant doses of GABA inhibitors, 3-mercaptoproprionic acid, picrotoxin, isonicotinic acid hydrazine, pentylenetetrazole and bicuculline. CBD also prevented 3-mercaptoproprionic acid-induced lethality [17]. Another in vitro model of generalized epilepsy showed that CBD reduces excitability, epileptiform EEG activity and reduces seizure severity and lethality [18]. The above evidence is clearly insufficient to conclude on the efficacy and safety of marijuana or CBD in epilepsy, but certainly seems sufficient to pursue rigorous research. According to the American Epilepsy Society [19], ‘at present, the epilepsy community does not know if marijuana is a safe and effective treatment, nor do they know the long-term effects that marijuana will have on learning, memory and behavior, especially in infants and young children’. Thus, the authors support the position of the American Epilepsy Society, which is to urge the informahealthcare.com

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DEA ‘to change marijuana from its current Schedule I status to allow researchers to conduct studies more efficiently’. At least one such trial is ongoing in children. What to do now?

In states where medical marijuana is legal, at this point (until more is known about the efficacy and safety), it would probably have a legitimate place in ‘desperate’ patients such as those frequently encountered at level IV epilepsy centers. A reasonable approach would be to license only those centers that are truly comprehensive and offer all ‘conventional’ treatments, including modern anti-epileptic drugs, neurostimulation and surgery. In this regard, CBD should be treated at this point like any ‘investigational’ treatment that is always preceded by EEG-video monitoring to confirm the diagnosis and identify candidates for standard therapies such as surgery and neurostimulation. For example, we certainly would not want CBD offered to patients with psychogenic seizures or patients with straightforward surgically remediable epilepsy. Once intractable epilepsy has been ascertained, exactly where CBD will belong in the treatment algorithm (vs medications, epilepsy surgery, diet and neurostimulation) is likely to vary among centers and evolve over time. Headaches

The pathophysiology of migraine is not fully understood, but is thought to involve the activation of the trigeminovascular system followed by neurogenic inflammation in the dura mater. Nitric oxide is thought to play a role in the activation of the trigeminovascular system by activating perivascular afferent nerve fibers (via serotonin) in the meninges, thereby contributing to the release of vasoactive neuropeptides, including substance P and calcitonin gene related peptide [20]. This activation is inhibited by acute antimigraine drugs, and inhibition of neuronal activation is highly predictive of the antimigraine potential. The role of the endocannabinoid system in migraine remains unclear. CB1 receptors are located in the trigeminal ganglion, in the spinal trigeminal tract and nucleus, and in other pain processing areas, such as the periacqueductal gray matter, thalamus, cingulate and frontal cortices and the amygdala [21]. Anandamide, N-arachidonolethanolamide (AEA), is an endocannabinoid thought to play a role in migraine. It potentiates 5-hydroxytryptamine (HT)1A and inhibits 5-HT2A receptors, supporting a potential therapeutic role in acute migraine similar to triptans (which are agonists at 5-HT1B/1D and 5-HT1A receptors). AEA is active in the periaqueductal gray matter, which is thought to be a migraine generator [22]. AEA may also have a modulatory role on the trigeminovascular system [23]. In a rat model, AEA was able to inhibit neurogenic dural vasodilation, calcitonin gene-related peptide, capsaicin and nitric oxide-induced dural vasodilation by binding to CB1 receptors in the spinal trigeminal tract and nucleus caudalis [24]. In the same model, a CB1 receptor antagonist, AM251, was able to reverse the inhibition of the dural vasodilation 1455

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mediated by anandamide. Another rat model demonstrated that CB1 receptors can inhibit trigeminal neurons with A fiber and C fiber input in the trigeminocervical complex in response to electrode activation of the ophthalmic division of the trigeminal nerve [24].

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Human data

There is anecdotal support and experimental evidence for the use of cannabis for migraine, but randomized controlled trials are lacking. Experimental evidence suggests there are reduced levels of AEA in the cerebrospinal fluid of patients with chronic migraine and analgesic overuse headache. These results suggest that impairment of the endogenous cannabinoid system may result in increased calcitonin gene-related peptide and no production, allowing for activation of the trigeminovascular system, subsequent sensitization and potential for ‘chronification’ of pain [25]. Evidence suggests that there is increased degradation of AEA in platelets of female (but not male) migraineurs, suggesting that the decreased level of circulating AEA may contribute to a reduced pain threshold [26]. PET has also demonstrated increased CB1 receptor binding in women with migraine, most pronounced in the anterior cingulate, mesial temporal and prefrontal and superior frontal cortices, areas well known to be involved in the affective component of pain [27]. There are anecdotal individual case reports of cannabis use for cluster headaches, one of the most disabling types of headache. For example, acute cluster attacks can be aborted with dronabinol, a synthetic THC, and within 5 min of inhalation of marijuana [28,29]. By contrast, in a survey of cluster headache patients who used cannabis, a significant portion of patients reported worsening, requiring reduced use during the active cluster headache periods [30]. Randomized controlled studies of cannabis for treatment of chronic headache are needed. Until there is adequate evidence, the exact role of cannabis for the management of chronic headache disorders remains unclear. At this point, therefore, cannabis may be considered in patients who are refractory to all conventional therapies, including adequate trials of oral preventive and rescue agents, optimization of non-pharmacological interventions (biofeedback, physical therapy and cognitive behavioral therapy) and injections (nerve blocks and botulinum toxin). Multiple sclerosis

Unlike other neurologic diseases, MS has not had specific treatments for a long time. FDA-approved disease-modifying treatments were not available until 1993. This created an environment where complementary and alternative medicine therapies became an important option for MS, and their use is still common. Complementary and alternative medicine therapies for MS include low-dose naltrexone, hyperbaric oxygen, Ginkgo biloba, bee venom and cannabinoids (marijuana derivatives) [31,32]. Of the complementary and alternative medicine therapies, cannabinoids have been the most studied in MS. They have been studied in different formulations, such as oral 1456

cannabinoids, mucosally delivered cannabinoids and smoked cannabis. Despite a decent amount of research conducted on cannabinoids and their potential symptomatic benefit in MS, many questions remain. Chief among them is what particular symptoms of MS – pain, spasticity, tremor and urinary dysfunction – could benefit from its use relative to potential side effects [2]. Human evidence

A large UK clinical trial was conducted in the early 2000s to assess the benefit of oral cannabinoids (synthetic THC) for MS-related spasticity [33]. The trial was placebo controlled involving 630 subjects. Cannabinoids did not improve spasticity (primary outcome measure), but did demonstrate benefit in the secondary outcome measures assessing patient-reported effects on spasticity and mobility. A limitation of the study was that subjects became ‘unblinded’ due to the side effects of cannabinoids, such as lightheadedness and dry mouth. This study, along with a separate one specifically addressing another oral cannabinoid’s effect on tremor in MS patients failed to show any significant improvement in MS-related tremor [33,34]. In another UK placebo-controlled clinical trial, oral cannabinoids were administered to assess for symptomatic relief of muscle stiffness and pain [35]. The study met its primary outcome measure, as the proportion of subjects experiencing relief of muscle stiffness was nearly twice as large in the cannabinoid arm versus placebo. Similar results were reported in relief from body pain and sleep quality. The ‘unblinding’ effect of adverse events (dizziness and dry mouth) was again a possible confounder. Nabiximols (Sativex, GW Pharmaceuticals, London, UK), an oromucosal delivery system for cannabinoids, has been studied extensively for MS-related symptoms. It is currently available for MS-related spasticity in 11 countries, and has received regulatory approval in an additional 13 countries. One large multicenter European clinical trial had a unique study design [36]. Phase A was a preliminary, single-blind, 4-week treatment period to identify responders to nabiximols. The investigator was aware that all subjects were receiving nabiximols, but the subjects were told they would receive either placebo or nabiximols. Those subjects with at least a 20% reduction in spasticity as determined by a validated selfreporting tool were eligible for entry into Phase B, which was a 12-week, double-blind, randomized, placebo-controlled, parallel-group study. The study design was an attempt at creating a ‘real-world’ clinical setting that reflects how symptomatic therapies are used, that is, patients who have side effects or no efficacy are unlikely to remain on treatment. Results showed that nabiximols improved spasticity, specifically in subjects who had undergone a successful 4-week ‘treatment trial’ and demonstrated failure to adequately respond to other antispasticity therapies. Studies of nabiximols for other MS-related symptoms such as tremor and urinary dysfunction were not as conclusive [36,37]. Specifically, a small study to assess its ability to treat detrusor overactivity in MS patients failed to show a reduction in urinary incontinence episodes [38]. Expert Rev. Neurother. 14(12), (2014)

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Medical marijuana in neurology

Smoked cannabis has also been studied for its effect on various symptoms of MS. One such small study found that smoked cannabis was superior to placebo in reducing treatmentresistant spasticity [39]. Another small study examined the shortterm effects of smoked marijuana on balance, and found that it led to worsening objective balance and posture [40]. Symptomatic management of MS is challenging, and there is a clear need for additional options. Nabiximols (Sativex) is available in many countries for the treatment of MS-related spasticity, and may have a role. Other marijuana derivatives and smoked marijuana have shown benefit in spasticity and pain, but whether they could also effectively treat other symptoms of MS remains unclear. Nonetheless, MS symptoms of pain and spasticity were the ones in which marijuana was ‘probably effective’ according to the recent AAN review [2]. Neuromuscular disease

Cannabis is often self-administered to relieve symptoms of neuromuscular diseases. There are numerous anecdotal reports and testimonies on the benefit of cannabis on pain, spasticity, mood and even survival. As in other neurologic diseases, the poor efficacy and tolerability of currently available treatments have driven the search for alternative treatments for neuropathic pain. Neuropathic pain

Neuropathic pain is defined as ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’ [41]. Pain can be experienced with lesions affecting peripheral or CNS pain integration centers. Current treatment options have limited efficacy and many patients have pain that is refractory to existing treatments. Oral medications, including tricyclic antidepressants, serotonin reuptake inhibitors and calcium channel ligands (gabapentin and pregabalin), are often used as first-line treatments. Compounding their limited efficacy, these medications cause significant side effects that limit tolerability. Tramadol and opioid analgesics have shown efficacy, but there is concern regarding their long-term safety and risk of addiction and overdose. The interest in cannabis dates back to the 1800s when smoked cannabis administered to dogs was found to attenuate their response to pain [42]. The mechanism by which cannabis mediates pain appears to be through the cannabinoid receptors CB1 and CB2, since they are found in central and peripheral nervous system sites associated with pain processing [43,44]. Various animal models of induced neuropathic pain have shown that cannabinoids can attenuate hyperalgesia and allodynia [45]. There are few human trials evaluating the efficacy and safety of smoked and vaporized cannabis in treating neuropathic pain. In patients with HIV-associated distal sensory predominant polyneuropathy, smoked cannabis resulted in a 30% pain relief versus placebo and was well tolerated [46]. Another placebocontrolled trial of smoked cannabis for HIV painful sensory neuropathy also demonstrated efficacy with a drop in daily pain by 34% [47]. In patients with both central and peripheral neuropathic pain, vaporized cannabis had an analgesic effect informahealthcare.com

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with minimal psychoactive effects, but the effect lasted only 1–2 h [48]. Thus, while a modest efficacy of cannabis on neuropathic pain has been demonstrated, the benefit of cannabis over currently available treatments is less clear. Side effects of oral neuroleptics and tricyclic antidepressants often limit their usefulness. On the other hand, few patients withdrew from cannabis studies due to tolerability. Typical side effects included feeling high, psychoactive effects and memory dysfunction at higher concentrations, all of which rapidly reversed [49]. In addition, cannabis not only improves pain but also other common comorbid symptoms such as nausea, depressed mood, anxiety and disturbed sleep [50]. Thus, cannabis may allow simplification of treatment regimen and avoidance of polypharmacy. Of course, opioids are also used in the treatment of neuropathic pain. A benefit of cannabis over opioid medications is the low risk of respiratory depression, possibly due to the low levels of cannabinoid receptors in areas that control heart rate and respiration [45]. The role that cannabis will play in the treatment of neuropathic pain is yet to be determined. For patients whose pain is well controlled on currently available therapies, there is no clear benefit of either adding or switching to cannabis. However, patients with chronic neuropathic pain refractory to other analgesic medication have benefited from various formulations of cannabinoids [45]. Amyotrophic lateral sclerosis

Cannabis has some theoretical benefits in patients with amyotrophic lateral sclerosis (ALS). Neuroinflammation may play a role in the pathogenesis of ALS, and cannabis may participate in the regulation of the immune system via its action at the CB2 receptors, which are present on the immune cells. Cannabinoids can downregulate cytokine and chemokine production, which are pro-inflammatory. In addition, endogenous cannabinoids may also provide neuroprotection by its modulation of the excitotoxic glutaminergic neurotransmission [51]. In a transgenic mice model, cannabinol delivered subcutaneously significantly delayed disease onset by 2 weeks, although survival was not affected [52]. In another study using the same mice model, THC administered at the onset of symptoms delayed motor impairment and prolonged survival versus control [53]. There are several symptoms in ALS that potentially can be ameliorated by cannabis. These symptoms include pain, spasticity, weight loss, dyspnea, sialorrhea and depression. While there are multiple studies showing that cannabis decreased these symptoms in other disorders, there is a dearth of clinical trials assessing the effect of cannabis, specifically in ALS. However, in surveys of patients with ALS, cannabis use was credited with improving speech, swallowing, appetite loss, sialorrhea and mood [51,54]. Clearly, additional research into the benefit of cannabis in ALS is needed, especially, again, in regards to specific compounds, routes of administration and dosing. In addition, the challenge of delivering effective dose to patients with compromised lung and swallowing function has to be overcome. 1457

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Movement disorders

The cannabinoid receptor (CB1) and its endogenous cannabinoid ligand, arachidonylethanolamide (anandamide), have been shown to be heavily distributed in the basal ganglia [55]. Animal research with synthetic cannabinoid agonists and antagonists can either increase or decrease the locomotor activity depending on the dose, site of injection (brain or systemic) and species [56,57]. The consideration of cannabinoids in humans to treat movement disorders, including Parkinson’s disease (PD), is theoretically reasonable, as high densities of G protein-coupled CB1 receptors are present in the globus pallidus and pars reticulata of substantia nigra regions of brain that are part of the neural network critical for the automatic execution of learned movements [58]. As in other areas, there is little clinical research on the use of cannabis for treatment of movement disorders. Parkinson’s disease

Although the successful use of tincture of C. indica to treat PD was first described in Europe by Sir William Gowers in his landmark textbook of neurology [59], the number of clinical reports on pharmacotherapeutics of cannabis for PD and other movement disorders is limited. In a survey of 630 PD patients, cannabis use was reported by 25% of 339 patients who responded to the questionnaires [60]. Many patients reported daily oral intake of half a teaspoon of fresh or dried leaves. None of the patients had a history of cannabis ingestion prior to using it to treat PD symptoms, nor were they advised by a medical professional to ingest it. Approximately 46% of patients noted mild or substantial improvement of their PD symptoms. Thirty percent experienced improvement in resting tremor, 45% reported diminished bradykinesia and 38% reported reduced rigidity. A recent open-label observational study on the effects of smoked cannabis in 22 patients reported improvement in both motor and non-motor features of PD [61]. The mean total score on the motor component of the Unified Parkinson Disease Rating Scale improved significantly. Analysis of specific motor symptoms revealed statistically significant improvement in tremor, rigidity and bradykinesia. The authors also reported significant improvement in sleep and pain scores and no clinically significant adverse effects (AEs). There are currently few options available to treat levodopainduced dyskinesias, experienced by advanced PD patients. These involuntary choreiform movements are associated with overactivity of the globus pallidus and glutamatergic striatal excitation [61]. Striatal cannabinoid receptors exist on GABA terminals and could theoretically improve dyskinesia by enhancement of GABA transmission in the globus pallidus [62]. These findings have been echoed by several preclinical experiments [63], although clinical trials have not demonstrated consistent results. One randomized, double-blind, crossover study evaluated the use of oral cannabis for treatment of levodopa-induced dyskinesia in 19 PD patients, and found no significant improvement in patients using cannabis compared to placebo [64]. Conversely, another randomized, double-blind, placebo-controlled study in seven PD patients 1458

found that nabilone, a cannabinoid agonist, resulted in a 22% mean reduction in levodopa-induced dyskinesia compared to placebo [65]. The AAN review deemed marijuana ‘probably ineffective’ for treating levodopa-induced dyskinesias [2]. Huntington’s disease

Huntington’s disease (HD) is a hereditary neurodegenerative disease that affects mood, mentation and movement. Research with gene-silencing agents is advancing in preclinical animal models, but at present there are no human studies with siRNA to stop or reverse the progression of the disease. This leaves neurologists with a set of medications that can provide relief from the symptoms of chorea, psychosis and depression. Preclinical studies with cannabinoids have been performed in HD animal models, several of which demonstrated preservation of striatal neurons [66]. Despite anecdotal reports circulating in the social media on the benefits of cannabis for relief of chorea, painful dystonia and as a mood enhancer, there are no well-powered, double-blind, placebo-controlled studies of cannabinoids for the treatment of HD. One double-blind, randomized, crossover study evaluated the use of CBD versus placebo in 15 neuroleptic-free HD patients [67]. No improvements were reported in primary variables, although the study was underpowered. Another double-blind, placebo-controlled crossover study evaluated nabilone as treatment for HD in 44 patients and found no significant improvements in the total or motor subscores [68,69]. Dystonia

Dystonia is a hereditary or acquired condition of generalized or focal abnormal muscle posturing and movement. The effect of cannabinoids on dystonia is unclear. In one report, cannabinoids improved generalized dystonia in a patient with Wilson’s disease [70]. An open-label evaluation of CBD in doses up to 600 mg/day over a 6-week period demonstrated a 20–50% dose-related reduction in dystonia [71]. Conversely, another double-blind, randomized, placebo-controlled study of nabilone in patients with generalized and segmental primary dystonia did not find any significant improvement [72]. Tourette’s syndrome

Gilles de la TS is characterized by motor and vocal tics. Several anecdotal reports indicate that cannabis and THC may improve TS symptoms. A small double-blind, placebo-controlled, randomized, crossover, single-dose trial of THC, using an examiner and self-rating scales as outcome measures, found a significant improvement of tics following treatment compared to placebo, and no serious adverse events [73]. Another randomized, doubleblind, placebo-controlled study of 24 TS patients over 6 weeks on THC found no significant difference [74]. Sleep disorders

Limited data exist on the utility of cannabis/cannabinoids in the treatment of sleep disorders. Furthermore, the studies that have been performed have serious limitations, including a small sample size and lack of randomization or control group. Only Expert Rev. Neurother. 14(12), (2014)

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Medical marijuana in neurology

a handful of studies with small sample sizes looked at objective polysomnogram (PSG) findings [75]. There are no studies available on the effects of cannabinoids in patients with narcolepsy, restless legs syndrome and obstructive sleep apnea syndrome. The majority of published studies looked at the effect of cannabinoid on the quality of sleep, sleep architecture and sleep latency. The most robust data available are in patients with spasticity, pain or a medical condition leading to sleep problems [76]. The studies showed reduced nocturnal sleep disturbance and improved sleep. There is also some evidence that showed cannabinoids may possibly decrease the amount of slow-wave sleep. Multiple studies have also demonstrated decreased sleep latency without significant effect on the number of nocturnal arousals [75]. This finding is in keeping with subjective sensation of relaxation that cannabis users describe [76]. Conversely, sleep problems are a commonly reported withdrawal problem in patients abstaining from cannabis use [77]. There is also some evidence that patients with post-traumatic stress disorder and sleeping problems use cannabis for coping. About half of these patients with post-traumatic stress disorder reported using cannabis for treatment of sleep problems. Furthermore, the patients with the most severe post-traumatic stress disorder tended to use cannabis more frequently [78]. Patients also self-reported using cannabis for the treatment of anxiety and depression [78–80], which are extremely common in patients with psychophysiological insomnia. A PSG study of patients after cessation of heavy marijuana use found lower total sleep times, less slow-wave sleep, worse sleep efficiency, longer sleep latency and shorter REM latency [81]. Indeed, sleep disturbances are an important reason for failure to discontinue marijuana use. Cannabis may be used for its actual or perceived sleeppromoting properties. Although evidence suggests that cannabis is likely beneficial for sleep initiation, tolerance may develop over time, potentially leading to cannabis use disorder. Again sleep disturbances are a primary symptom of cannabis withdrawal, and may be a significant risk factor for relapse and abuse [82]. More studies are needed to further elucidate the role of cannabis in the treatment of commonly encountered sleep disorders such as insomnia and restless legs syndrome, and its effects in patients with narcolepsy and obstructive sleep apnea syndrome.

Review

It has been established that abnormalities in the endogenous cannabinoid system are present in AD. Conflicting data exist with regard to CB1 receptor expression, which in some cases shows a decrease and in others shows no change [83,84]. However, CB2 receptor expression increases, and correlates with the levels of Ab42 and plaque density [85]. In addition, cannabinoids have been demonstrated to inhibit tau hyperphosphorylation [86], inhibit acetylcholinesterase (the same mechanism by which three of the four currently FDA-approved medications for AD work) and prevent Ab aggregation [87]. CB receptor agonism has been shown to double the clearance of Ab across the blood–brain barrier [88], and CBD and THC have been shown to have neuroprotective antioxidant effects [89]. Several studies have shown that stimulation of CB2 receptors decreases migroglial activation and lowers the Ab levels in transgenic mice [90]. Because of these in vitro and animal model effects on known mechanisms of AD, many have postulated that cannabis may have a role as a potential therapeutic agent for AD. However, limited data exist in that regard. C. sativa extract administered to normal mice was associated with impaired performance in the Morris water maze test, a standard animal model of learning and memory [91]. In humans, recreational use of marijuana has been shown to impair critical thinking and memory, both during and for days after use [92], and to cause neuropsychological decline from childhood to midlife in persistent users [93]. Though this effect is most often attributed to the psychoactive properties of THC, to some it seems counterintuitive to treat a progressive cognitive disorder with the derivatives of a drug known to worsen cognitive impairment. On the other hand, CBD was recently shown to improve socialization and object recognition in transgenic AD mice [94]. This reinforces the concept that the therapeutic effects of cannabinoids, particularly those without significant psychoactive effects, should continue to be examined. Limited human data does exist with regard to treatment of behavioral disturbances in dementia with cannabinoids. Several pilot studies with dronabinol have shown significant decreases in agitation, as well as improvement in Clinical Global Impression scores, sleep and eating in patients with severe dementia [95]. As there are no FDA-approved medications for agitation, and many of the traditionally used medications carry black box warnings for elderly dementia patients, this is an area that warrants further exploration.

Alzheimer’s disease

Alzheimer’s disease (AD) accounts for more than half of the cases of dementia and affects 30–50% of people over the age of 85. The main pathological features include plaques comprising amyloid-b (Ab) and neurofibrillary tangles resulting from hyperphosphorylation of tau protein fibrils. Accumulation of these is felt to lead to inflammation, oxidative stress, deficits in neurotransmission and ultimately cell death. Presently, the only medications approved by the FDA to treat AD simply target symptoms and have a modest effect on the slope of cognitive and functional loss over time, without any real diseasemodifying properties. informahealthcare.com

Adverse effects of cannabis preparations

The recent AAN review [2] on medical cannabis preparations for selected neurologic disorders compiled and analyzed the AEs gathered from analysis of 29 studies. Of 1619 patients treated with cannabinoids for less than 6 months, 6.9% stopped the medication because of AEs. Of the 1118 who received placebo, 2.2% stopped because of AEs. Symptoms that caused medication withdrawal were not recorded in some studies. However, symptoms that appeared in at least two studies in patients treated with cannabinoids included nausea, increased weakness, behavioral or mood changes, suicidal 1459

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ideation or hallucinations, dizziness or vasovagal symptoms, fatigue and feelings of intoxication. With preparations containing higher doses of THC, psychosis, dysphoria and anxiety were more likely to be reported. Higher THC concentrations, however, were not typical for the clinical studies reviewed. A recent review of AEs of short-term use included impaired short-term memory, motor incoordination, altered judgment and in high doses, paranoia and psychosis [92]. One study of chronic medical cannabis for a duration of 1 year revealed 31 of 207 patients treated with cannabis extract (15%) stopped medication, as did 28 of 197 treated with THC (14%) and 10 of 207 given placebo (5%) [96]. However, AEs were not necessarily the reason medication was stopped. For example, cannabinoids inhibit many enzymes of the cytochrome P450 system, which will cause interactions with other medications being taken concurrently, especially opiates for pain. No direct fatalities (overdoses) have been attributed to marijuana, even in recreational users of increasingly potent marijuana, possibly because of the lack of endocannabinoid receptors in the brainstem [2]. Of course, the sedative effects of some cannabis preparations can indirectly endanger patients who perform dangerous tasks such as driving and operating heavy machinery. In addition, smoking and, possibly, even the use of vaporized preparations expose users to carbon monoxide and other respiratory toxins. A review of 25 studies on the safety and efficacy of CBD reported that administration did not induce side effects across a wide range of dosages, including acute and chronic dose regimens, using various modes of administration [97]. Oral administration of 10 mg CBD daily for 21 days did not induce any changes in neurological (including EEG), clinical (including ECG), psychiatric, blood or urine examinations. Oral CBD in epileptic patients (200–300 mg daily for 135 days) was well tolerated and no signs of toxicity or serious side effects were detected on neurological and physical examinations, blood and urine analysis, and repeated ECGs and EEGs [12]. The only mild AE was initial somnolence that resolved in most subjects. Exacerbation of psychosis in pre-existing schizophrenia is commonly reported as a potential AE of cannabis. However, several studies demonstrate that cannabis use does not cause or increase the likelihood of schizophrenia [98,99]. In one study, the frequency of cannabis use increased substantially in the UK over a period from 1996 to 2005 in a cohort of 600,000 subjects per year (aged 16–44), while the incidence and prevalence of schizophrenia declined or remained stable. More recently, another study [99] found that an increased familial morbid risk for schizophrenia is the most likely underlying basis for schizophrenia in cannabis users and not cannabis use by itself. However, cannabis use may precipitate disorders in persons who are vulnerable to developing psychosis or exacerbate the disorder in those who have already developed schizophrenia [92].

fluctuations in blood pressure. These effects are uncommon in controlled clinical trials, but several case reports have described atrial fibrillation, myocardial infarction and TIA associated with cannabis use [5,100]. When it is smoked, marijuana carries a risk of pulmonary complications. Cannabis contains a similar number of carcinogenic compounds to cigarette smoke. Some formulations may even contain higher concentrations of these detrimental components. This puts patients at risk for cancers such as lung or head and neck cancers [5,101]. In addition, cannabis use has been associated with overall decreased pulmonary function, chronic obstructive pulmonary diseases and pulmonary infections. There are also reports that failed to find significant pulmonary pathology in long-term cannabis smokers, especially if they were light smokers, 2–3 times per month [102]. In a federally sponsored ‘Compassionate Investigational New Drug program of the FDA’, mild changes in pulmonary function were found in patients who smoked marijuana daily for at least a decade (averaging 10 marijuana cigarettes daily) [103].

Cardiopulmonary AEs

AEs on neuro-imaging

Cannabis use has been reported to result in AEs on the cardiovascular system, including tachycardia, palpitations and

Imaging studies have suggested that subjects who regularly smoke cannabis, when compared to occasional smokers, exhibit

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Cannabis dependence & abuse

The potential for drug dependence and abuse is a concern of those who promote tight restrictions and insist on maintaining cannabis in Schedule I, in the company of heroin, LSD and 3,4-methylenedioxy-methamphetamine, drugs with ‘no acceptable medical use and with a high abuse liability’. It is estimated by the National Institute on Drug Abuse that about 10% of adult users are at risk for development of drug dependence; this risk increases drastically for those who start young or who use marijuana daily [92]. Chronic use of cannabis results in tolerance to many of its effects, gradual escalation of amount of drug used over time and development of psychological dependence, a transient state of drug-seeking behavior and craving. Unlike dependence on CNS depressants (opioids, barbiturates, alcohol and benzodiazepines), there is sparse evidence for the development of physical dependence to cannabis preparations. Some individuals may experience transient anxiety and insomnia and other psychological symptoms upon cessation of chronic high dose of marijuana [1]. There is no frank withdrawal syndrome with attendant physiological signs of abstinence (i.e., seizures, tremors, perspiration or abdominal cramps) that would be required to infer a state of physical dependence. Some authors view cannabis as the most commonly abused drug in the USA and worldwide [80], often seen as a gateway drug, that is, leading to addiction to more dangerous drugs. However, a recent study of a representative sampling of US 12 graders showed that alcohol was the ‘gateway’ drug, leading to the use of tobacco, marijuana and other illicit substances. Moreover, students who used alcohol exhibited a significantly greater likelihood of using both licit and illicit drugs [104].

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gray matter volume reduction in the medial temporal cortex, temporal pole, parahippocampal gyrus, insula and orbitofrontal cortex, regions rich in cannabinoid CB1 receptors [105]. Onset of smoking cannabis before the age of 18 correlated with the magnitude of gray matter volume reduction in the cerebral hemispheres. However, significant gray matter atrophy was also noted in ‘heavy’ users of cannabis, regardless of the age of onset. Another study reported that young marijuana smokers have brain ‘abnormalities’ even if they only smoked one joint per week [106]. A closer examination of this report reveals flaws in subject selection, analysis of data and interpretation. This team of researchers performed a single MRI scan of 20 young persons between 18 and 25 years of age. Brain MRI scans from 10 subjects who smoked marijuana at least once per week (but were not ‘dependent’) were compared to MRI scans from 10 ‘control’ subjects who had not smoked in the last year and had smoked less than five-times in their lifetime. The amount smoked by these two cohorts was based on self-report, and hence the sorting of subjects into smokers and non-smokers was not absolute. The marijuana user group did not exclude a subject if they had used other illicit substances in the past. However, subjects’ self-report on other drugs may be unreliable. A person is not likely to reveal the truth to the authority figures about the extent and nature of their personal illicit substance use. To deal with illicit substance use objectively, the researchers performed urine toxicology screens to make sure all subjects had not recently used any of a spectrum of psychoactive drugs (ranging from amphetamines to benzodiazepines and ethanol). All subjects were assessed for evidence of problem alcohol use, and if positive, they were not included. However, the marijuana smokers reported drinking a greater number of alcoholic drinks per week than the control participants. The primary analysis was a comparison of brain structures of smokers to that of ‘non-smokers’. The overall findings indicated that the volumes of the left nucleus accumbens and amygdala, but not the right side, were different in marijuana users compared to that of controls. Of course, the better comparison would have been a study of brain structures before ever using cannabis and after a year of using it regularly. Despite the weak design of this study, the difference indicated these two left brain structures were very slightly larger (‘abnormal’?) than in control subjects. The clinical relevance of this observation is not clear, especially since the cannabis and non-cannabis users had no cognitive or behavioral problems. These differences might reflect normal variations in brain structure, just as men and women’s brains differ slightly in structure. Moreover, these brain differences might have already been present in those who chose to smoke more frequently and just as likely could have been interpreted as a predictor of those who were predisposed to enjoy smoking at least one cannabis joint per week. Thus, the data provide an association, but no cause and effect. Expert commentary

Cannabis in various preparations has a long history as a medical substance. Only in the last century was its use relegated by informahealthcare.com

Review

legislation to the underground as a recreational substance. Despite the outlaw designation, practitioners of alternative and complementary medicine have continued to explore medical applications of cannabis. A wave of legal restrictions on the medical use of cannabis is gradually being lifted, opening the doors for legitimate research and well-controlled clinical trials. Eventually, there may be widespread availability of cannabinoid-based medications, which physicians are illprepared to prescribe. On the one hand, cannabis derivatives cannot be suddenly made available without rigorous scientific data on efficacy and safety. On the other hand, excessive regulations such as prohibition and rigid ‘war-on-drugs’ rhetoric make research impossible. As if often true, those extreme passionate positions are unlikely to be helpful and moderation is in order. Cannabinoid drugs should neither be completely outlawed to the point of preventing research nor available without regulations. Five-year view

A review of the Pubmed publications reveals that the number of papers on the effects of cannabis preparations in humans has nearly doubled in the last 5 years. Therefore, one might predict that in the next 5 years, the number of publications will continue to increase. However, the total number of human studies is low and will remain low till the current regulatory restrictions on human studies are changed. For example, the absolute number of human studies published in 2009 was 23, and by 2013, there were 43 papers. The 5-year total number of human studies (from 2009 to 2013) was only 178, a fraction (16%) of the total 1074 papers pulled up with the key words cannabis or cannabinoids. There are at least five reasons to expect research on the therapeutic applications of cannabis to increase in the near future. The prohibition on the use of medical cannabis is being lifted by individual states. Presently, there are 23 states in the US that permit cannabis for a number of medical indications. This number is projected to increase despite opposition by organizations that either benefit from the current prohibition or who are concerned about the spread of use for non-medical reasons, that is, recreational use. Re-scheduling of cannabis from Schedule I by the FDA and DEA will likely take place sooner than later. For the first time in 20 years, a federal appellate court is hearing evidence challenging the DEA’s classification of cannabis as a Schedule I drug. Re-scheduling cannabis so that it can be prescribed similar to approved controlled substances such as benzodiazepines will provide a strong impetus for both basic research and therapeutic trials. Greater understanding of the endogenous cannabinoid system in the context of neurological disease and aging will provide a strong rationale to apply specific cannabinoids (alone or in combination) for treatment of specific diseases. Neuropharmacologists, who have been trained on the one drug–one receptor model, are starting to recognize that agents like the phyto-cannabinoids (THC and CBD) have greater therapeutic effects when given together than when given in isolation (the ‘entourage’ effect). Hence, the newer 1461

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commercial pharmaceutical agents, like Sativex, will contain various proportions of THC and CBD. Major pharmaceutical companies will develop novel drugs that can alter the activity of endogenous cannabinoids to either increase anandamide (the primary endogenous cannabinoid) or to block the cannabinoid receptor in brain (CB1). Considering the reasons mentioned earlier, there will likely be a surge of clinical research to elucidate the optimal cannabis products for specific neurologic conditions.

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Financial & competing interests disclosure

K Kalidas is on the speakers’ bureau for Allergan and Depomed. L Katzin is on the speakers’ bureau for Grifols and Baxter pharmaceuticals. D Robertson has served as a consultant for Biogen Idec, Genzyme/Sanofi Aventis, Teva Neuroscience and Pfizer; is on the speakers’ bureau for Biogen Idec, Pfizer, EMD Serono, Genzyme/Sanofi Aventis, Novartis, Teva Neuroscience, Mallinckrodt and Acorda; and has received grant support from Biogen Idec, Genzyme/Sanofi Aventis, Novartis, Sun Pharma, MedImmune,

GlaxoSmithKline and Roche/Genetech. T Vu is on the speakers’ bureau for Allergan. AG Smith has received grant/research support from Merck, Eli Lilly, AVID Radiopharmaceuticals, Eisai, TauRx and Cognate nutritionals. T Zesiewicz receives research support from GSK Pharmaceuticals, UCB Pharmaceuticals, Astellas Pharmaceuticals, Friedreich’ s Ataxia Research Alliance, Allon Pharmaceuticals, Edison Pharmaceuticals and ViroPharma Inc. J Sanchez-Ramos is on the speakers bureau for UCB Pharmaceuticals. Dr. Benbadis has served as a consultant for Cyberonics, Eisai, Lundbeck, Sunovion, Supernus, UCB pharma, Upsher-Smith. He is on the speakers bureau for Cyberonics, Eisai, Glaxo Smith Kline, Lundbeck, Sunovion, Supernus, UCB pharma and has received grant support from Cyberonics, Lundbeck, Sepracor, Sunovion, Supernus, UCB pharma, Upsher-Smith. Dr. Benbadis received royalties as an author or Editor for Emedicine-Medscape-WebMD, UpToDate. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • The Cannabis plant consists of a large number of cannabinoids, many of which interact with CNS receptors to produce biological effects that may improve neurologic functions and disorders for which there are few effective treatments. • Most of the evidence for beneficial effects of cannabis is from observation and open-label studies, but there are some high-quality clinical trials of cannabinoids using gold standard designs (double-blind, placebo-controlled studies) that report its therapeutic effects. • In our view, the adverse effects reported in the literature are most often benign, though there are deleterious effects that depend highly on the route and frequency of administration (e.g., inhalation and pulmonary symptoms). • Some reports overemphasize the potential for drug dependence, even suggesting that cannabis is a ‘gateway’ drug to ‘hard’ drugs of abuse. In addition, the ‘amotivational syndrome’ that is often mentioned as an adverse effect of chronic use is poorly documented. • Medical (regulated) use is clearly not the same as recreational use. • There is a need for more research, both basic and clinical. Pharmaceutical companies would do well to research specific cannabinoid molecules or agents that selectively benefit specific symptoms or conditions. The critical variables are the respective proportions of specific compounds, routes of administration and dosing. • It is possible that combinations of cannabinoids are necessary to produce clinical benefits, so that quality control measurements of the principal bioactive components of the preparation will be helpful when conducting future clinical studies. • Sensationalized media anecdotes tend to not provide a denominator and do not report failures because those do not increase ratings. They should not be the basis for our decisions. • A common theme of all neurology specialties is that referral centers treat the most refractory, difficult and often ‘desperate’ patients. For these, medical marijuana should be considered. However, until we have more and better data, they should only be considered after more standard and proven treatments have been exhausted, and should not be offered ‘out of order’ to patients who are not compliant with, or want to bypass, standard treatments.

American Academy of Neurology. Neurology 2014;82(17):1556-63

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Medical marijuana in neurology.

Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are Δ(9)-tetrahyd...
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