Cannabis: Old medicine with new promise for neurological disorders
Gregory T Carter1* & Patrick Weydt2
'HSDUWPHQW RI 5HKDELOLWDWLRQ 0HGLFLQH DQG
8QLYHUVLW\ RI:DVKLQJWRQ 6FKRRO RI 0HGLFLQH
(PDLO JWFDUWHU#X ZDVKLQJWRQ HGX
7R ZKRP FRUUHVSRQGHQFH VKRXOG EH DGGUHVVHG
&XUUHQW 2SLQLRQ LQ ,QYHVWLJDWLRQDO 'UXJV
¤ 3KDUPD3UHVV ,661
Marijuana is a complex substance containing over 60
different forms of cannabinoids, the active ingredients.
Cannabinoids are now known to have the capacity for
neuromodulation, via direct, receptor-based mechanisms at
numerous levels within the nervous system. These have
therapeutic properties that may be applicable to the
treatment of neurological disorders; including antioxidative,
neuroprotective, analgesic and anti-inflammatory
actions; immunomodulation, modulation of glial cells and
tumor growth regulation. This article reviews the emerging
research on the physiological mechanisms of endogenous
and exogenous cannabinoids in the context of neurological
Over the past few decades there has been widening interest in
the viable medicinal uses of cannabis . The National
Institutes of Health, the Institute of Medicine and the Food
and Drug Administration have all issued statements calling
for further investigation [1-3]. The discovery of an
endogenous cannabinoid system with specific receptors and
ligands has led the progression of our understanding of the
actions of cannabis from folklore to valid science. It now
appears that the cannabinoid system evolved with our species
and is intricately involved in normal human physiology,
specifically in the control of movement, pain, memory and
appetite, among others. The detection of widespread
cannabinoid receptors in the brain and peripheral tissues
suggests that the cannabinoid system represents a previously
unrecognized ubiquitous network in the nervous system.
Dense receptor concentrations have been found in the
cerebellum, basal ganglia and hippocampus, accounting for
the effects on motor tone, coordination and mood state [4,5].
Low concentrations are found in the brainstem, accounting
for the remarkably low toxicity. Lethal doses in humans have
not been described [5-7].
7KH FKHPLVWU\ RI FDQQDELV
Marijuana is a complex plant, with several subtypes of
cannabis, each containing over 400 chemicals [8,9].
Approximately 60 are chemically classified as cannabinoids
[5,9]. The cannabinoids are 21 carbon terpenes, biosynthesized
predominantly via a recently discovered deoxyxylulose
phosphate pathway . The cannabinoids are lipophilic and
not soluble in water. Among the most psychoactive is '9-
tetrahydrocannabinol (THC), the active ingredient in
dronabinol (Unimed Pharmaceuticals Inc) . Other major
cannabinoids include cannabidiol (CBD) and cannabinol
(CBN), both of which may modify the pharmacology of THC
or have distinct effects of their own. CBD is not psychoactive
but has significant anticonvulsant, sedative and other
pharmacological activity likely to interact with THC . In
mice, pretreatment with CBD increased brain levels of THC
nearly 3-fold and there is strong evidence that cannabinoids
can increase the brain concentrations and pharmacological
actions of other drugs .
Two endogenous lipids, anandamide (AEA) and 2-
arachidonylglycerol (2-AG), have been identified as
cannabinoids, although there are likely to be more . The
physiological roles of these endocannabinoids have been only
partially clarified but available evidence suggests they
function as diffusible and short-lived intercellular messengers
that modulate synaptic transmission. Recent studies have
provided strong experimental evidence that endogenous
cannabinoids mediate signals retrogradely from depolarized
postsynaptic neurons to presynaptic terminals to suppress
subsequent neurotransmitter release, driving the synapse into
an altered state . In hippocampal neurons, depolarization
of postsynaptic neurons and the resultant elevation of calcium
lead to transient suppression of inhibitory transmitter release.
Depolarized hippocampal neurons rapidly release both AEA
and 2-AG in a calcium-dependent manner. In the
hippocampus, cannabinoid receptors are expressed mainly by
GABA-mediated inhibitory interneurons. Synthetic
cannabinoid agonists depress GABA release from
hippocampal slices . However, in cerebellar Purkinje cells,
depolarization-induced elevation of calcium causes transient
suppression of excitatory transmitter release . Thus
endogenous cannabinoids released by depolarized
hippocampal neurons may function to downregulate GABA
release [12,13]. Further, signaling by the endocannabinoid
system appears to represent a mechanism enabling neurons to
communicate backwards across synapses in order to
modulate their inputs.
There are two known cannabinoid receptor subtypes;
subtype 1 (CB1) is expressed primarily in the brain, whereas
subtype 2 (CB2) is expressed primarily in the periphery
[4,14]. Cannabinoid receptors constitute a major family of G
protein-coupled, 7-helix transmembrane nucleotides, similar
to the receptors of other neurotransmitters such as
dopamine, serotonin and norepinephrine [4,5]. Activation of
protein kinases may be responsible for some of the cellular
responses elicited by the CB1 receptor .
1HXURPRGXODWLRQ DQG QHXURSURWHFWLRQ
As we are developing an increased cognizance of the
physiological function of endogenous and exogenous
cannabinoids it is becoming evident that they may be
involved in the pathology of certain diseases, particularly
neurological disorders. Cannabinoids may induce
proliferation, growth arrest or apoptosis in a number of
cells, including neurons, lymphocytes and various
transformed neural and non-neural cells [16-21]. In the CNS,
most of the experimental evidence indicates that
cannabinoids may protect neurons from toxic insults such as
glutamatergic overstimulation, ischemia and oxidative
damage [22-26]. The neuroprotective effect of cannabinoids
may have potential clinical relevance for the treatment of
neurodegenerative disorders such as amyotrophic lateral
sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease,
cerebrovascular ischemia and stroke. Both endogenous and
exogenous cannabinoids appear to have neuroprotective
and antioxidant effects. Recent studies have demonstrated
the neuroprotective effects of synthetic, non-psychotropic
cannabinoids, which appear to protect neurons from
chemically induced excitotoxicity [23-25]. Direct
measurement of oxidative stress reveals that cannabinoids
prevent cell death by antioxidation. The antioxidative
property of cannabinoids is confirmed by their ability to
antagonize oxidative stress and consequent cell death
induced by the powerful oxidant, retinoid anhydroretinol.
Cannabinoids also modulate cell survival and the growth of
B-lymphocytes and fibroblasts [23-25,27].
The neuroprotective actions of cannabidiol and other
cannabinoids have been examined in rat cortical neuron
cultures exposed to toxic levels of the excitatory
neurotransmitter glutamate. Glutamate toxicity was reduced
by both CBD (non-psychoactive) and THC . The
neuroprotection observed with CBD and THC was unaffected
by a cannabinoid receptor antagonist, indicating it to be
cannabinoid receptor-independent. CBD was more protective
against glutamate neurotoxicity than either ascorbate (vitamin
C) or D-tocopherol (vitamin E) .
Cannabinoids have demonstrated efficacy as immune
modulators in animal models of neurological conditions
such as MS and neuritis . Current data suggests that the
naturally occurring, non-psychotropic cannabinoid, CBD,
may have a potential role as a therapeutic agent for
neurodegenerative disorders produced by excessive cellular
oxidation, such as ALS, a disease characterized by excess
glutamate activity in the spinal cord .
It is not yet known how glutamatergic insults affect in vivo
endocannabinoid homeostasis, including AEA, 2-AG, as
well as other constituents of their lipid families, Nacylethanolamines
(NAEs) and 2-monoacylglycerols (2-
MAGs). Hansen et al used three in vivo neonatal rat models
characterized by widespread neurodegeneration as a
consequence of altered glutamatergic neurotransmission
and assessed changes in endocannabinoid homeostasis
. A 46-fold increase of cortical NAE concentrations and
a 13-fold increase in AEA was noted 24 h after
intracerebral NMDA injection, while less severe insults
triggered by mild concussive head trauma or NMDA
receptor blockade produced a less pronounced NAE
accumulation. In contrast, levels of 2-AG and other 2-
MAGs were unaffected by the insults employed, rendering
it likely that key enzymes in biosynthetic pathways of the
two different endocannabinoid structures are not equally
associated to intracellular events that cause neuronal
damage in vivo. Analysis of cannabinoid CB1 receptor
mRNA expression and binding capacity revealed that
cortical subfields exhibited an upregulation of these
parameters following mild concussive head trauma and
exposure to NMDA receptor blockade. This suggests that
mild-to-moderate brain injury may trigger elevated
endocannabinoid activity via concomitant increase of
anandamide levels, but not 2-AG, and CB1 receptor
Panikashvili et al demonstrated that 2-AG has an important
neuroprotective role . After closed head injury (CHI) in
mice, the level of endogenous 2-AG was significantly
elevated. After administering synthetic 2-AG to mice
following CHI they found a significant reduction of brain
edema, better clinical recovery, reduced infarct volume and
reduced hippocampal cell death compared with controls.
When 2-AG was administered together with additional
inactive 2-acyl-glycerols that are normally present in the
brain, functional recovery was significantly enhanced. The
beneficial effect of 2-AG was dose-dependently attenuated
by SR-141716A (Sanofi-Synthélabo), an antagonist of the
CB1 receptor . Ferraro et al looked at the effects of the
cannabinoid receptor agonist Win-55212-2 (Sanofi Winthrop
Inc) on endogenous extracellular GABA levels in the
cerebral cortex of the awake rat using microdialysis .
Win-55212-2 was associated with a concentration-dependent
decrease in dialysate GABA levels. Win-55212-2-induced
inhibition was counteracted by the CB1 receptor antagonist
SR-141716A, which by itself was without effect on cortical
GABA levels. These findings suggest that cannabinoids
decrease cortical GABA levels in vivo .
Sinor has shown that AEA and 2-AG increase cell viability
in cerebral cortical neuron cultures subjected to 8 h of
hypoxia and glucose deprivation. This effect was observed
at nanomolar concentrations, was reproduced by a
non-hydrolyzable analog of anandamide, and was unaltered
by CB1 or CB2 receptor antagonists . In the immune
system, low doses of cannabinoids may enhance cell
proliferation, whereas high doses of cannabinoids usually
induce growth arrest or apoptosis [27,33,34].
In addition, cannabinoids produce analgesia by modulating
rostral ventromedial medulla neuronal activity in a manner
similar to, but pharmacologically distinct from, that of
morphine. Cannabinoids have been shown to produce an
anti-inflammatory effect by inhibiting the production and
action of tumor necrosis factor (TNF) and other acute phase
cytokines. These areas are discussed in great detail in a
recent paper by Rice .
*OLD DV WKH FHOOXODU WDUJHWV RI FDQQDELQRLGV
There is now accumulating in vitro evidence that glia
(astrocytes and microglia in particular) have cannabinoid
signaling systems. This provides further insight into the
understanding of the therapeutic effects of cannabinoid
compounds. Glial cells are the non-neuronal cells of the
CNS. In humans they outnumber neurons by a factor of
about 10:1. Because of their smaller average size they make
up about 50% of the cellular volume of the brain. Glial cells
of the CNS fall into three general categories: astrocytes,
oligodendrocytes and microglia. Schwann cells and the less
well-recognized enteric glia are their counterparts in the
peripheral nervous system. Glia are ubiquitous in the
nervous system and are critical in maintaining the
extracellular environment, supporting neurons, myelinating
axons and immune surveillance of the brain. Glia are
involved, actively or passively, in virtually all disorders or
insults involving the brain. This makes them logical targets
for therapeutic pharmacological interventions in the CNS.
Astrocytes are the most abundant cell type of the CNS. They
express CB1 receptors, and take up and degrade the
endogenous cannabinoid anandamide [36,37]. The
expression of CB2 receptors in this population appears to be
limited to gliomas and may be an indicator of tumor
malignancy . Two recent studies suggest that some of the
anti-inflammatory effects of cannabinoids, such as the
inhibition of nitric oxide (NO) and TNF release are mediated
by CB1 receptors on astrocytes [39,40].
The most recent therapeutic role for cannabinoids in the
CNS evolved from the discovery that cannabinoids
selectively induce apoptosis in glioma cells in vitro and that
THC and other cannabinoids lead to a spectacular
regression of malignant gliomas in immune-compromised
rats in vivo [41,42]. The mechanism underlying this is not yet
clear but it appears to involve both CB1 and CB2 receptor
activation [42,43]. A recent study comparing the
antiproliferative effects of cannabinoids on C6 glioma cells
suggests the involvement of vanilloid receptors .
Microglia are the tissue macrophages of the brain. In
variance from other immune tissue but in accordance with
their place in the CNS microglia appear to lack CB2
receptors and have been shown to express CB1 receptors
on protein and RNA levels . Similar to their effect on
peripheral macrophages, cannabinoids inhibit the release
of NO and the production of various inflammatory
cytokines in microglia [46-48]. Interestingly, the inhibition
of NO release seems to be CB1 receptor-mediated, whereas
the differential inhibition of cytokines is not mediated by
either CB1 or CB2 receptors, suggesting as yet unidentified
receptors or a receptor-independent mechanism.
Irrespective, the potential of cannabinoids to modulate the
immune response of microglia must be considered when
interpreting the effects of cannabinoids on inflammatory
processes such as a mouse model of MS or future
experiments on brain tumors in immunocompetent
Nothing is known of the effects of cannabinoids on
oligodendroglia. In the light of the clinical and
experimental evidence suggesting the beneficial effects of
cannabinoids in MS, investigations in this direction appear
A growing number of strategies for separating the
sought-after therapeutic effects of cannabinoid receptor
agonists from the unwanted consequences of CB1 receptor
activation are now emerging. However, further
improvements in the development of selective agonists and
antagonists for CB1 and CB2 receptors are needed. This
would allow for the refinement of cannabinoids with good
therapeutic potential and would facilitate the design of
effective therapeutic drugs from the cannabinoid family.
Customized delivery systems are also needed; as the
cannabinoids are volatile, they will vaporize at a
temperature much lower than actual combustion. Thus
heated air can be drawn through marijuana and the active
compounds will vaporize and can easily be inhaled.
Theoretically this removes most of the health hazards of
smoking, although this has not been well studied. Recently,
pharmacologically active, aerosolized forms of THC have
been developed . This form of administration is achieved
via a small particle nebulizer that generates an aerosol
which penetrates deeply into the lungs.
From a regulatory perspective, the scientific process should
be allowed to evaluate the potential therapeutic effects of
cannabis, dissociated from the societal debate over the
potentially harmful effects of nonmedical marijuana use.
This class of compounds not only holds tremendous
therapeutic potential for neurological disease but is also
confirmed as having remarkably low toxicity [52-54].
1. Hollister LE: Interactions of cannabis with other drugs in man. In:
(Braude MC, Ginzburg HM: Eds) Strategies for Research on the
Interactions of Drugs of Abuse. National Institute on Drug Abuse
Research Monograph 68 DHHS Pub No (ADM)86-1453: Washington
DC, USA. US Govt Print Office (1986); 110-116.
2. Institute of Medicine. Division of Health Sciences Policy. Marijuana and
Health: Report of a Study by a Committee of the Institute of Medicine,
Division of Health Sciences Policy. Washington DC, USA: National
Academy Press, (1982).
3. FDA Guideline for the Clinical Evaluation of Analgesic Drugs. DHHS
Pub No 93-3093, Rockville, MD, USA: US Department of Health and
Human Services, Public Health Service, Food and Drug Administration,
4. Pertwee RG: Cannabinoid receptor ligands: clinical and
neuropharmacological considerations, relevant to future drug
discovery and development. Expert Opin Investig Drugs (2000)
5. Di Marzo V, Bisogno T, De Petrocellis L: Endocannabinoids: new
targets for drug development. Curr Pharm Des (2000) 6:1361-1380.
6. Benowitz NL, Jones RT: Cardiovascular and metabolic
considerations in prolonged cannabinoid administration in man. J
Clin Pharmacol (1981) 21:214S-223S.
7. Voth EA, Schwartz RH: Medicinal applications of '
tetrahydrocannabinol and marijuana. Ann Intern Med (1997)
8. Adams IB, Martin BR: Cannabis: Pharmacology and toxicology in
animals and humans. Addiction (1996) 91:1585-1614.
9. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie, H,
Hollister L: Pharmacokinetics and metabolism of delta
1-tetrahydrocannabinol and other cannabinoids with emphasis on
man. Pharmacol Rev (1986) 38:21-43.
10. Fellermeier M, Eisenreich W, Bacher A, Zenk MH: Biosynthesis of
cannabinoids. Incorporation experiments with 13C-labeled
glucoses. Eur J Biochem (2001) 268:1596-1604.
11. Reid MJ, Bornheim LM: Cannabinoid-induced alterations in brain
disposition of drugs of abuse. Biochem Pharmacol (2001) 61:1357-
12. Wilson RI, Nicoll RA: Endogenous cannabinoids mediate retrograde
signalling at hippocampal synapses. Nature (2001) 29:588-592.
13. Maejima T, Ohno-Shosaku T, Kano M: Endogenous cannabinoid as a
retrograde messenger from depolarized postsynaptic neurons to
presynaptic terminals. Neurosci Res (2001) 40:205-210.
14. Klein TW, Lane B, Newton CA, Friedman H: The cannabinoid system
and cytokine network. Proc Soc Exp Biol Med (2000) 225:1-8.
15. Rueda D, Galve-Roperh I, Haro A, Guzman M: The CB1 cannabinoid
receptor is coupled to the activation of c-Jun N-terminal kinase.
Mol Pharmacol (2000) 58:814-820.
16. DeSanty KP, Dar MS: Involvement of the cerebellar adenosine A1
receptor in cannabinoid-induced motor incoordination in the acute
and tolerant state in mice. Brain Res (2001) 29:178-187.
17. Campbell VA: Tetrahydrocannabinol-induced apoptosis of cultured
cortical neurones is associated with cytochrome c release and
caspase-3 activation. Neuropharmacology (2001) 40:702-709.
18. Valjent E, Pages C, Rogard M, Besson MJ, Maldonado R, Caboche J:
9-tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation
in vivo depends on dopaminergic transmission. Eur J Neurosci
19. Friedman H, Klein TW, Newton C, Daaka Y: Marijuana, receptors and
immunomodulation. Adv Exp Med Biol (1995) 373:103-113.
20. Chen Y, Buck J: Cannabinoids protect cells from oxidative cell
death: a receptor-independent mechanism. J Pharmacol Exp Ther
21. Guzman M, Sanchez C, Galve-Roperh I: Control of the cell survival/death
decision by cannabinoids. J Mol Med (2001) 78:613-625.
22. Akinshola BE, Chakrabarti A, Onaivi ES: In vitro and in vivo action of
cannabinoids. Neurochem Res (1999) 24:1233-1240.
23. Hampson AJ, Grimaldi M, Axelrod J, Wink D: Cannabidiol and (-)'
tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl
Acad Sci USA (1998) 95:8268-8273.
24. Hampson AJ Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J:
Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci
25. Nagayama T, Sinor AD, Simon RP, Chen J Graham SH, Jin K,
Greenberg DA: Cannabinoids and neuroprotection in global and
focal cerebral ischemia and in neuronal cultures. J Neurosci (1999)
26. Eshhar N, Striem S, Biegon A: HU-211, a non-psychotropic
cannabinoid, rescues cortical neurones from excitatory amino acid
toxicity in culture. Neuroreport (1993) 5:237-240.
27. Hollister LE: Marijuana and immunity. J Psychoactive Drugs (1988)b
28. Carter GT, Rosen BS: Marijuana in the management of amyotrophic
lateral sclerosis. Am J Hosp Palliat Care (2001) 18:264-270.
29. Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F,
Manzanares J, Ikonomidou C, Schmid HH, Fernandez-Ruiz JJ, Hansen HS:
Anandamide, but not 2-arachidonoylglycerol, accumulates during in
vivo neurodegeneration. J Neurochem (2001) 78:1415-1427.
30. Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A,
Mechoulam R, Shohami E: An endogenous cannabinoid (2-AG) is
neuroprotective after brain injury. Nature (2001) 413:527-531.
31. Ferraro L, Tomasini MC, Cassano T, Bebe BW, Siniscalchi A, O'Connor
WT, Magee P, Tanganelli S, Cuomo V, Antonelli T: Cannabinoid
receptor agonist WIN 55,212-2 inhibits rat cortical dialysate J-
aminobutyric acid levels. J Neurosci Res (2001) 66:298-302.
32. Sinor AD, Irvin SM, Greenberg DA: Endocannabinoids protect
cerebral cortical neurons from in vitro ischemia in rats. Neurosci
Lett (2000) 278:157-160.
33. Gurley RJ, Aranow R, Katz M: Medicinal marijuana: a comprehensive
review. J Psychoactive Drugs (1998) 30:137-147.
34. Robson P: Therapeutic aspects of cannabis and cannabinoids.Br J
Psychiatry (2001) 178:107-115.
35. Rice ASC: Cannabinoids and pain. Curr Opin Investig Drugs (2001)
36. Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz JC,
Piomelli D: Formation and inactivation of endogenous cannabinoid
anandamide in central neurons. Nature (1994) 372:686-691.
37. Bouaboula M, Bourrie B, Rinaldi-Carmona M, Shire D, Le Fur G,
Casellas P: Stimulation of cannabinoid receptor CB1 induces krox-
24 expression in human astrocytoma cells. J Biol Chem (1995)
38. Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C,
Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzman M:
Inhibition of glioma growth in vivo by selective activation of the
CB2 cannabinoid receptor. Cancer Res (2001) 61:5784-5789.
39. Molina-Holgado F, Lledo A, Guaza C: Anandamide suppresses nitric
oxide and TNF-alpha responses to Theiler's virus or endotoxin in
astrocytes. Neuroreport (1997) 8:1929-1933.
40. Esposito G, Izzo AA, Di Rosa M, Iuvone T: Selective cannabinoid CB1
receptor-mediated inhibition of inducible nitric oxide synthase
protein expression in C6 rat glioma cells. J Neurochem (2001)
41. Sanchez C, Galve-Roperh I, Canova C, Brachet P, Guzman M: '
tetrahydrocannabinol induces apoptosis in C6 glioma cells. FEBS
Lett (1998) 436:6-10.
42. Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M,
Guzman M: Anti-tumoral action of cannabinoids: involvement of
sustained ceramide accumulation and extracellular signalregulated
kinase activation. Nature Med (2000) 6:313-319.
43. Recht LD, Salmonsen R, Rosetti R, Jang T, Pipia G, Kubiatowski T,
Karim P, Ross AH, Zurier R, Litofsky NS, Burstein S: Antitumor effects
of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid.
Biochem Pharmacol (2001) 62:755-763.
44. Jacobsson SO, Wallin T, Fowler CJ: Inhibition of rat C6 glioma cell
proliferation by endogenous and synthetic cannabinoids. Relative
involvement of cannabinoid and vanilloid receptors. J Pharmacol
Exp Ther (2001) 299:951-959.
45. Sinha D, Bonner TI, Bhat NR, Matsuda LA: Expression of the CB1
cannabinoid receptor in macrophage-like cells from brain tissue:
immunochemical characterization by fusion protein antibodies. J
Neuroimmunol (1998) 82:13-21.
46. Klein TW, Newton C, Friedman H: Cannabinoid receptors and immunity.
Immunol Today (1998) 19:373-381.
47. Waksman Y, Olson JM, Carlisle SJ, Cabral GA: The central cannabinoid
receptor (CB1) mediates inhibition of nitric oxide production by rat
microglial cells. J Pharmacol Exp Ther (1999) 288:1357-1366.
48. 48. Puffenbarger RA, Boothe AC, Cabral GA: Cannabinoids inhibit
LPS-inducible cytokine mRNA expression in rat microglial cells.
Glia (2000) 29:58-69.
49. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW,
Layward L: Cannabinoids control spasticity and tremor in a multiple
sclerosis model. Nature (2000) 404:84-87.
50. Consroe P, Musty R, Rein J, Tillery W, Pertwee R: The perceived effects
of smoked cannabis on patients with multiple sclerosis. Eur Neurol
51. Lichtman AH, Peart J, Poklis JL, Bridgen DT, Razdan RK, Wilson DM,
Poklis A, Meng Y, Byron PR, Martin BR: Pharmacological evaluation
of aerosolized cannabinoids in mice. Eur J Pharmacol (2000)
52. Pope HG, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D:
Neuropsychological performance in long-term cannabis users.
Arch Gen Psychiatry (2001) 58:909-915.
53. Renn E, Mandel S, Mandel E: The medicinal uses of marijuana.
Pharm Therapeut (2000) 25:536-524.
54. Hubbard JR, Franco SE, Onaivi ES: Marijuana: medical implications.
Am Fam Physician (1999) 60:2583-2588.