Cannabinoids seminar: Physiology,Related Pathology and targets showing pharmacology i.e Drugs

1. Seminar
Cannabinoids
Dr. RAHUL SAINI
Assistant Professor
Department of Pharmacology
BPS GMC for women Khanpur kalan,Sonipat

2. Flow of presentation
• Introduction
• History
• Phytocannabinoids
• Endocannabinoid system
• Physiological role and pharmacological effects
• Pathological involvement
• Clinical applications
• Recent advances

3. Cannabinoids
• Originally used to describe the family of
naturally occurring chemicals found in
cannabis, of which Δ9 – tetrahydrocannabinol
(THC) is the principal member
• Current definition: All those substances
capable of activating cannabinoid receptors

4. History of Cannabinoid Research
• At least 5000 years history
• 1753-Carolus Linnaeus classified marijuana as Cannabis
sativa
• 1855- Chemical isolation of the cannabis plant by Personne
Robiquet (‘a good analysis of hemp’)
• 1899: Wood found the first natural cannabinoid called
cannabinol (CBN) which was later structurally established in
1940 by Adams
• 1941-42: Adams and Cahn founded the cannabinoid called
cannabidiol (CBD)

5. • 1964: Major psychoactive terpene Δ9 – tetrahydrocannabinol
(THC) isolated in its pure form by Gaoni and Mechoulam and then
structurally established in 1967 by Mechoulam and Gaoni
• 1969: The activity of THC was established in rhesus monkeys by
Grunfeld and Edery
• 1988- Discovery of CB1 receptors
• 1992- Identification of anandamide as an endocannabinoid
• 1993- Discovery of CB2 receptors
• 1995-Identification of 2-arachidonoylglycerol (2-AG) as another
endocannabinoid

6. Types of Cannabinoids
• Organic cannabinoids
▫ From cannabis plant (Phytocannabinoids)
▫ Synthesized in brain (Endocannabinoids)
• Synthetic cannabinoids

7. Phytocannabinoids
• Also called natural cannabinoids, plant-derived
cannabinoids, herbal cannabinoids or classical
cannabinoids
• At least 85 cannabinoids have been isolated from
Cannabis sativa (the hemp plant)
• Concentrated in a viscous resin that is produced in
glandular structures known as trichomes

8. Various forms of cannabis usage
• Bhang
▫ Dried leaves
▫ Oral route
▫ Slow action
• Ganja
▫ Dried female inflorescence
▫ Smoked
▫ Instantaneous effect
• Charas (Hashish)
▫ Dried resinous extract from the flowering tops
and leaves
▫ Smoked with tobacco
▫ Most potent

9. Important Cannabinoids from
Cannabis Plant
• Δ9 -tetrahydrocannabinol (THC)
▫ The principle psychoactive constituent
• Cannabidiol (CBD)
▫ Precursor of THC
▫ Lack psychoactive property
• Cannabinol (CBN)
▫ Breakdown product of THC
▫ Lack psychoactive property

10. Endocannabinoid system
• Consists of
▫ Cannabinoid receptors
▫ Endogenous cannabinoids (endocannabinoids)
▫ Enzymes that synthesize and degrade
endocannabinoids

11. Cannabinoid(CB) receptors
• G-protein-coupled receptors
• Contain seven transmembrane spanning domains with an
extracellular N-terminus and cytoplasmic C-terminus
• Activated by three major group of ligands
▫ Endocannabinoids
▫ Plant cannabinoids
▫ Synthetic cannabinoids
• Currently two known subtypes
▫ CB1 & CB2
• Some endocannobinoids also activate vanilloid receptors

13. CB1 receptors in brain- location &
function
• Abundantly present in brain
• Not homogeneously distributed
• More concentrated in
▫ hippocampus (Memory)
▫ cerebellum (loss of coordination)
▫ hypothalamus (control of appetite, reproductive function)
▫ substantia nigra, mesolimbic dopamine pathways (psychological
'reward')
▫ Association areas of cerebral cortex

14. • Less concentrated in the brain stem (lack of
serious respiratory or cardiovascular toxicity of
the cannabinoids)
• Localised presynaptically
▫ Inhibit transmitter release
• Mediate psychotropic effects of cannabis

16. CB1 receptors in periphery- location &
function
• Liver (lipogenesis)
• Blood vessels (hypotension during hemorrhagic
and septic shock)
• GIT(inhibition of intestinal motility)
• Peripheral nerve endings (pain modulation)
• Other sites: lungs, kidneys, Adipocytes

17. CB2 receptors
• Only approximately 45% amino acid homology with CB1
• Location
▫ Mainly in lymphoid tissue (spleen, tonsils and thymus as well as
circulating lymphocytes, monocytes and tissue mast cells)
▫ B lymphocytes > natural killer cells >>monocytes > neutrophils > T8
lymphocytes > T4 lymphocytes
▫ Also present on microglia
• Function
▫ Little known
▫ Inhibitory effects of cannabis on immune function

18. Signaling mechanisms
CB1 receptors
• Linked via Gi/o to adenylate cyclase
• Hyperpolarization
▫ Inhibition of adenylate cyclase
▫ Inhibition of voltage-operated calcium channels (VOC)
▫ Activation of G-protein-sensitive inward-rectifying potassium (GIRK)
channels
• Altered gene expression
▫ Activati0n of mitogen-activated protein kinase (MAPK)
▫ ↓ activity of protein kinase A (PKA)
CB2 receptors
• Similar to CB1, but not linked to voltage-operated calcium channels (VOC)

19. Cellular actions
of cannabinoids
GIRK: G-protein-
responsive
potassium channel
MAPK: mitogen-activated
protein kinase
PKA: protein kinase A
VOC: voltage-operated
calcium channel

20. Cannabinoid receptor agonists
• Classical cannabinoids
▫ Tricyclic dibenzopyran derivatives
 Compounds occurring naturally in the plant C. sativa (eg: Δ9-THC) or
 Synthetic analogues of these compounds (eg: HU-210)
• Non-classical cannabinoids
▫ Synthetic THC analogues that lack the dihydropyran ring (Eg:CP-55 940)
• Aminoalkylindoles
▫ Eg: WIN-55212–2
• Eicosanoids
▫ Eg: Anandamide, 2-AG

21. Cannabinoid receptor antagonists
• Diarylpyrazoles
▫ SR 141716A, SR 144528
• Substituted benzofuranes
▫ LY 320135
• Aminoalkylindoles
▫ AM 630
• Triazole derivatives
▫ LH-21

22. CB receptor Agonists and antagonists
Cannabinoid receptor
type
CB1 CB2
Endogenous agonists Anandamide
2-arachidonoyl glycerol
Anandamide
2-arachidonoyl glycerol
Agonists THC
HU210
CP55,940
WIN55212-2
THC
HU308
HU210
CP55,940
WIN55212-2
Antagonists SR141716A (Rimonabant)
AM281
SR144528
AM630

23. Endocannabinoids
• Substances produced from within the body that activate
cannabinoid receptors
• Belong to the family of eicosanoids
• Believed to play important role in almost every major life
function in the human body
• Not stored but instead are rapidly synthesized by neurons
in response to depolarization and consequent calcium
influx
• Function as ‘retrograde synaptic messengers’

24. Endocannabinoids
Endocannabinoid Selectivity
Definite endocannabinoids
Anandamide* CB1 > CB2
2-Arachidonoyl glycerol (2-AG) CB1 = CB2
Less well-established endocannabinoid candidates
Virhodamine$ (O-arachidonoyl ethanolamine) CB2 > CB1
Noladin CB1 >> CB2
N-Arachidonoyl dopamine (NADA) CB1 >> CB2
* Bliss (sanskrit) + amide
$ Opposition (sanskrit) + amine

25. Biosynthesis of endocannabinoids
• Synthesized 'on demand' basis
• Produced by hydrolysis of precursors derived from phospholipid
metabolism
• Anandamide
▫ Key enzyme: NAPE-PLD(N-acyl phosphatidylethanolamine-specific
phopholipase D)
• 2-AG
▫ Key enzymes - diacylglycerol lipases (DAGL-α and DAGL-β)
• Little is known about the biosynthesis of other recent endocannabinoids

26. Termination of the endocannabinoid
signal
• Diffusion through plasma membrane down a concentration
gradient
• Uptake via ‘Endocannabinoid membrane transporter (EMT)’
▫ Transports cannabinoids from postsynaptic neurons to the
synaptic cleft, where they access CB1 receptors, and into
presynaptic terminals, where 2-AG is metabolised
• Hydrolysis by specific enzymes
▫ Anandamide degraded by Fatty acid amide hydrolase (FAAH)
▫ 2-AG degarded by monoacyl glycerol lipase (MAGL)

27. Biosynthesis and inactivation of endocannabinoids
MAGL- monoacyl glycerol lipase
EMT- endocannabinoid membrane
transporter
2-AG: 2-arachidonoyl glycerol
A: arachidonic acid
FAAH- fatty acid amide hydrolase
DAGL- diacylglycerol lipase
GPL- glycerophospholipid
PLC- phospholipase C
NAPE: N-acyl-phosphatidylethanolamine
NAPE-PLD: NAPE-specific phopholipase D
NAT: N-acyl-transferase
PE: phosphatidylethanolamine
E- ethanolamine

28. Released from postsynaptic neurons
↓
Travel backwards across synapses
↓
Activation of CB1 receptors on presynaptic
neurons
↓
Suppression of transmitter release (transient or
long-lasting)
Endocannabinoids as retrograde
synaptic messengers

30. Physiological role & Pharmacological
Effects
 The activation of the cannabinoid system through THC ,
phytocannabinoids, synthetic cannabinoids and
endocannabinoids causes numerous actions:
 Central Effects
 Peripheral Effects

31. Central effects include:
 Antinociceptive
 Neuroprotection
 Alleviation of painful spasms and spasticity
 Anti emetic
 Regulate food intake and energy expenditure
 Effects on Reproductive system

32. Peripheral effects are:
 Effect on immune system
 Vasodilatation, which is particularly marked on the scleral
and conjunctival vessels
 Antiproliferative
 Bronchodilatation
 Reduction of intraocular pressure

33. Antinociception

34.  Receptors are present at all levels.
 Supraspinal :Periaqueductal gray (PAG) , thalamus ,
rostral ventromedial medulla (RVM) :they participate
in descending supraspinal pain modulation
 Spinal:Primary afferents neurons at pre- and post-
synaptic sites , dorsal horn , CB1receptors have been
found on interneurons
 Peripheral:Cannabinoid CB1 and CB2 receptors are
also found in the DRG, primary afferent
neurons, cutaneous nerve fibers :contribute to
peripheral antinociceptive actions

35.  Peripheral pain- ‘Gate mechanism’ along with opioid
peptide.
 Regulate pain initiation at the site of injury CB2
receptors (anti-inflammatory)
 Interaction with opioid receptors predominantly
acting via kappa, receptors producing antinociception
effect without respiratory depression

36. Neuroprotection
 Short-term adaptation to neuronal stress : limiting
excitotoxicity
 Longer-term adaptations : enhancing neurogenesis
 Decrease excitotoxicity
 Direct inhibition of the NMDA receptor
 inhibition of presynaptic Ca2+ entry - suppression of
excessive glutamatergic synaptic activity
 In neuroinflammation: CB2 receptors are upregulated in
microglia and astrocytes -control the local production of
proinflammatory mediators such as IL-1β &PGs
 Role in chronic neurodegenerative Parkinson’s and
Alzheimer’s disease ,multiple sclerosis.

37. Alleviation of painful spasms and spasticity
Affect mediated mainly through CB1 receptors
 Release serotonin
 Inhibit the synthesis of prostaglandins within the CNS
and elevate brain acetylcholine and reduce its utilization
Clinical implications : Use in Multiple sclerosis ,in phase
III trial

38. Regulation of food and energy intake
 Upon stimulation, it increases food intake and weight gain,
promotes lipogenesis.
 Reduced levels of leptin associated with elevated levels of
endocannabinoids in the hypothalamus
 Leptin reduces food intake by upregulating appetite-reducing
neuropeptides and downregulating appetite-stimulating factors
 Potential pathway by which to treat obesity & type 2 diabetes
 CB1 antagonists- decrease appetite & causes weight loss -
Rimonabant

39. Anti-Emetic Effects
 CB1 ligands act as retrograde synaptic messengers
 Post-synaptic neuron releases endocannabinoids-
diffuse back and bind to the pre-synaptic CB1
receptor-reduction of neurotransmitter release -
depolarization-induced suppression of inhibition
(DSI)

41. Effect on reproductive system
In Male
 It decreases
 Serum Testosterone & Leutinizing Hormone levels
 Spermatogenesis and motility (oligospermia)
Blockade of acrosome reaction
In Female
 Disruption of menstrual cycle
 Decrease in surge of LH levels: inhibiting ovulation
 Inhibition of prolactin secretion
 Increase the incidence of preterm birth & intrauterine foetal
growth restriction

42. Effects on Immune system
 Cannabinoids impair cell-mediated and humoral immunity
in rodents
 CB2 receptors :B cells > NK cells > monocytes >
polymorphonuclear neutrophils > CD8 lymphocytes > CD4
lymphocytes
 Decreases the proinflammatory mediators :interferon-
gamma ,TNF, IL-1,IL-2 etc
 Inhibits differentiation into macrophages & monocytes
 Effective against inflammation with a strong Th1 reaction, e.g.
in multiple sclerosis, Crohn’s disease and arthritis

43. Immune cells Functions affected Receptors involve
T-lymphocytes Inhibit proliferation, Cell death
by apoptosis
CB2
B-lymphocytes Inhibition of antibody
formation;
CB2
Macrophages Decreased Inflammatory
mediators; antigen
presentation; migration;
phagocytosis
CB2
Mast cells Inhibits
mast cell activation
Non-CB1, CB2
CB1, CB2

44. Cardiovascular system
 Profound decrease in arterial blood pressure, cardiac
contractility, and heart rate :hypotension
 Modulation of the autonomic outflow in both the
central and peripheral nervous systems
 Direct effects on the myocardium and vasculature
 CB1 receptors are present in vascular tissue as well as
the myocardium

45. Antiproliferative effect
Inhibition of proliferation
Immunosuppressant-down regulation of anti tumor
blocking factors
Induction of apoptosis
Inhibition of metastasis & angiogenesis
Prostate cancer,Breast cancer- CB1,Glioma- CB1&CB2

46. Respiratory system:
• Modulating ratio of pro- and anti-inflammation
mediators released by airway epithelial
• Alter contractility through modulation of Ca2+-
entry
Eye- reduces Intraocular pressure

47. CLINICAL IMPLICATIONS

48. Pathological involvement
 Abnormalities of endocannabinoid signalling have
been reported in
 Neurodegenerative disorders
 Hypotensive shock
 Advanced cirrhosis of liver
 Miscarriage
 Malignancy

49. Established Effects
 Marino (dronabinol, ∆9-THC)
 Approved for use in refractory nausea and vomiting - anti-
neoplastic drugs
 Appetite loss in anorexia and cachexia of HIV/AIDS
patients.
 Adverse effects: vasodilation/facial flush,Asthenia
Palpitations, tachycardia ,Conjunctivitis, hypotension
Depression, nightmares, speech difficulties,Tinnitus

50. NABILONE
 Analogue of D9-THC
 Treatment of the delayed stages of emesis
 patients who do not respond to existing treatments
 used infrequently
 Adverse Reactions
 drowsiness, vertigo, dry mouth, euphoria, ataxia,
headache, and concentration difficulties

51. Rimonabant
 First selective CB 1 blocker
 Significant reduction in waist circumference and
improvements in lipid and glycemic profiles
Adverse effects:
Nausea, mood alteration with depressive
symptoms, depressive disorders, anxiety and
dizziness
Banned because of suicidal thoughts

52. Pharmacokinetics
 THC is absorbed :digestive and respiratory tract
 Oral ingestion absorbed more slowly than smoking.
 Terminal half life of THC in plasma ranges from 18 hrs
to 3 days
 Highly lipophilic THC and its metabolites (11-OH
THC) are sequestered in the body fat and adipose
tissue
 Sixty-five per cent : faeces, 20% : renal excretion.

53. TOLERANCE AND DEPENDENCE
 Both occurs only to a minor degree and mainly in
heavy users
 Symptoms are similar to those of ethanol or opiate
withdrawal -nausea, agitation, irritability, confusion,
tachycardia and sweating -relatively mild
 Psychological dependence does occur with cannabis,
but it is less compelling than with the major drugs of
addiction

54. Adverse effects
 Low doses :euphoria and drowsiness, sometimes
accompanied by sensory distortion and hallucinations
 In overdose :relatively safe, producing drowsiness and
confusion but not life-threatening respiratory or
cardiovascular depression
 In this respect, it is safer than most abused substances
like opiates and ethanol.

55. {
RECENT
ADVANCE
CANNABINOIDS
MANJUNATH S.M.

56. CNS DISORDERS
 Neurotrauma
 Stroke
 Movement disorders (basal ganglia disorders)
 Huntington’s disease
 Gilles de la Tourette’s syndrome
 Amyotrophic lateral sclerosis
 Alzheimer’s disease
 Schizophrenia
 Epilepsy

57. CVS & RESPIRATORY DISORDERS
 Circulatory shock
 Myocardial reperfusion injury
 Atherosclerosis
 Asthma
EYE DISORDERS
 Galucoma
GASTROINTESTINAL & LIVER DISORDERS
 Liver cirrhosis
MUSCULOSKELETAL DISORDERS
 Rheumatoid arthritis
 Osteoporosis

58. 1)Modulation of excitatory glutamatergic
transmissions via presynaptic CB1 receptors
2)Modulation of immune responses and the release of
inflammatory mediators by CB1 , CB2, and non CB1
/CB2 receptors on neurons, astrocytes, microglia,
macrophages, neutrophils and lymphocytes
3)Activation of cytoprotective signaling pathways,
such as protein kinase B/Akt or neurotrophic factors
PROPOSED MECHANISMS

59. 4)Modulation of excitability and calcium
homeostasis via effects on Ca2+, Na+ and K+
channels, NMDA receptors, gap junctions, and
intracellular Ca2+ stores
5)Antioxidant properties of cannabinoids
6)CB1 receptor mediated hypothermia, possibly
by reducing metabolic rate and oxygen demand

60. NEUROTRAUMA
Characterized by cerebral edema,
axonal & neuronal injury, increased
permeability of BBB
TBI also triggers glutamate induced
excitotoxicity, oxidative stress, release
of inflammatory cytokines

61.  Dexanabinol (HU-211), a behaviorally inactive
cannabinoid and noncompetitive antagonist of NMDA
receptors
CLINICAL TRIAL
 A multicenter, double-blind, randomized, placebo-
controlled phase II trial conducted in 67 patients with
severe closed head injury found dexanabinol
EFFECTIVE and also, safe and well tolerated

62.  2% population each year
Preclinical studies
 Dexanabinol at doses of 2 to 10 mg/kg
 Decreased infarct size and histological damage
and
 Improved neurological score in rat and gerbil
models - both global and focal cerebral ischemia
STROKE

63. HUNTINGTON’S DISEASE
 Inherited, autosomal dominant, progressive
neuropsychiatric disorder
 Motor disturbances, such as chorea (involuntary
movements) and dystonia, psychiatric symptoms, and
dementia
 Endocannabinoid signaling in the basal ganglia is hypofunctional
in HD, which probably contributes to the hyperkinesia associated
with the disease
 Cannabinoid agonists - therapeutic benefit in HD
 anthyperkinetic and
 neuroprotective effects
PRECLINICAL STUDIES
 Arvanil, a hybrid endocannabinoid and vanilloid compound, was
also reported to alleviate hyperkinesias in a rat model of HD

64. GILLES DE LA TOURETTE’S
SYNDROME
 Neurological syndrome - evident in early
childhood and is characterized by multiple motor
and vocal tics
CLINICAL TRIAL
 In 24 patients with Tourette’s syndrome, a
randomized double-blind, placebo-controlled
study
 THC (5-10 mg) vs placebo
 RESULTS
 Significant improvement of vocal and motor tics

65. AMYOTROHIC LATERAL SCLEROSIS
 Most common motor neuron disease
 Effect of cannabinoids against
 Oxidative cell damage
 Excitotoxicity,
 Antispastic effect
PRECLINICAL STUDIES
 Transgenic mice experimental model of ALS have
demonstrated that either THC or WIN55,212-2
administered after the onset of the disease delayed
disease progression

66. ALZHIEMER’S DISEASE
 Most common cause of dementia in elderly
CLINICAL STUDY
 open-label pilot study of six patients in the late stages
of dementia
 Treatment with 2.5 mg of dronabinol daily for 2
weeks significantly improved
 Neuropsychiatric Inventory total score and
 Subscores for agitation and aberrant motor and
nighttime behaviors

67. SCHIZOPHRENIA
 Prevalance 0.2 - 2%
 Hypoglutamatergic and hypodopaminergic transmission
in the prefrontal cortex is involved in the negative
symptoms,
 Whereas hyperactivity of dopamine neurotransmission in
the mesencephalic projections to the nucleus
accumbens may underlie the positive symptoms
 Overactivity of the endocannabinoid system may
lead to a hyperdopaminergic and hypoglutamatergic
state, which may underlie some of the symptoms

68. CLINICAL TRIAL
 In a trial conducted on 481 patients of
schizophrenia with positive and negative
symptoms, a double blind placebo
controlled study
 SR141716 – CB1 antagonist vs placebo
RESULTS
 No improvement was seen

69.  More than 1% population affected by epilepsy
PATHOGENESIS
Excitotoxicity
CLINICAL STUDY
 An epidemiological study found that chronic marijuana use
is protective against seizures
 To date, there have been no large-scale, controlled clinical
trials to examine the beneficial effects of cannabinoids in
various forms of epilepsy
EPILEPSY

70. CARDIOVASCULAR & RESPIRATORY
SYSTEMS
CIRCULATORY SHOCK
 SR141716 – CB1 receptor antagonist
cardiodepressant and hypotensive effects of
LPS inhibited in animal models of shock
 Modulation of β-adrenergic vasodilatation
rather than direct suppression of a direct
vasodilator effect by endocannabinoids

71. ISCHAEMIA REPERFUSION INJURY
 Protection mediated by endocannabinoids
acting on CB2 receptors
 Anandamide and HU-210 both decreased the
incidence of ventricular arrhythmias and
reduced infarct size through activation of CB2
ATHEROSCLEROSIS
 Using the apolipoprotein E knockout mouse
model of atherosclerosis, orally administered
THC significantly inhibited disease
progression

72. ASTHMA
 Bronchodilation without side effects was
observed in asthmatic patients after a low
dose (0.2 mg) of nebulized THC
 In contrast, aerosols containing larger doses
of THC (5–20 mg) caused paradoxical
bronchoconstriction attributed to local
irritation
 Anti-inflammatory properties

73. EYE DISORDERS
GLAUCOMA
 THC or marijuana decreased intraocular pressure
whether administered orally, topically, or
intravenously, with no major tolerance to their effect
reported
 Decrease aqueous humor production & improve the
uveoscleral outflow by dilating blood vessels of the
anterior uvea

74. LIVER CIRRHOSIS
 CB1 receptor blockade with SR141716
 Reversed the hypotension and low peripheral
resistance and
 Decreased the elevated mesenteric blood flow and
portal pressure - with carbon tetrachloride-induced
cirrhosis
 Additional benefits by slowing progression of
cirrhosis

75. RHEUMATOID ARTHRITIS
 Ajulemic acid, a potent analog of the acid metabolites of
THC and cannabidiol have been shown to have analgesic,
antiinflammatory, and immunosuppressive effects in
animal models of arthritis
OSTEOPOROSIS
 Selective CB2 agonist HU308, attenuated ovariectomy-
induced bone loss and markedly stimulated cortical
thickness through the suppression of osteoclast number
and stimulation of endocortical bone formation
 CB2 receptors role in bone remodeling

76. DISEASE MECHANISM OF
BENEFIT
RECEPTORS DRUG EVIDENCE
Traumatic brain
injury
Suppression of
excitotoxicity, anti-
oxidant, anti-
inflammatory
CB1 agonism Dexanabinol Phase II
Stroke Suppression of
excitotoxicity, anti-
oxidant, anti-
inflammatory
CB1 agonism Dexanabinol Preclinical
Huntington’s
disease
Anti-hyperkinetic &
neuroprotective
CB1 , TRPV1
receptors
agonism
Arvanil Preclinical
Gilles de la
tourette’s
syndrome
Improvement of
vocal & motor tics
CB1 agonism THC Phase II
Amyotrophic
lateral sclerosis
Suppression of
excitotoxicity, anti-
oxidant, anti-spastic
CB1 agonism THC,
WIN55,212-2
Preclinical

77. DISEASE MECHANISM OF
BENEFIT
RECEPTORS DRUG EVIDENCE
Alzhiemer’s
disease
Anti-
inflammatory,
neuroprotective
CB1
agonism
Dronabinol Small pilot
study
Schizophrenia Reduce positive
& negative
symptoms
CB1
antagonism
SR141716 Phase II
Epilepsy Reduce
excitotoxicity
CB1
agonism
Marijuana Epidemiologi
-cal study
Circulatory
shock
Modulation of β –
adrenocreceptors
induced
vasodilatation
CB1
antagonism
SR141716 Preclinical
Ischaemia
reperfusion
injury
Reduction of
infarct size
CB2
agonism
Anandamide Preclinical

78. DISEASE MECHANISM OF
BENEFIT
RECEPTORS DRUG EVIDENCE
Atherosclerosis Anti-inflammatory,
anti-oxidant,
immunomodulatory
CB2
receptors
THC Preclinical
Asthma Bronchodilatation,
anti-inflammatory
CB1
receptors
THC Phase II
Glaucoma Decreased aqueous
production,
increased uveoscleral
outflow
CB1
receptors
THC Phase II
Liver cirrhosis Decrease elevated
mesenteric blood
flow and portal
pressure
CB1
antagonism
SR141716 Preclinical
Rheumatoid
arthritis
Analgesic, anti-
inflammtory
CB1 agonism Ajulemic
acid
Preclinical
Osteoporosis Suppression of
osteoclast number
and stimulation of
endocortical bone
formation
CB2 agonism HU-308 Preclinical

79. CONCLUSION
Cannabinoids have important role
in various CNS & other disorders
Most drugs are in preclinical and
early clinical phase

80.  Pharmacol Rev 58:389–462
 Rang and Dale’s pharmacology – 6th
edition
 Brazilian Journal of Medical and
Biological Research (2006) 39: 421-429
 Pharmacol Rev 62:588–631, 2010
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