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Plant and brain cannabinoids: major players in physiology. Raphael Mechoulam Beit Dagan, January 2007  LOH 2003.

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Presentation on theme: "Plant and brain cannabinoids: major players in physiology. Raphael Mechoulam Beit Dagan, January 2007  LOH 2003."— Presentation transcript:

1 Plant and brain cannabinoids: major players in physiology. Raphael Mechoulam Beit Dagan, January 2007  LOH 2003

2 Gan-zi-gun-nu – the drug that takes away the mind Azallu – hand of ghost, poison of all limbs (neurological diseases?) Qunnabu – used in religious rites

3 Pliny, the Elder (79 AD): The roots boiled in water ease cramped joints, gout too and similar violent pain. Dioscorides (90 AD): The sodden root when placed on inflammations sooths them, eliminates edema and disperses obdurate matter above inflammed joints.  LOH 2003

4 For the relief of certain kinds of pain, I believe, there is no more useful medicine than Cannabis within our reach. J. Russell Reynolds, Archives of Medicine, Vol 2, 154, 1859


6   -tetrahydrocannabinol (   -THC) (Gaoni and Mechoulam, 1964) CH 3 O OH C 5 H 11 cannabidiol (CBD) (Mechoulam and Shvo, 1963) HO C 5 H 11 OH CH 3 3 cannabigerol (CBG) (Gaoni and Mechoulam, 1964) HO OH C 5 H 11 cannabichromene (CBC) (Claussen et al., 1966; Mechoulam and Gaoni, 1966) O C 5 H 11 OH Representative natural cannabinoids CH 3 cannabinol (CBN) (Adams et al., 1940) O OH C 5 H 11 OC 5 H OH cannabicyclol (CBL) (Crombie et al., 1968)  LOH 2003

7 Gaoni and Mechoulam: J.Amer.Chem.Soc. 86, 1646 (1964) O OH CH 3  9 -tetrahydrocannabinol (  9 -THC) Mechoulam and Shvo: Tetrahedron 19,2073 (1963)


9 Brain regions in which cannabinoid receptors are abundant Reward pathwayNucleus accumbens Link between cerebral hemispheresIntrabulbar anterior commissure Higher cognitive functionCerebral cortex, especially cingulate, frontal, and parietal regions Learning and memory, stressHippocampus Body-movement coordinationCerebellum Putamen Globus pallidus Enteropeduncular nucleus Substantia nigra pars reticulata Movement controlBasal ganglia

10  LOH 2004

11 Binding to cannabinoid receptors LigandCB1 (nM) CB2 (nM) GPR55 EC50 (nM)  9 -THC 60.48 cannabidiol> 30000 445 * anandamide312718 2-arachidonoylglycerol5196183 palmitoylethanolamide> 30000198004 HU-2100.20.526

12 GG AC Calcium entry blocked [Ca 2+ ] Decreased release of neurotransmitters Cannabinoid receptor Agonists (e.g. THC, anandamide) Ca 2+ (-) K +Potassiumchannelsopen [cAMP] (-) K+K+

13 Science (STKE, 23 April, 2002)

14 What do endocannabinoids do? “Relax, eat, sleep, forget and protect” Di Marzo, 1998

15 Physiological systems and conditions affected by endocannabinds (a partial list) Anxiety Inflammation Appetite/feeding Memory Blood pressure Mood Bone formation Movement Cerebral blood flow Neuroprotection Digestive system Pain Emesis and nausea Reproduction Immune system Stress  LOH 2004

16 Neuroprotection



19 2-AG Reduces Infarct Volume 24 h After CHI control 2-AG (5 mg/kg) 0.0 2.5 5.0 7.5 10.0 12.5 15.0 control 2-AG 5 mg/kg * n=9 n=7 unpaired t-test, P=0.0 3 infarct volume(%) 2-AG control

20 glutamate cytokines, ROS cerebral ischemia neuronal & glial cell death Brain injury Vasoconstrictors (e.g. ET-1, Thromboxane) 2-AG cerebroprotection

21 Regulation of vasodilation

22 Corticosteroids Androgens Estrogens Aldosterone Progesteron Costicosteroids Digitalis

23 Plasma Membrane



26 HO COOH N O C H arachidonoyl serine

27 Inflammation

28 Eur.J.Pharmacol. 406, R5-R7 (2000)

29 0 500 1000 1500 2000 LPS LPS + 2-AG LPS + 2-AG + +2-LG + 2-PG TNF  in serum (S50 units) Inhibition of TNF  production by 2-AG in mice In vivo  LOH 2004


31 Synovium is the most critical site of cytokine production in arthritis. Synovial cells from arthritic mice spontaneously produce large amounts of TNF when cultured in vitro. Cells from arthritic mice which had been treated with CBD produced significantly less (50%) TNF.  LOH 2003


33 Appetite and feeding

34 Dronabinol Placebo Mean change in weight from baseline in patients with AIDS treated with dronabinol (THC) and placebo (Beal et al., 1995)

35 Effect of anandamide on food intake (16 mouse in each group).

36  LOH 2004


38 SR141716A

39 Memory extinction

40 d1 d2 d3d6 0 10 20 30 40 50 Per cent freezing (60 s tone) CS Co Experimental day ** ***    LOH 2004

41 The endogenous cannabinoid system could represent a therapeutic target for the treatment of diseases associated with inappropriate retention of aversive memories or inadequate responses to aversive situations, such as post-traumatic stress disorders, phobias, and certain forms of chronic pain.  LOH 2004

42 Cannabinoids and anxiety. 1. In animal models as well as in limited clinical trials cannabidiol has been shown to lower anxiety. Mechanism unknown. 2. Blocking of anandamide hydrolysis in vivo (rats) enhances anandamide levels in brain and lowers anxiety. This effect is blocked by endocannabinoid antagonists.

43 Cannabinoids and schizophrenia. 1. Large doses of cannabis (particularly if they lack cannabidiol) may cause a psychotic state resembling psychosis. 2. In schizophrenic patients cannabis use may worsen positive symptoms. 3. Heavy use of cannabis may precipitate schizophrenia in susceptible individuals. Frequent cannabis use was associated with 6 fold increase of in high risk individuals (family history). 4. Increase in density of CB1 receptors in several brain areas in postmortem schizophrenic brains. Two fold increase of anandamide levels in CSF of patients.

44 Cannabidiol treatment of positive schizophrenia. High doses of the non psychoactive Cannabis constituent cannabidiol have shown effectiveness in the treatment of schizophrenics (lowering of positive effects). Mechanism – unknown.

45 Endocannabinoids and depression. Although at low doses cannabis may enhance mood it is not antidepressive. A selective inhibitor of the enzyme which causes endocannabinoid hydrolysis (in vivo) exerts potent anti-depressant effects in the rat forced swim test.

46 Hepatic encephalopathy. Hepatic encephalopathy (HE) is a neuropsychiatric syndrome due to liver disease. It is the feature that defines prognosis in acute liver injury. 1. In a mouse model of HE (produced by the toxin thioacetamide) 2-AG levels are enhanced in the brain. 2. Administration of either 2-AG or the specific CB2 agonist HU-308 improves a neurological score, activity, cognitive function. 3. A specific CB2 receptor antagonist blocks these effects.

47 Alzheimer ’ s disease Compared to currently approved drugs prescribed for the treatment of Alzheimer ’ s disease, THC is considerably superior inhibitor of A  aggregation and thus cannabinoid molecules may directly impact the progression of this debilitating disease. (Eubanks et al., Mol. Pharmac. 2006)

48 Collaboration in Israel Jerusalem Prof. L. Hanuš Prof. E. Fride Dr. W. A. Devane Dr. A. Breuer Dr. S. Ben-Shabat D. Panikashvili G. Milman N. Kogan Y. Maor Jerusalem Prof. E. Shohami Prof. R. Gallily Prof. E. Berry Prof. M. Schlesinger Dr. Y. Avraham Haifa Prof. A. Mandelbaum Rehovot Prof. Z. Vogel Tel Hashomer Dr. S. Almog Dr. A. Gopher  LOH 2003

49 Collaboration abroad Aberdeen R. Pertwee Bonn M. Karsak A.Zimmer Brno A.Šulcová Greece C. Simeonidou Richmond B. Martin A.H. Lichtman Canada L. A. Parker Bethesda G. Kunos M. Spatz Napoli V. Di Marzo Rome M. Maccarrone Siberia L. Maslov London M. Feldmann A.M. Malfait P. F. Sumariwalla  LOH 2003

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