Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Roger Pertwee

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1 Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Roger Pertwee UNIVERSITY OF ABERDEEN

2 The pharmacological properties of Cannabis have been exploited for at least 5000 years Cannabis was one of the first plants to be used by man: for religious ceremonies socially/recreationally as a medicine swellings, bruises, pain (local application) toothache, headache, pain from minor surgery arthritis, rheumatic, menstrual & labour pain control of spasms, cramps & convulsions anti-emesis, appetite stimulation Queen insomnia, fever Victoria bronchitis, asthma, coughs symptoms of dysentery & cholera (diarrhoea) Mechoulam, R. (1986) In: Mechoulam, R. (ed). Cannabinoids as Therapeutic Agents, pp.1-19, CRC Press, Boca Raton.

3 Information about the phytocannabinoid constituents of cannabis emerged much more recently Cannabinol (CBN) late 1800 s - isolated 1930 s - structure elucidated 1940 s - synthesized Sativex at least 441 Other compounds Cannabis Tetrahydrocannabinol (THC) 1940 s - isolated structure elucidated synthesized (±) Marinol THC THC + CBD Cannabidiol (CBD) 1940 s - isolated structure elucidated synthesized (±) Phytocannabinoids at least 112 Other phytocannabinoids THCV (1970) Cannabidiolic acid (CBDA) Cannabigerol (CBG) etc etc Pertwee, ElSohly, R.G. M.A. (2006) & Gul, Cannabinoid W. (2014) Constituents pharmacology: of Cannabis the first sativa. 66 year. Br Handbook J Pharmacol of Cannabis, 147: S163-S171 Chapter 1, pp. 3-22

4 Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Three phytocannabinoids tetrahydrocannabivarin (THCV) cannabidiolic acid (CBDA) cannabigerol (CBG) Just some of their many pharmacological targets the 5-HT 1A receptor the α 2 adrenoreceptor the CB 1 receptor the CB 2 receptor etc etc etc Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA Δ 9 -tetrahydrocannabivarin O H Δ 9 -THCV O THCV: Potential therapeutic applications: CB 1 antagonism + CB 2 partial agonism Dependence/relapse: e.g. nicotine, alcohol Neurodegenerative disorders e.g. Parkinson s disease Systemic sclerosis Alcohol-induced liver injury Liver damage from ischaemia & reperfusion Nausea and vomiting Diabetic nephropathy Obesity Stroke Retinitis pigmentosa

5 Some potential therapeutic applications for tetrahydrocannabivarin (THCV) Effects of Δ 8 -tetrahydrocannabivarin (Δ 8 -THCV) on appetitive effects of cocaine and nicotine in rodents Z-X Xiong, P. Muldoon, X-F Wang, G-H Bi, M. Imad Demaj, A.H. Lichtman, RG Pertwee and E.L. Gardner (2014) 24th Annual Symposium on the Cannabinoids, International Cannabinoid Research Society, Research Triangle Park, NC, USA, p. 31 Δ 8 -THCV (3 to 20 mg/kg i.p.) inhibited i.v. self-administration of nicotine in alcohol-preferring rats and wild-type mice. Results obtained with AM630 and with CB 2 receptor knockout mice suggest that this effect of Δ 8 -THCV was partly CB 2 receptor-mediated Δ 8 -THCV also inhibited nicotine-induced conditioned place preference and nicotine-seeking behaviour. Δ 8 -THCV did not inhibit i.v. self-administration of cocaine in wild-type or CB 2 knockout mice.

6 Some potential therapeutic applications for tetrahydrocannabivarin (THCV) Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ 9 -THCV in animal models of Parkinson s disease C García, C Palomo-Garo, M García-Arencibia, JA Ramos, RG Pertwee and J Fernández-Ruiz (2011) Br J Pharmacol 163: Δ 8 -Tetrahydrocannabivarin prevents hepatic ischaemia/reperfusion injury by decreasing oxidative stress and inflammatory responses through CB 2 receptors S Bátkai, P Mukhopadhyay, B Horváth, M Rajesh, RY Gao, A Mahadevan, M Amere, N Battista, AH Lichtman, LA Gauson, M Maccarrone, RG Pertwee and P Pacher (2012) Br J Pharmacol 165:

7 Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Four phytocannabinoids tetrahydrocannabivarin (THCV) cannabidiolic acid (CBDA) cannabigerol (CBG) Just some of their many pharmacological targets the 5-HT 1A receptor the α 2 adrenoreceptor the CB 1 receptor the CB 2 receptor etc etc etc Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA THCV: Potential therapeutic applications: 5-HT 1A receptor-mediated e.g. Opioid dependence Positive and negative symptoms of schizophrenia THCV: Potential therapeutic applications: CB 1 antagonism + CB 2 partial agonism Dependence/relapse: e.g. nicotine, alcohol Neurodegenerative disorders e.g. Parkinson s disease Systemic sclerosis Alcohol-induced liver injury Liver damage from ischaemia & reperfusion Nausea and vomiting Diabetic nephropathy Obesity Stroke Retinitis pigmentosa

8 partly via 5-HT 1A positive modulation? +ve Locomotor activity: number of photocell beam breaks +ve THCV may have antipsychotic activity -ve Active social behaviour: time spent on this Stereotyped behaviour: time spent in stereotypy cognitive Novel object recognition test: discrimination index Effects of acute administration to rats of the NMDA receptor antagonist, phencyclidine (PCP) or of its sub-chronic administration plus 7-day withdrawal significantly reduced by THCV (2 mg/kg i.p.) Forced swim test: time spent immobile -ve Forced swim test: time spent swimming Forced swim test: time spent climbing and via CB 1 antagonism? AM251 data -ve -ve Cascio, Zamberletti, Marini, Parolaro & Pertwee (2015) Br J Pharmacol 172: WAY100635

9 % Displacement of 8-[ 3 H]-OH-DPAT ± SEM Δ 9 -THCV enhances agonism induced by the 5-HT 1A receptor agonist, 8-OH-DPAT, in human 5-HT 1A CHO cell membranes % Stimulation above basal SEM Human 5-HT 1A CHO cell membranes 8-OH-DPAT 9 -THCV Concentration (log M) Human 5-HT 1A CHO cell membranes DMSO 100 nm 9 -THCV OH-DPAT (log M) Cascio, M.G., Zamberletti, E., Marini, P., Parolaro, D. and Pertwee, R.G. (2015). The phytocannabinoid, Δ 9 -tetrahydrocannabivarin, can act through 5-HT 1A receptors to produce anti-psychotic effects. Br J Pharmacol 172:

10 THCV: quo vadimus? Synthesize a peripherally-restricted analogue of THCV that behaves as a CB 1 antagonist & CB 2 agonist in vivo and could be investigated for its efficacy against peripheral disorders such as diabetic renal nephropathy. Perform human clinical studies to establish which of the many potential therapeutic uses of THCV revealed by in vivo or in vitro preclinical research truly are clinically important and which are hype. Nicotine dependence? Parkinson s disease? Facilitation of solid organ transplantation (vs I/R injury)? Diabetic renal nephropathy? Schizophrenia? Investigate why THCV behaves both as a CB 1 antagonist and as a CB 1 agonist in vivo but only as a CB 1 antagonist in vitro.

11 Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Four phytocannabinoids tetrahydrocannabivarin (THCV) cannabidiolic acid (CBDA) cannabigerol (CBG) Just some of their many pharmacological targets the 5-HT 1A receptor the α 2 adrenoreceptor the CB 1 receptor the CB 2 receptor etc etc etc Δ 9 -tetrahydrocannabivarin CBDA OH (and OH CBD): Potential O therapeutic H applications: 5-HT 1A receptor-mediated Opioid dependence Positive and negative Δ 9 -THCV symptoms CBD HO of schizophrenia CBD O HO Depression Anxiety disorders Cognitive disorders Neuropathic pain Nausea and vomiting Extrapyramidal syndrome OH Symptoms of Parkinson s disease L-DOPA-induced COOH dyskinesia Cerebral infarction/stroke Heat Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA HO CBDA

12 CBD & CBDA both seem to enhance 5-HT 1A receptor-mediated effects in vivo: anti-emesis in shrews and anti-nausea in rats 5-HT 1A receptormediated 5-HT 1A receptormediated

13 Cannabidiolic acid potently enhances agonism induced by the 5-HT 1A receptor agonist, 8-OH-DPAT, in rat brainstem membranes % Stimulate above basal SEM % Stimulate above basal SEM % Stimulate above basal SEM % Stimulate above basal SEM % Stimulate above basal SEM % Stimulate above basal SEM A 60 VEH 0.01 nm CBDA 40 B 60 VEH 0.1 nm CBDA 40 * C 60 VEH 1.0 nm CBDA 40 * OH-DPAT (log M) OH-DPAT (log M) OH-DPAT (log M) D 60 VEH 10 nm CBDA 40 * E 60 VEH 100 nm CBDA 40 * F 60 VEH 1 M CBDA OH-DPAT (log M) OH-DPAT (log M) OH-DPAT (log M) Bolognini et al. (2013) Br J Pharmacol 168:

14 Bolognini, Rock, Cluny, Cascio, Limebeer, Duncan, Stott, Javid, Parker & Pertwee (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT 1A receptor activation. Br J Pharmacol 168: 1456 E max of 8-OH-DPAT in [ 35 S]GTPγS binding assays performed with rat brainstem membranes ND ND ND Concentration of CBD (nm) Concentration of CBDA (nm) Suppression of lithium-induced gaping behaviour in rats ND ND ND Dose of CBD (mg kg -1 i.p.) Dose of CBDA (mg kg -1 i.p.) ND so CBDA may be more druggable than CBD CBD & CBDA are both antagonized by WAY ND

15 CBDA: quo vadimus? Synthesize an analogue of CBDA that has greater stability than CBDA but similar potential therapeutic uses Perform human clinical studies with CBDA or with a stable CBDA analogue to establish which of the many potential therapeutic uses of CBDA or its analogue revealed by in vivo or in vitro preclinical research truly are clinically important and which are hype. Nausea/vomiting e.g. in response to chemotherapy? Schizophrenia? One or more of many other 5-HT 1A -related disorders? Also THCV and CBD for some/all of the above? Are the established anti-psychotic effects of CBD observed in humans mediated partly or wholly by 5-HT 1A receptors?

16 Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Three phytocannabinoids tetrahydrocannabivarin (THCV) cannabidiolic acid (CBDA) cannabigerol (CBG) Just some of their many pharmacological targets the 5-HT 1A receptor the α 2 adrenoreceptor the CB 1 and the CB 2 receptor etc etc etc Possible new therapeutic benefits of exploiting pharmacological actions of THCV, CBG, CBD or CBDA? CBG: Potential therapeutic applications: αcbda (and CBD): 2 -adrenoceptor-mediated OH Potential Acute & therapeutic inflammatory Cannabigerol applications: pain 5-HT Migraine; 1A receptor-mediated headaches Cannabis Opioid dependence & opioid dependence Alcohol Positive & and nicotine negative dependence symptoms HO Anxiety of schizophrenia & panic CBG disorders Post-traumatic Depression stress disorder Attention-deficit Anxiety disorders hyperactivity disorder Tourette Cognitive syndrome disorders (vs tics) Insomnia; Neuropathic sleep pain hyperhidrosis Menopausal Nausea and hot vomiting flushes Hypertension Extrapyramidal syndrome Symptoms of Parkinson s disease 5-HT 1A L-DOPA-induced receptor-mediated dyskinesia Positive Cerebral and infarction/stroke negative symptoms of schizophrenia Depression Neuropathic pain

17 % Stimulation above basal [ 35 S]GTP S binding ± s.e. Cannabigerol (CBG) modulates [ 35 S]GTP S binding to MF1 mouse brain membranes high-potency but lowefficacy stimulation of GTPγS binding 20 HO OH highish potency 5-HT 1A receptor antagonism (K B < 50 nm) via α 2 -adrenoceptor activation: potent antagonism by yohimbine also in vivo Cascio, Gauson, Stevenson, Ross & Pertwee (2010) Br J Pharmacol 159: EC 50 = 0.2 nm E max = 15.5% CBG (log M) lowish potency antagonism of CP55940 (K B = 936 nm) bell-shaped curve low potency inhibition of GTPγS binding

18 Cannabigerol induces α 2 -adrenoceptor mediated antinociception in two mouse models of inflammatory pain Carrageenan (mice; i.pl) Mechanical allodynia Thermal hyperalgesia α 2 -adrenoceptor antagonist, yohimbine (1 mg/kg i.p.) Cannabigerol (10 mg/kg i.p.) behaved like clonidine (0.2 mg/kg i.p.) Cannabigerol (5 or 10 mg/kg i.p.) Cannabigerol (5 or 10 mg/kg i.p.) α 2 -adrenoceptor antagonist, yohimbine (1 mg/kg i.p.) 2 nd phase only Formalin (mice; i.pl) Cannabigerol (10 mg/kg i.p.) behaved like clonidine (0.2 mg/kg i.p.) Persistent inflammatory pain Comelli, Filippi, De Gioia, Pertwee & Costa (2012)

19 Cannabigerol may have antipsychotic activity cognitive via 5-HT 1A receptorantagonism? +ve Locomotor activity: number of photocell beam breaks +ve -ve Active social behaviour: time spent on this Stereotyped behaviour: time spent in stereotypy Novel object recognition test: discrimination index Effects of acute administration to rats of the NMDA receptor antagonist, phencyclidine (PCP) or of its sub-chronic administration plus 7-day withdrawal significantly reduced by CBG (5 mg/kg i.p.) -ve Forced swim test: time spent in immobility Forced swim test: time spent swimming Forced swim test: time spent climbing -ve -ve Gabaglio, Zamberletti, Speziali, Flamini, Rubino, Pertwee & Parolaro (2012)

20 CBG: quo vadimus? Explore the apparent anti-psychotic effect of CBG and the clinical relevance of this effect. Perform human clinical studies to establish which of the many potential therapeutic uses of CBG revealed by in vivo or in vitro preclinical research with CBG truly are clinically important for CBG and which are hype. Schizophrenia? Acute and inflammatory pain? Headache and migraine? Post-traumatic stress disorder?...etc etc Explore the likely ability of CBG to interact synergistically via α 2 -adrenoceptor activation with a CB 1 receptor agonist such as THC for pain relief.

21 A potential adjunctive therapeutic strategy: co-administer CBG with low-dose Δ 9 -THC Yoon MH, Choi J (2003) Pharmacologic interaction between cannabinoid and either clonidine or neostigmine in the rat formalin test. Anesthesiology 99: Tham SM, Angus JA, Tudor EM, Wright CE (2005) Synergistic and additive interactions of the cannabinoid agonist CP55,940 with µ opioid receptor and α 2 -adrenoceptor agonists in acute pain models in mice. Br. J. Pharmacol. 144: Hence: low-dose CBG + low-dose Δ 9 -THC versus e.g. acute or inflammatory pain? Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol. 156: Pertwee, RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Phil. Trans. R. Soc. B. 367:

22 Pharmacological Actions and Potential Novel Therapeutic Uses of Plant Cannabinoids: Great Expectations Three phytocannabinoids fighto cannabinoids tetrahydrocannabivarin (THCV) cannabidiolic acid (CBDA) cannabigerol (CBG) Four pharmacological targets the CB 1 and the CB 2 receptor the α 2 adrenoreceptor the 5-HT 1A receptor in vitro & in vivo Possible therapeutic benefits of numerous targeting one or more of these receptors with THCV, CBG or CBDA THCV ( CB 1 plus CB 2 ) CBG ( ) THCV ( ) CBDA ( ) & CBG ( )

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24 Handbook of Cannabis Edited by Roger Pertwee Includes scientific information about cannabis valuable to academic and industrial researchers Contains wide-ranging information about cannabis providing policymakers, government advisers, politicians, lawyers, journalists, students and parents with important relevant information about cannabis Each chapter is written by a group of one or more authors recognized internationally as an established expert Hardback August

25 Main conclusions and some possible future directions Seek out all unknown pharmacological actions of all phytocannabinoid & non-phytocannabinoid cannabis constituents. Seek out (1) potentially beneficial combined actions, and (2) allosteric modulators of CB 1 or CB 2 or other receptors. Identify the best potential & actual therapeutic applications for individual phytocannabinoid & non-phytocannabinoid cannabis constituents &/or mixtures of two or more of these. Identify synthetic analogues of phytocannabinoids displaying improved therapeutic value (e.g. better benefit:risk ratios). increased stability and/or beneficial alterations in metabolism. broader effective dose ranges. peripheral restriction (for peripheral targets e.g. kidney). improved water solubility and/or pharmacokinetics.

26 Any Questions or Comments?

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