Cannabinoids: Nausea, Anxiety, Depression and Addiction

Reem Smoum-Jaouni and Raphael Mechoulam The Institute for Drug Research The Hebrew University of Jerusalem Bioactive Compounds

Δ9- Δ9-Tetrahydrocannabinolic acid (THC) (THCA)

Cannabinol (CBN) (CBD) (CBDA) Cannabigerolic acid (CBGA) -CO2

Cannabigerol (CBG)

Cannabidiolic acid Δ9-Tetrahydrocannabinolic acid (CBDA) (Δ9-THCA) (CBCA)

-CO2 -CO2 -CO2

Cannabidiol Δ9-Tetrahydrocannabinol (CBD) (Δ9-THC) (CBC) Cannabidiolic Acid Methyl Ester: A Stable Synthetic Analogue of Cannabidiolic Acid

Methanol, CH2Cl2

DCC. 4-Pyrrolidinopyridine

Cannabidiolic Acid Cannabidiolic Acid Methyl Ester (CBDA) (CBDA Me, HU-580)

(Krejčí and Šantavý, 1955; Mechoulam and Gaoni, 1965) (Mechoulam and Ben Zvi, 1969) CBDA Me in Nausea, Anxiety and Depression Nausea

• The sensation of nausea is one of the most debilitating human experiences

• Current antiemetic therapies are less effective in reducing acute nausea and are completely ineffective in reducing anticipatory nausea

• Pre-clinical findings suggest that CB1 receptor agonists, FAAH and MAGL inhibitors, CBD and CBDA reduce acute and anticipatory nausea Nausea

CBDA Me (HU-580) enhanced 5-HT1A receptor activation

Acute nausea Anticipatory nausea

R.G. Pertwee et al. / Br J Pharmacol 175 (2017) 100-112 Anxiety and Depression

Evidence supporting clinical benefits of cannabis-based therapies in mood disorders is scarce, and limited to low- grade evidence supporting the beneficial effect of CBD in social anxiety & depression & of medical marijuana in PTSD ECS influences on mood and behavior Anxiety

Foot shockFootFoot or shock Shock or Anxiolytic effects No Foot shockorNo No Foot Foot stress shock Shock stressStress

(6 min) (6 minmin) 24 h VEH, CBDA, CBDA ME Light-Dark Emergence45 min Test Light-Dark Emergence Test VEH, CBDA, HU-580 VEH, CBDA, HU-580 (0.01 µg.kg-1, i.p.) (0.01 µg.kg-1, i.p.)

R.G. Pertwee et al. / Br J Pharmacol 175 (2017) 100-112 Antidepressant effects

CBDAMe reduced depression-like behavior in animal models of depression

Hen-Shoval et al. / Behav Brain Res 231 (2018) 1-3 Summary CBDA Me displayed greater potency than CBDA at suppressing signs both of acute nausea and anticipatory nausea, and of stress induced anxiety in rats, and it produced these effects in a 5-HT1A receptor-dependent manner

CBDA Me showed a very potent anti-depression-like effect in rats

CBDA Me could possibly be effective against other disorders ameliorated by enhancement of 5-HT1A receptor activation such as cerebral infarction and pain The and Addiction Substance Use Disorder (SUD) is a global problem, with over 30 million individuals estimated to have an SUD

The ECS plays an important role in neurobiological processes underlying SUD, by mediating the rewarding and motivational effects of substances

Rimonabant and Nabiximols have the potential for pharmacological treatment for substance dependence

Cannabidiol (CBD), has been proposed as a potentially effective treatment for the management of SUD The Endocannabinoids to Date

N-Arachidonoylethanolamine 2-Arachidonoylglycerol (AEA) (2-AG)

2-Arachidonoylglycerylether O-Arachidonoylethanolamine Noladin-ether

N-Arachidonoyldopamine (NADA) The Endocannabinoid-like Compounds

N-Palmitoylethanolamine (PEA) N-Oleoylethanolamine (OEA) Antiinflammatory, Antinociveptive, Regulates food intake Neuroprotective and Anticonvulsant

Arachidonoyl serine (AraS) Oleoyl serine (OS) Vasoactive, Pro-angiogenic, Pro- Antiosteoporotic neurogenic Addiction Cigarette smokers with brain damage involving the insular cortex display cessation of smoking, so that this region may contribute to nicotine addiction N.H. Naqvi et al. / Science 315 (2007) 531

OlGly levels in the Insula Hippocampus Hypothalamus Insula

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O O O 0 0 0 Oleoyl glycine I I I e m B e m B e m B iv a T iv a T iv a T a h a h a h N N N S S S G. Donvito et al. / Neuropharmacology 148 (2019) 320-331 Nicotine Addiction

14 days 15 min 25 min Elevated Plus Maze Physical (somatic) withdrawal signs Mecamylamine Mice Nicotine/Saline For Nicotine group, OlGly (10, 30, or 60 mg/kg)/VEH

Elevated Plus-Maze

G. Donvito et al. / Neuropharmacology 148 (2019) 320-331 Nicotine Addiction

Somatic signs

OlGly reduced mecamylamine-precipitated withdrawal responses in nicotine-dependent mice

G. Donvito et al. / Neuropharmacology 148 (2019) 320-331 Nicotine Addiction

Conditioned Place Preference (CPP)

OlGly prevented nicotine reward, weakly inhibited FAAH and behaved as a PPAR-α receptor agonist

G. Donvito et al. / Neuropharmacology 148 (2019) 320-331 Morphine Addiction

Conditioned Place Aversion (CPA)

OlGly blocked the aversive effects of Morphine Withdrawal (MWD), an effect that is reversed by CB1 antagonist

G.N. Petrie et al. / Psychopharmacology 236 (2019) 2623-2633 Morphine Addiction

Mouthing Movement Abdominal Contractions

Diarrhea Lying on Belly

OlGly suppressed acute naloxone-precipitated MWD nausea-like somatic behaviors, an effect that was prevented by PPAR-α and CB1 antagonists

G.N. Petrie et al. / Psychopharmacology 236 (2019) 2623-2633 amide bond

Oleoyl glycine α-methylation of Anandamide

Anandamide Methanadamide Abadji, V, et al. (1994)

Methyl Oleoyl glycine (HU-595) Dimethyl Oleoyl glycine (HU-596) Morphine Addiction

VEH Pretreatment Oleoyl Glycine Pretreatment HU-595 Pretreatment

Monomethyl oleoyl glycine (HU-595) produced a longer lasting interference than OlGly with acute naloxone-precipitated MWD, an effect that was

prevented by both a PPAR- and a CB1 antagonists

S.M. Ayoub et al. / Psychopharmacology (2019) Summary

• The EC-like compound OlGly interferes with nicotine addiction and acute naloxone-precipitated morphine withdrawal

• Monomethylated OlGly, may be a more stable agent to combat the aversive effects of acute naloxone- precipitated MWD than OlGly Acknowledgments

Scotland USA Roger G. Pertwee Aron H. Lichtman (Nausea) (Addiction)

Canada Italy Linda Parker Vincenzo Di Marzo (Nausea and Addiction) (Addiction)

Israel Aron Weller (Depression) Thank you