Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol

Douglas L Boggs, Jacques D Nguyen, Daralyn Morgenson, Michael A Taffe and Mohini Ranganathan

Neuropsychopharmacology Reviews, 2018, 43, 142–154.

doi : 10.1038/npp.2017.209;

The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are 4550 chemical compounds and 4100 phytocannabinoids isolated from cannabis, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC-induced anxiety, psychosis, and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from preclinical and human studies, particularly with reference to anxiety and psychosis-like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings, including the individual and interactive effects of CBD and THC.

 

INTRODUCTION

The plant Cannabis sativa, or cannabis, has been used for millennia for its medicinal, psychotropic, and mind-altering effects (Callaway, 2004). Clinical and preclinical research efforts over the past decades have defined many effects of cannabis on physiology and behavior and more recent research has focused its efficacy for various medicinal purposes (Izzo et al, 2009; Pertwee, 2008). There are 4550 chemical compounds and 4100 plant cannabinoids or phytocannabinoids isolated from Cannabis sativa, including
Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) (ElSohly et al, 2017). THC is the most studied of these phytocannabinoids and likely the most psychoactive. Research from the 1960s and 1970s identified THC as the main cause of the psychoactive effects of cannabis (Grunfeld and Edery, 1969; Mechoulam et al, 1970), and further research led to the introduction of synthetic THC for medicinal use (Pertwee, 2008). Unlike THC, CBD does not appear to have psychotomimetic effects but it may interact with some of the effects of THC when co-administered (Morgan and Curran, 2008; Morgan et al, 2010a; Morgan et al, 2011; Morgan et al, 2010b). CBD is also currently being researched for medicinal purposes (Izzo et al, 2009; Pertwee, 2008). This article aims to review the interactive effects of CBD and THC on several domains from preclinical, human field/epidemiological and human laboratory studies. Further, there is a paucity of research on the interactive effects of THC and CBD, and several studies compare the effects of THC and CBD rather than their interactive effects. Nevertheless, a consideration of what is known about THC/CBD interactions will help to better understand gaps in knowledge and frame directions for future research.

ENDOCANNABINOID SYSTEM

Cannabis and its component cannabinoids exert their effects primarily via the endogenous cannabinoid system. The two primary receptors of the endogenous cannabinoid system are cannabinoid 1 receptors (CB1Rs) and cannabinoid 2 receptors (CB2Rs)(Cabral et al, 2008; Devane et al, 1988). Both CB1Rs and CB2Rs are G-protein coupled receptors with CB1Rs predominantly located on neurons in the central and
peripheral nervous systems and CB2Rs primarily located in immune cells, although also found in some neurons (Onaivi et al, 2006). CB1Rs are located in several areas of the brain, including the basal ganglia, frontal cortex, hippocampus, and cerebellum, on GABAergic and glutamatergic terminals and cannabinoids produce their psychotomimetic effects primarily via activation of CB1Rs (Huestis et al, 2007). The primary endogenous cannabinoid ligands (endocannabinoids) identified thus far are anandamide (AEA) (Devane et al, 1992) and 2-arachidonoyl-glycerol (2-AG) (Mechoulam et al, 1995;
Sugiura et al, 1995), both of which act as retrograde messengers at synapses in the central nervous system. They are produced on demand based on neuronal activity, released from postsynaptic neurons, and diffuse backward across the synapse to presynaptic neurons where they bind and activate CB1Rs (Hashimotodani et al, 2007). Binding and activation of CB1Rs cause inhibition of voltage-sensitive N-type and P/ Q-type calcium channels, which inhibits further release of neurotransmitters, including GABA, glutamate, and acetylcholine (Parsons and Hurd, 2015). The primary source of catabolism of AEA and 2-AG are the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively (Justinova et al, 2015). FAAH is found in the dendrites and somas of neurons and MAGL is found in presynaptic neurons (Hashimotodani et al, 2007). Both FAAH and MAGL have become potential targets for new medications aimed at enhancing levels of endocannabinoids as treatment of pain and depression (Justinova et al, 2015).

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