Clinical and preclinical evidence for functional interactions of cannabidiol and δ9-tetrahydrocannabinol

ABSTRACT 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 >550 chemical compounds and >100 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. SIMILAR CONTENT BEING VIEWED BY OTHERS HEXAHYDROCANNABINOL (HHC) AND

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DISORDER: FINDINGS FROM A RANDOMISED CLINICAL TRIAL FOR THE TREATMENT OF CANNABIS USE DISORDER Article Open access 21 April 2023 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 >550 chemical

compounds and >100 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). EXOGENOUS CANNABINOIDS Exogenous cannabinoids include compounds extracted from herbal cannabis (phytocannabinoids), such as THC and CBD as well as synthetic

cannabinoids (compounds included in spice/K2) that are increasing in popularity recreationally particularly among youth (Spaderna et al, 2013). Δ9-TETRAHYDROCANNABINOL THC’s structure and

stereochemistry were determined in the 1960s. (Gaoni and Mechoulam, 1964). THC is a partial agonist at both CB1R and CB2R. THC’s psychoactive effects are principally mediated by agonist

effects at CB1R and its potential immunological or anti-inflammatory effects are likely mediated via CB2Rs (Pertwee, 2008). Intravenous (i.v.) THC administration produces a wide range of

psychoactive effects, including feeling ‘high’, anxiety, paranoia, perceptual alterations, and cognitive deficits, particularly deficits in verbal recall (D'Souza et al, 2004) in

healthy individuals and exacerbates psychotic symptoms in patients with schizophrenia (D'Souza et al, 2005). Cannabis users, however, often report stress as a primary factor for chronic

use (Hyman and Sinha, 2009). Activation of CB1R by THC results in perturbation of GABA/glutamatergic neurotransmission as well as dopamine release; although the magnitude of THC-induced

dopamine release is small compared with drugs such as amphetamine and cocaine, which produce larger striatal dopamine release (Bossong et al, 2015). The disruption of inhibitory/excitatory

balances could contribute to THC’s psychotomimetic effects (Farkas et al, 2010; Hampson et al, 2011; Li et al, 2010). Cognitive deficits seen with acute exposure to THC are generally acute,

transient, and self-limited. However, chronic use of cannabis, especially in adolescents, is associated with more chronic deficits in memory (Meier et al, 2012; Ranganathan and D'Souza,

2006), though other studies have not replicated this finding (Jackson et al, 2016; Mokrysz et al, 2016). SYNTHETIC THC FORMULATIONS Currently, two synthetic pharmaceutical forms of

cannabinoids are approved for administration in the United States, nabilone (a synthetic derivative of THC) (Ward and Holmes, 1985) and dronabinol (synthetic THC). Clinically, the effects of

both are similar to oral administration of cannabis (Badowski, 2017). Both synthetic forms of THC are approved for the treatment of chemotherapy-induced nausea and vomiting in patients who

failed to respond to conventional antiemetic medications (Marinol (package insert), 2017, Cesamet (package insert), 2013). Additionally, dronabinol is approved to treat anorexia associated

with weight loss in people with AIDS. CANNABIDIOL CBD was originally isolated in 1940 and its structure and stereochemistry were determined in the 1960s (Adams et al, 1940; Mechoulam et al,

2002). It was originally proposed that CBD functions as an allosteric negative modulator (antagonist) at CB1R and CB2R (Laprairie et al, 2015; Mechoulam et al, 2007; Petitet et al, 1998;

Thomas et al, 2007; Turkanis and Karler, 1986). Further studies have identified pharmacological promiscuity of CBD (Campos et al, 2012; De Petrocellis and Di Marzo, 2010; Pertwee, 2009),

therefore it is probably premature to draw firm conclusions about all of the compound’s mechanisms of action. There is mounting evidence that CBD produces many of its effects _in vivo_ via

facilitatory interactions with serotonin 1A (5-HT1A) receptors (Gomes et al, 2012; Magen et al, 2010; Resstel et al, 2009; Stern et al, 2012) in rodents. CBD reduces immobility in a forced

swim in a manner that depends on 5-HT1A activity in male rats (Sartim et al, 2016). The anxiolytic effects of intralimbic administration of CBD are blocked by an 5-HT1A antagonist in male

rats (Fogaca et al, 2014) as are the anxiolytic effects of intraperiaqueductal gray CBD on elevated plus maze in male rats (Campos and Guimaraes, 2008); these latter are unaffected by the

CB1R antagonist AM251. The evidence also extends to nonhuman primate models as the subjective effects of CBD in male rhesus monkeys are overlapping with those observed for a 5-HT1A agonist

8-hydroxy-2-dipropylaminotetralin and do not exhibit significant CB1R agonist or antagonist-like activity (McMahon, 2016). There is also evidence for activity of CBD at the _μ_ and _δ_

opioid receptors and transient receptor potential vanilloid type-1 (TRPV1) cation channels (Pertwee, 2008). CBD also increases levels of AEA due to AEA reuptake inhibition and FAAH

inhibition (Bisogno et al, 2001; Ligresti et al, 2006). Unlike THC, CBD has no psychotomimetic effects and, instead, may have antipsychotic effects. CBD may also have potential clinical

effects on anxiety disorders, movement disorders, neuropathic pain, epilepsy, and cancers as well as anti-inflammatory effects(Izzo et al, 2009). Δ9-TETRAHYDROCANNABINOL/CANNABIDIOL

Combinations of THC/CBD available for clinical use or nabiximols (Sativex) are prescription botanical drug substances developed from a 1 : 1 combination of two selected cannabis strains. One

strain (Tetranabinex) yields a high THC content and the other (Nabidiolex) yields a high CBD content. The flowers are dried, extracted, and utilized to formulate nabiximols. Nabiximols is

comprised mainly of THC and CBD (70% w/w) but also contains other phytocannabinoids derived from the plant material (Russo and Guy, 2006). The 1 : 1 combination of THC:CBD appears to allow

for higher doses of THC without increasing the risk of adverse side effects, as CBD acts to antagonize some of the psychoactive and sedative effects of THC without interfering with intended

THC effects, such as muscle relaxation and reduction of spasticity. MECHANISMS OF POTENTIAL CBD/THC INTERACTIONS PHARMACODYNAMIC EFFECTS In contrast with THC, which acts primarily as a CB1R

receptor partial agonist, the pharmacological mechanism of action of CBD is less well understood (see above). The diametrically opposing actions of CBD on CB1Rs provides a potential

pharmacological mechanism for any _in vivo_ effects that appear to oppose those of THC. As one review argues, however, CBD influence on THC-related effects may also be mediated through

non-CB1R mechanisms (McPartland et al, 2014), consistent with evidence that human cognitive effects of CBD may not depend solely on CB1R activity (Stadelmann et al, 2011). Thus, given its

wide pharmacological targets, the precise mechanism underlying CBD and THC interactions need further work to be fully understood. PHARMACOKINETIC EFFECTS Consideration of the pharmacokinetic

distribution and metabolism of THC in the presence and absence of CBD should be included in any interpretation of the interactive effects. As briefly reviewed (Zuardi et al, 2012), the

direction of CBD/THC interactions in preclinical models, particularly rodents, may depend on the pretreatment offset. In some cases, when CBD is administered 30 min (or up to 24 h) prior to

THC in rats or mice a potentiation can be observed, whereas co-administration results in blockade or amelioration of THC effects. In contrast, the beneficial effects of CBD in a monkey model

of THC-induced behavioral impairment were present when CBD was either administered simultaneously with or 30 min prior to the THC (Wright et al, 2013). The fact that significant

pretreatment intervals for CBD in rodent models potentiate the effects of THC may be related to an increase in the effective brain exposure to THC via alterations in pharmacokinetic

distribution and metabolism. Co-administration of an equal CBD dose roughly doubled brain THC levels 30 min after i.p. injection in male adolescent rats (Klein et al, 2011). CBD pretreatment

also increased plasma THC levels and the distribution of THC to the brain of mice (and vice versa), likely because CBD inhibits the hepatic metabolism of THC (Bornheim et al, 1995; Reid and

Bornheim, 2001). Prolongation of THC-appropriate responding by CBD in one rat study (Hiltunen and Jarbe, 1986) may be a consequence of this pharmacokinetic effect. The picture is

complicated even further by a suggestion that CBD/THC ratios on the order of 8 may be necessary for antagonistic properties and only 1.8 for potentiation of THC-related effects in rodents

(Zuardi et al, 1984). In contrast, CBD administered in 1 : 1–3 : 1 ratios relative to THC are effective in attenuating cognitive effects of THC in monkeys (Jacobs et al, 2016; Wright et al,

2013). Although overwhelming evidence on pharmacokinetic interactions of CBD and THC in humans are not available, one study reported that oral co-administration of 5.4 mg CBD with 10 mg THC

in humans did not alter the pharmacokinetic distribution of THC in plasma (Nadulski et al, 2005). Oral administration of 1500 mg CBD likewise did not alter the pharmacokinetics of i.v. THC

(Hunt et al, 1981). Furthermore, Karschner et al (2011a) found that maximum plasma levels of THC after oral administration (5, 15 mg, p.o.) were similar to levels obtained after oromucosal

administration of 5.4 and 16.2 mg THC combined with 5.0 and 15.0 mg of CBD, respectively. PRECLINICAL STUDIES OF CBD AND THC INTERACTIONS Cannabis and THC induce a ‘tetrad’ of behavioral

effects characterized by hypolocomotion, hypothermia, catalepsy, and analgesia reliably in rodents (Metna-Laurent et al, 2017). This preclinical model is often used to examine the effects of

cannabinoid agonists (such as THC) and drugs that may interact with it. Below, we first briefly review the effects of CBD on some of the THC-induced tetrad of effects followed by effects on

anxiety and cognition. EFFECTS OF CBD ON THC-INDUCED HYPOTHERMIA AND HYPOLOCOMOTION A profound and lasting reduction in body temperature is a consistent effect of THC in laboratory monkeys

(Matsuzaki et al, 1987; McMahon et al, 2005; Taffe, 2012) and rodents (Tulunay et al, 1981; Vann et al, 2008). THC also reduces the spontaneous activity of rats (Smirnov and Kiyatkin, 2008;

Taffe et al, 2015; Whitlow et al, 2002). These measures are two of the canonical tetrad of signs of cannabinoid activity in rodent models and thus useful to examine potential interactive

effects of CBD with THC, even though there are no established, direct parallels of these preclinical models with the effects of THC on human thermoregulation or spontaneous activity thus

far. The effects of CBD on the locomotor and thermoregulatory effects of THC in rodents may vary depending on species, dose ratios, and the experimental measure. For example, CBD both

potentiated locomotor suppression and attenuated hypothermia caused by THC when administered in 1 : 1 CBD:THC ratio in mice (Todd and Arnold, 2016) but potentiated locomotor suppression and

hypothermia caused by THC when administered in 10 : 1 or 50 : 1 ratio (Hayakawa et al, 2008). CBD appears to slightly potentiate the locomotor-suppressive and hypothermic effects of a

threshold dose of THC (0.3 mg/kg, i.v.; 10–100 : 1 CBD:THC ratio) in mice but had no influence on the effects of a 10-fold higher dose of THC (Varvel et al, 2006). CBD increased the

hypothermia and locomotor suppression caused by THC in rats when equal doses (20 mg/kg, i.p.) were administered simultaneously (Fernandes et al, 1974). In that study, CBD acted mostly to

prolong the duration of hypothermia and hypolocomotion, whereas in our recent study (Taffe et al, 2015) CBD also increased the magnitude of temperature reduction in rats when administered at

a 1 : 1 dose ratio either simultaneously or at a 15 min CBD:THC offset. CBD had negligible effects by itself on locomotor activity and body temperature in mice and rats (Fernandes et al,

1974; Taffe et al, 2015; Todd and Arnold, 2016; Wiley et al, 2005) and did not interact with the hypothermic or hypolocomotor effects of another cannabinoid, cannabinol, in male rats

(Hiltunen et al, 1988). EFFECTS OF CBD ON THC-INDUCED ANTINOCICEPTION A decrease in the sensitivity to a noxious stimulus (such as immersion of the tail in a ~50 °C warm water bath or

intraplantar injection of formalin) is another consistent effect of THC in rodents (Martin et al, 1998; Reche et al, 1996). Similar antinociceptive effects of THC or cannabis are also

reported in humans (Cooper and Haney, 2016) and nonhuman (Vivian et al, 1998) primates. This item from the tetrad of cannabinoid activity in rodents may therefore offer enhanced

translational and interpretive relevance. It has been shown that CBD potentiated the antinociceptive effects of a threshold dose of THC (0.3 mg/kg, i.v.) when administered in a 10–100 : 1

CBD:THC ratio in mice but had no influence on the effect of a 10-fold higher dose of THC (Varvel et al, 2006). Finn et al (2004) reported no effect of CBD on THC-induced antinociception in

rats when administered in 2.5–5.0 : 1 CBD:THC ratios. There is also some evidence that CBD can act via CB1, serotonin 1A, adenosine, and TRPV1 receptors to decrease nociception (Maione et

al, 2011) in anesthetized rats, but these may not synergize with the effects of THC in the awake animal. At present, the available preclinical evidence does not support a general conclusion

that CBD consistently alters the antinociceptive effects of THC. Nevertheless, these data are from rodent models. As no similar evidence is available in human or nonhuman primates at

present, it would be premature to overgeneralize the potential for CBD to alter the antinociceptive effects of THC. EFFECTS OF CBD ON THC-INDUCED ANXIETY- AND DEPRESSION-LIKE BEHAVIOR

Evidence for the effects of CBD on THC-induced anxiety- and depression-like behavior in animal models is limited. CBD potentiated the anxiogenic effects of THC in rats treated chronically in

a 1 : 1 CBD:THC ratio assessed on both an open field test and an elevated plus maze (Klein et al, 2011). In a separate study, intralimbic administration of CBD was either anxiogenic or

anxiolytic in rats depending on the behavioral assay (Fogaca et al, 2014); this could be related to the specific brain site of CBD action (Campos and Guimaraes, 2008). Further, acute

administration of CBD attenuated the THC-induced reduction in social interaction, another putative anxiety-like behavior (Malone et al, 2009). Together, these results suggest that CBD may

have mixed effects on THC-induced affective-like behaviors in rodent models, in some cases by attenuating the effect of THC. Interpretation is complicated, however, by the fact that CBD may

have effects on these measures by itself. For instance, CBD administered alone reduced marble-burying behavior in mice (Nardo et al, 2014), a putative anticompulsive effect. Given a

substantial interest in the therapeutic use of CBD and cannabis for anxiety symptoms and disorders, this may be an area of pressing interest for additional preclinical investigation. EFFECTS

OF CBD ON THC-INDUCED COGNITIVE DEFICITS Animal models are useful in probing the putative protective effect of CBD on THC-induced effects, particularly given the inherent limitations of

human studies. These limitations include being unable to control for environmental and preexisting differences in the individuals who are exposed to CBD-rich _vs_ -poor cannabis as well as

the inability to accurately determine users’ ongoing history of exposure in terms of CBD/THC dose or ratio. In contrast, preclinical investigations can use random assignment of drug-naive

populations or fully balanced repeated-measures designs to minimize such confounds. In addition, human laboratory studies can be limited with respect to the ranges of CBD and THC doses that

participants may be exposed to, unlike animal studies in which a full dose range can be assessed. An early study conducted in rhesus macaque monkeys reported that a 30 mg/kg, i.m., CBD

blocked THC-induced reductions in fixed-interval responding for food when administered 60 min prior to 0.3 mg/kg, i.m., THC in macaques but had no effect when administered prior to 1.0 

mg/kg, i.m., THC (Brady and Balster, 1980). This study also reported a minor performance impairment following 30 mg/kg, but not 10 mg/kg, i.m., CBD when administered alone. This latter is

consistent with a demonstration that CBD by itself did not have any effects on repeated acquisition accuracy in Old World monkeys over a range of 0.32–3.2 mg/kg, i.m. (Winsauer et al, 1999).

A study by our group (Taffe et al, 2015) found that CBD could ameliorate or reverse some of the detrimental effects of THC on bimanual motor coordination and object-spatial memory tasks in

macaque monkeys (Wright et al, 2013). These latter effects were observed when CBD and THC were administered in equal amount (0.5 mg/kg, i.m.) that may be critical, as CBD:THC ratios in

street cannabis do not typically exceed 1 : 1 (Burgdorf et al, 2011; Morgan et al, 2010a). Similarly, Jacobs et al (2016) showed that CBD attenuated the detrimental effect of THC (0.32 

mg/kg, i.m.) on go-trial success in a stop-signal task in male macaque monkeys. In this case, CBD was effective when administered in a 3 : 1 CBD:THC ratio. In these nonhuman primate studies,

CBD administered by itself had negligible or no behavioral effects. The use of repeated-measures designs in these two nonhuman primate laboratory studies enhances confidence that the

protective effects of CBD in the study of human recall (Morgan et al, 2010b) was due, at least in part, to pharmacological interactions and not to preexisting differences in cognitive

capability. In contrast with the effects in monkeys, the data from rodent models do not consistently confirm any ability of CBD to ameliorate the detrimental effects of THC on learning and

memory. In fact, CBD may exacerbate some of the effects of THC. CBD further impaired spatial working memory in male rats beyond that associated with THC alone when administered in a 5 : 1

ratio (Fadda et al, 2004); there was no effect of CBD when administered with THC in a 5 : 2 ratio in that study. In another study, the reconsolidation of fear memory in male rats was

disrupted by either THC or CBD with approximately 10-fold higher CBD required to produce similar effects (Stern et al, 2012; Stern et al, 2015). When subthreshold doses of THC and CBD were

co-administered, they combined additively to disrupt the reconsolidation of fear memory (Stern et al, 2015). Despite the interaction with the effects of THC, CBD does not produce any

detrimental effects on spatial working memory or delayed match-to-sample performance in rats (Fadda et al, 2004; Heyser et al, 1993; Lichtman et al, 1995) when administered by itself. These

data suggest that rodent models may not be ideal for preclinical modeling of the effects of THC and CBD on complex cognitive tasks. CBD/THC INTERACTIONS ON REWARD, AVERSION, AND

INTEROCEPTIVE CUES The subjective effects of THC in animal models appear to depend in large part on the dose. Lower doses of THC decreased the self-stimulation brain reward threshold of rats

while higher doses increased reward thresholds, indicating an aversive state (Katsidoni et al, 2013). The i.v. self-administration of THC has so far only been established in one species of

New World monkey by one laboratory (Justinova et al, 2005; Justinova et al, 2004; Justinova et al, 2003) but this may not generalize to Old World monkeys (John et al, 2017) or rats (Lefever

et al, 2014; Panlilio et al, 2010). Perhaps as a consequence of the lack of consistent self-administration models, the interactive effects of CBD and THC have only been assessed in

drug-discrimination and place-conditioning assays. CBD prevented the establishment of a conditioned place aversion produced by 10 mg/kg THC in rats when administered in a 1 : 10 or 1 : 1

(but not 3 : 1) ratio with THC (Vann et al, 2008). Interestingly, CBD did not have any effect on the subjective, discriminative stimulus effects of THC in a drug-discrimination assay in the

same study. This may be dose related, as CBD in 30 : 1 ratio did prolong the duration of THC-appropriate responding in rats (but not pigeons) in another drug-discrimination study (Hiltunen

and Jarbe, 1986). CBD also increased the potency of THC in a drug-discrimination assay in male rhesus monkeys, while not substituting for THC when administered by itself (McMahon, 2016);

However, the interactive effect was only observed with a 100 : 1 CBD:THC ratio. Thus the evidence for CBD effects on subjective effects in preclinical models is mixed but overall it appears

that very high CBD:THC ratios result in an additive or potentiating effect. The study by Vann et al (2008) is one of the few to show that CBD can attenuate the effects of THC in rodents. In

combination with the finding of Malone et al (2009) (see above), this may indicate that CBD has a specific role in ameliorating aversive subjective effects of THC in rodent models. In humans

as well, the effects of CBD on the rewarding effects of THC are mixed. Morgan et al (2010b) reported that in recreational cannabis users high CBD:THC ratio was associated with a reduced

attentional bias to cannabis and food-related cues, suggesting that it may reduce THC-associated reward. In contrast, others have reported that oral CBD at several doses had no rewarding

effects on its own nor did it alter the subjective high associated with smoked THC (Babalonis et al, 2017; Haney et al, 2016). Thus further studies are needed to examine the effects of CBD

on THC-associated reward. THC–CBD INTERACTIONS IN HUMANS Several investigators have examined the interactive effects of THC and CBD over the past few decades; however, much of this data

comes from preclinical studies. Human data on THC–CBD interactions come largely from cross-sectional population-based studies and a handful of clinical trials comparing the effects of THC

and CBD and/or examining their interactive effects. ANXIETY THC reliably increases subjective effects of anxiety acutely in a biphasic dose-related manner—with lower doses producing

decreases in anxiety and higher doses being anxiogenic. In contrast, CBD may have anxiolytic properties. A few clinical studies have examined the interaction of THC and CBD on anxiety. In

one of these earliest studies, Karniol et al (1974) examined the effects of oral CBD by itself and on THC-induced effects. Although oral CBD (15, 30, and 60 mg) did not reduce anxiety on its

own, it did reduce oral THC (30 mg) induced anxiety when given simultaneously (Karniol et al, 1974). This was replicated by Zuardi et al (1982) using a combination of oral CBD (1.0 mg/kg)

and oral THC (0.5 mg/kg). In contrast, Karschner et al (2011b) reported no effect of CBD on THC-induced anxiety. They examined the effects of two doses of oral THC (5 mg; 15 mg) with

oramucosal nabiximols (low dose: 5.4 mg THC, 5.0 mg CBD; and high dose: 16.2 mg THC, 15.0 mg CBD). All four conditions produced anxiety relative to placebo, but there were no differences

between THC alone and the combination on measures of anxiety. A series of studies have compared the effects of oral CBD (600 mg) and THC (10 mg) in healthy volunteers who were shown fearful

faces designed to elicit anxiety (Fusar-Poli et al, 2010; Fusar-Poli et al, 2009). As expected, THC alone increased subjective anxiety as well as the skin conductance response to the fearful

faces while CBD alone trended toward a reduction in anxiety. Furthermore, CBD reduced the blood-oxygenation-level-dependent (BOLD) signal in the amygdala and the anterior and posterior

cingulate cortex during the viewing of the fearful faces and disrupted connectivity between the amygdala and anterior cingulate during this task. The CBD-associated reduction in BOLD

response was correlated with the reduction in skin conductance response, suggesting that this underlies CBD’s anxiolytic effects. Of note, though, these studies did not examine the

interactive effects of THC and CBD. Thus CBD may attenuate the anxiolytic effects of THC acutely although the data remain mixed. Further studies are required to understand the potential

dose/route-related interactive effects of THC and CBD on anxiety and the neural substrate of CBD’s anxiolytic effects. COGNITION The endocannabinoid system is important to cognitive

processes, including learning and memory (Marsicano and Lafenetre, 2009), and prolonged use of cannabis (Meier et al, 2012) has been associated with cognitive impairment. Meier et al (2012)

reviewed records of 1037 individuals born between 1972 and 1973 in New Zealand. Neuropsychiatric testing was conducted before age 13 years and again at age 38 years. At several yearly

intervals, participants were followed and questioned about their cannabis use. These who reported persistently using cannabis at ⩾3 interval times had a full-scale intelligence quotient that

was about 10 points lower at age 38 years than those that reported never using cannabis or never regularly using cannabis. Acute exposure to THC as well (D'Souza et al, 2004;

Ranganathan and D'Souza, 2006) produces acute, transient, and dose-related cognitive impairments in executive function, abstract ability, and decision making. The most robust effects

are on verbal learning, short-term memory, working memory, and attention (Hart et al, 2001; Heishman et al, 1990; Hooker and Jones, 1987; Leweke et al, 1998; Marks and MacAvoy, 1989; Miller

et al, 1977; Ranganathan and D'Souza, 2006), consistent with effects in rodents and nonhuman primates (Lichtman et al, 2002; Wilson and Nicoll, 2002). CBD by itself does not appear to

produce cognitive deficits. On the other hand, some studies suggest that CBD may decrease the cognitive impairing effects of THC, although the results are mixed. Morgan et al (2010b) have

conducted a series of cross-sectional studies examining the subchronic and acute effects of cannabis in recreational and heavy cannabis users. Cannabis-using individuals completed the same

verbal memory at baseline and then returned 7 days later with their own supply of cannabis and completed the verbal memory task while intoxicated (Morgan et al, 2010b). Cognition was

examined at baseline when subjects were not acutely intoxicated as well as after acute cannabis ingestion. Samples of cannabis smoked were assayed for the levels of THC and CBD. In this

study, specimens with higher levels of CBD were associated with better prose recall (Morgan et al, 2010b). In a follow-up study, recreational and heavy users were examined while not

intoxicated (subchronic THC exposure). Hair samples were obtained to assay for the THC/CBD levels. Daily cannabis users with high hair THC concentrations performed worse on verbal recall.

Although CBD was not associated with a difference in prose recall in this sample, the presence of CBD was associated with better recognition recall (Morgan et al, 2012). Taken together,

these data suggested that the presence of CBD in recreational cannabis may protect against the memory-impairing effects of THC. However, it must be noted that these cross-sectional studies

are limited by self-report with regard to dose, frequency, and potency of cannabis used, possible relationship of type of cannabis with individual factors (eg, it cannot be determined

whether individuals who sought more perceptual-altering effects used cannabis with greater THC content or vice versa), and recall bias regarding the types of symptoms experienced.

Furthermore, the studies relied on individuals who continued to use cannabis and therefore possibly excluded those who may have had worse experiences. Experimental laboratory-based studies

can address some of these limitations of epidemiological studies and have also examined the effects of THC and CBD on cognition in humans. In a series of experiments, the effects of oral CBD

(600 mg) and oral THC (10 mg) in a healthy cohort have been examined on verbal memory, executive function, and attention (Bhattacharyya et al, 2010; Borgwardt et al, 2008). Interestingly,

in these studies, neither CBD nor THC significantly affected performance on cognitive tasks in these studies, although there were differences in brain-activation patterns as described below.

It is possible that the lack of effects on performance reflects load/timing of the task or the dose/oral route of THC and CBD. Of note, these studies compared the effects of THC and CBD but

did not examine the interactive effects. In contrast, Englund _et al_ (2013) pretreated healthy subjects with CBD (600 mg PO)/placebo prior to receiving i.v. THC and demonstrated a

protective effect on CBD on THC-induced verbal learning deficits. Wade et al (2003) evaluated the effects of both THC and CBD in a clinical population of 24 individuals with a range of

neurological symptoms, including multiple sclerosis, spinal cord injuries, brachial plexus damage, and neurofibromatosis. Individuals were given a 2.5 mg sublingual dose of CBD and then

evaluated on the Short Orientation-Memory Concentration (SOMC) test (Wade and Vergis, 1999). CBD did not affect memory and concentration when administered alone but reversed the deficits on

the SOMC seen with sublingual THC (2.5 mg). The effects of cannabinoids on social cognition have also been evaluated. A large randomized double-blind placebo controlled crossover study of 48

cannabis users (_n_=24 light users, _n_=24 heavy users) examined the effects of oral CBD (16 mg), oral THC (8 mg), placebo, or the combination of THC+CBD on an emotional facial recognition

task (Hindocha et al, 2015). The task consisted of showing a range of emotions of varying intensities from 20 to 100%. The results found that CBD improved facial recognition at the 60%

emotional intensity, while THC impaired facial recognition of ambiguous faces at 40% intensity. The combination of THC+CBD resulted in no difference in emotion recognition from placebo,

suggesting that CBD attenuated the THC-induced impairments. DATA FROM NEUROIMAGING STUDIES Brain imaging studies employing functional magnetic resonance imaging (fMRI) and electrophysiology

outcome measures provide an opportunity to assess the effects of THC/CBD in the brain during various perceptual/cognitive tasks. One of the earliest reported fMRI studies on the interactions

of THC and CBD examined the effects of oral THC 10 mg, oral CBD 600 mg, and placebo on a go/no go task on three separate test days in 15 healthy volunteers in a double-blind randomized

study (Borgwardt et al, 2008). In general, performance was similar on the task during all 3 test days. However, CBD decreased the BOLD response in the left insula and left

superior/transverse gyri relative to placebo and THC decreased the BOLD response in the right inferior frontal gyrus, anterior cingulate gyrus, and bilaterally in the precuneus. THC also

increased the BOLD response in the right hippocampus/para hippocampal gyrus, temporal gyrus, caudate and fusiform gyrus, and in the left posterior cingulate gyrus, suggesting that THC may

specifically target areas involved in response inhibition, unlike CBD. The same research group has published several other fMRI studies with oral THC 10 mg, oral CBD 600 mg, and placebo in

healthy volunteers (Bhattacharyya et al, 2015; Bhattacharyya et al, 2010; Fusar-Poli et al, 2010; Fusar-Poli et al, 2009). Fusar-Poli et al (2009) evaluated the BOLD response related to THC

and CBD during a fearful face task. Relative to placebo, CBD decreased activation in the left medial temporal region (including the amygdala and anterior para hippocampal gyrus), the

anterior and posterior cingulate gyrus, the left middle occipital gyrus, and the right lobe of the cerebellum. THC increased BOLD response in the left precuneus and bilaterally in the

primary sensory cortex, but decreased BOLD response bilaterally in the middle frontal gyrus and in the posterior cingulate gyrus. A connectivity analysis showed that CBD but not THC

decreased forward connectivity with the amygdala and the anterior cingulate cortex (Fusar-Poli et al, 2010), suggesting that CBD may target a neural mechanism underlying anxiety disorders or

posttraumatic stress disorder. Bhattacharyya et al (2010) demonstrated that THC and CBD had diametrically opposite effects on BOLD response relative to placebo in the striatum during verbal

recall, in the hippocampus while conducting an inhibition task, in the amygdala during a fearful face task, in the superior temporal cortex during a verbal listening task, and in the

occipital cortex during a visual processing task. During an oddball salience processing task, THC and CBD also had opposite effects on functional connectivity between the dorsal striatum,

prefrontal cortex, and hippocampus. These studies show opposing actions on regional activation by THC and CBD but need replication given their relatively small sample size. Significantly

larger fMRI studies with behavioral outcomes will be required to continue to determine the neurobiological interactions of THC and CBD with acute administration. To summarize, limited

epidemiological and experimental data suggest that CBD may have a protective effect against THC-induced learning deficits. Further studies with larger sample sizes are needed to examine

dose-related acute as well as chronic effects and to examine the interactive effects of CBD on THC rather than comparative effects on patterns of brain activation. PSYCHOSIS Separate from

the subjective effects of feeling high, relaxed, or altered, cannabis extracts as well as THC alone, in susceptible individuals, can produce subjective effects, including suspiciousness,

paranoia, conceptual disorganization, and perceptual alterations, that can be measured on standardized rating scales such as the Positive and Negative Syndrome Scale (PANSS), Clinician

Administered Dissociative Symptoms Scale, Psychotomimetic States Inventory, Brief Psychiatric rating scale, etc. (D'Souza et al, 2004; Kleinloog et al, 2012; Liem-Moolenaar et al, 2010;

Morrison and Stone, 2011; Morrison et al, 2009). In contrast to THC, CBD does not produce acute psychotomimetic effects and in fact may have potential antipsychotic effects (Iseger and

Bossong, 2015). The interaction of THC and CBD on psychosis-like symptoms is one that has been extensively studied in humans. Schubart et al (2011) conducted a web-based survey where

information on the amount and the type of cannabis consumed by individuals (_n_=1877) was collected and psychiatric symptoms were evaluated using the Community Assessment of Psychic

Experiences (CAPE). Self-reported use of cannabis with high CBD content was correlated with lower CAPE-positive symptoms (_p_<0.001). Similarly, a linear regression showed a positive

relationship of THC/CBD ratio with positive symptoms (_p_<0.001). In two separate population-based studies by Morgan and colleagues, greater psychosis proneness was observed in

individuals using THC alone _vs_ THC+CBD using the Oxford Liverpool Inventory of Life Experiences (Morgan and Curran, 2008) and the Schizotypal Personality Questionnaire (Morgan et al,

2012). CBD may have a protective influence on long-term effects from frequent cannabis use. However, as discussed above, as these are based on a retrospective population analysis, it is not

known if individuals with higher psychosis proneness are more likely to use cannabis with lower CBD content. Several human laboratory studies have compared the effects of THC and CBD on

psychotomimetic effects and a few have also examined their interactive effects on this parameter. As expected, THC acutely produced intoxication and positive psychotic symptoms in healthy

volunteers, whereas CBD alone did not. Furthermore, pretreatment with CBD was associated with lower acute THC-induced psychotomimetic effects, including paranoia (Bhattacharyya et al, 2010;

Englund et al, 2013). Consistent with this, in one of the first human laboratory studies of CBD on psychosis, nine healthy individuals participated in a visual processing binocular depth

perception task (Leweke et al, 2000). Binocular depth perception is a model of illusionary perception and is found to be altered in people with schizophrenia (Schneider et al, 2002). The

study found that oral CBD (200 mg) had no effect on visual processing on its own. However, CBD reversed the acute impairment in binocular depth perception by the CB1R agonist nabilone. The

experimental and epidemiological data suggest that CBD reduces the psychosis-like effects of THC. These data as well as others suggesting endocannabinoid system alterations in psychosis give

support to the hypothesis that CBD may have antipsychotic effects on its own—a hypothesis that has been tested in clinical populations as discussed below. An early case report (Zuardi et

al, 1995) and a case series (Zuardi et al, 2006) in patients with psychosis also supported the antipsychotic potential of CBD. Leweke et al (2012) in a 4-week randomized double-blind study

of acutely psychotic patients with schizophrenia compared the effects of CBD 800 mg/day (_n_=21) with amisulpride 800 mg/day (_n_=21). Treatment with both medications resulted in a

clinically and statistically significant decrease in PANSS total, positive, negative, and general scores. However, no significant difference was seen in PANSS change scores between CBD and

amisulpride. CBD was well tolerated and resulted in significantly less extrapyramidal symptoms, weight gain, and prolactin increase than amisulpride. Although not placebo controlled, this is

the first controlled study suggesting CBD could be an effective antipsychotic in the treatment of schizophrenia. EFFECTS OF NABIXIMOLS: INTERACTIONS OF CBD AND THC The putative beneficial

effects of CBD in attenuating the unwanted psychotomimetic, anxiogenic, or cognitive impairing effects of THC have been harnessed in nabiximols. Nabiximols is approved for treatment of

symptoms of spasticity in adults with multiple sclerosis (MS) in several countries (Vermersch, 2011) and is available as an oromucosal spray (Russo and Guy, 2006) as described above. In a

placebo-controlled crossover study (Aragona et al, 2009) of 17 individuals, MS patients were evaluated after nabiximols administration. No significant deficits in cognition were detected

_vs_ placebo. However, these results need to be taken with caution due to the small sample size and short duration of treatment. In a larger crossover study, multiple doses of nabiximols

(10.8, 21.6, and 43.2 mg THC) was compared with placebo and the synthetic THC dronabinol (20, 40 mg) in recreational cannabis users (Schoedel et al, 2011). Few significant differences were

seen between nabiximols and dronabinol on psychomotor speed, attention, and short-term memory. One concern of the study is the lack of difference in cognitive outcomes with dronabinol and

placebo. Only reaction time for the short-term memory test was different for dronabinol 40 mg and placebo. The results suggest the doses of THC used in this study do not cause significant

cognitive deficits that could be reversed by CBD. To summarize, clinical data on THC-CBD interactions suggest that the data are mixed, although some studies suggest that CBD may attenuate

some effects of THC such as anxiety, cognitive deficits, and psychosis. The literature is limited not only by the scarcity of published studies but also by confounds such as recall bias in

self-reported consumption of cannabis, variability in the amount, duration and amount of prior exposure to cannabis and cannabinoids even within the same individual over a given time,

difference in methodology and outcome measures over studies, inadequate assessment of dose response, and reliance on self-report for subjective outcome measures. Despite this, there is a

growing interest in the ability of CBD to attenuate unwanted effects of THC (eg, Sativex). Preclinical studies may be better designed to address some of these limitations and to examine

THC–CBD interactions in a systematic manner as reviewed above. FUTURE DIRECTIONS As discussed above, the existing clinical and preclinical data suggest that CBD may attenuate several acute

and chronic effects of THC. However, the existing literature has several limitations that need further study as discussed below. ACUTE DOSE–RESPONSE RELATIONSHIP Clinical data on the

interactions between THC and CBD rely on a very limited dose range of CBD. Further, several of the existing studies on the acute interactions of THC and CBD include oral CBD that is limited

by poor and variable bioavailability. Thus future studies should include a wider dose range of CBD and alternate routes of administration. EFFECTS OF CBD ON CHRONIC THC EXPOSURE Both

recreational and putative therapeutic human use of cannabis involve repeated exposure, yet the majority of the information on potential interactive effects of CBD and THC from preclinical

models results from acute dosing. In the one noted exception, Klein et al (2011) found that chronic co-administration of CBD and THC produced more anxiety-like behavior and a greater

reduction in social interaction compared with chronic THC alone. Additional studies of chronic dosing would be critical to support translational inferences regarding the potential

interactive effects of CBD and THC. As a related issue, the majority of human cannabis consumption is via inhalation and yet only limited information exists on the preclinical effects of

inhaled THC (Ali et al, 1991; Lichtman et al, 2000; Lichtman et al, 2001) and there is as yet none on the effects of inhaled CBD. Recent development of techniques to deliver cannabinoids to

rodents using e-cigarette or Volcano technologies that are increasingly popular with human cannabis users are highly promising for future investigations (Manwell et al, 2014; Nguyen et al,

2016). SPECIES DIFFERENCES One of the greater limitations in translating preclinical research into predictions for human exposure to CBD, THC, and the combination lies in what appear to be

significant order differences in the results from nonhuman primate and rodent laboratory models. The clearest parallels to the memory-sparing effects of CBD in the studies by Morgan and

colleagues (Morgan _et al_, 2011; Morgan et al, 2010b) derive from the results from nonhuman primate models (Jacobs et al, 2016; Wright et al, 2013). In contrast, most of the behavioral

rodent studies suggest that CBD either fails to attenuate the effects of THC or instead potentiates such effects. Unfortunately, the relative paucity of information from nonhuman primate

models on interactive effects of CBD and THC make definitive conclusions about possible order differences difficult. In addition, the route of administration may be a critical contributor to

apparent species differences if the metabolic effects on THC and CBD following i.m. or i.p. administration vary significantly within or across species. This consideration raises the further

concern that, while humans frequently consume cannabis by inhalation, preclinical models of THC inhalation are only infrequently used (eg, Ali et al, 1991; Nguyen et al, 2016; Varvel et al,

2006). This is an area in which understanding would benefit greatly from additional research efforts. POLICY IMPLICATIONS As various municipalities and legislative bodies in the United

States, Canada and other countries grapple with enacting policy to shape the use of both medical and recreational cannabis, the constituents of that cannabis (most importantly, the

behaviorally active constituents) may come under regulatory guidance. Although this review focused on THC and CBD, there are other pharmacologically active cannabis constituents that may

also be important to study for properties relevant to regulation and personal decision making. For example, if CBD (or another cannabis constituent) is found to have negligible negative

effects on the main desired target of cannabis (such as the recreational ‘high’ or pain/spasticity), while providing some beneficial effects (such as sparing cognition), then a THC+high-CBD

strain of cannabis may be warranted. The initial findings of Morgan and colleagues are promising, but it is difficult to establish the potential benefit of such approaches as typical strains

of recreational market cannabis are limited in CBD:THC ratio (Burgdorf et al, 2011; Morgan et al, 2010b). A somewhat greater diversity of cannabis is emerging, particularly in

medical-marijuana-permitting jurisdictions and some of this cannabis may be focused on high CBD with low THC content (Kolikonda et al, 2016; Maa and Figi, 2014). Thus future epidemiological

studies may better address interactive effects of CBD and THC, particularly in the context of regular consumption. Relevant to THC/CBD interactions, whether CBD has an effect on the unwanted

effects of THC is not the only important question. If, for example, CBD is found to potentiate the medically desired effects of cannabis (eg, analgesia), then this may permit lower THC

content strains or products that contain substantial amounts of CBD to succeed. There are indeed recent efforts to validate high CBD/low THC strains of cannabis to treat refractory seizures

in children (O'Connell et al, 2017; Sulak et al, 2017). Thus a better understanding of THC/CBD interactions on several domains may help identify strains with specific ratios for

different indications. Clearly, further work is needed to definitively establish these interactions in preclinical and clinical research so that future policy decisions may rely on

scientific findings as much as possible. SUMMARY As has been made clear by this review, there are currently many unanswered questions about the potentially interactive effects of the

cannabis constituents, CBD and THC. There are studies in humans, nonhuman primates, and rodents that suggest some potential for CBD to attenuate the effects of THC, with the most direct

parallels in the memory/cognition-protecting effects observed in recreational users and verified in monkey findings. There are also indications, primarily from preclinical research, that CBD

may, in fact, potentiate some effects of THC. The mechanism of such interactions is unknown given the diversity of potential pharmacological targets of CBD and a propensity for CBD to

interfere with the distribution, metabolism, and/or excretion of THC. Ultimately, there is a profound lack of research on the manner by which CBD may affect the actions of THC across a wide

range of behavioral and physiological effects. This paucity is particularly acute when attempting to compare across human and nonhuman experimental studies that may use very different

behaviors to assess cannabinoid activity. Cannabis use is expanding in many regions of the world as prohibitions against recreational use are relaxed and as permission for medical use grows.

In the medical context particularly, there are claims of efficacy for CBD, THC, and other constituents that are only poorly evaluated or understood at present. This is particularly acute

when it comes to potentially interacting effects of key cannabis constituents, such as THC or CBD. Personal and public decision making on the use of cannabis would be improved by additional

research that can evaluate claims and establish potential mechanisms of action. FUNDING AND DISCLOSURE Preparation of this review was supported in part by grants provided by the U.S.

National Institutes of Health (R01DA035482; R44DA041967) and VA Connecticut Healthcare System, neither of which had any further input on the content or decision to publish. MR currently

receives research grant support administered through Yale University School of Medicine from Insys Therapeutics. The other authors declare no conflict of interest. REFERENCES * Adams R, Hunt

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Int Pharmacodyn Ther_ 269: 12–19. CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Psychiatry, Yale University School of Medicine,

New Haven, CT, USA Douglas L Boggs & Mohini Ranganathan * VA Connecticut Healthcare System, West Haven, CT, USA Douglas L Boggs, Daralyn Morgenson & Mohini Ranganathan * Department

of Neuroscience; The Scripps Research Institute, Jacques D Nguyen & Michael A Taffe * The Scripps Research Institute, La Jolla, CA, USA Jacques D Nguyen & Michael A Taffe Authors *

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Ranganathan. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Boggs, D., Nguyen, J., Morgenson, D. _et al._ Clinical and Preclinical Evidence for

Functional Interactions of Cannabidiol and Δ9-Tetrahydrocannabinol. _Neuropsychopharmacol._ 43, 142–154 (2018). https://doi.org/10.1038/npp.2017.209 Download citation * Received: 04 April

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