Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

Abstract

D-9-tetrahydrocannabinol (D-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether D-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by D-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of D-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered D-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by D-9-THC. D-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by D-9-tetrahydrocannabinol. D-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of D-9-THC.

Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis

“…Furthermore, there was no indication that cannabis bred to contain different levels of CBD (0.2, 1.0%) altered the subjective, physiological, or performance effects of smoked cannabis with varying THC concentrations (1.8, 3.6% THC; Ilan et al, 2005). Although CBD does not reduce THC's positive subjective effects (ie, ratings of 'high' or 'stoned'), there is evidence that it may reduce anxiety or transient psychosis-like side-effects of THC observed in infrequent cannabis smokers or when administered alone to patients with anxiety or psychosis (Bhattacharyya et al, 2010;Crippa et al, 2011;Bergamaschi et al, 2011a, b;Leweke et al, 2012;see Niesink and van Laar, 2013). Older studies report that CBD changes the type of psychological reaction induced by THC in infrequent cannabis smokers, reducing their anxiety and thereby rendering THC more enjoyable (eg, Karniol et al, 1974).…”

“…Mean peak plasma concentrations of CBD (77.9 ng/ml) following administration of CBD (800 mg) exceeded those from studies demonstrating a significant CBD effect on mood or fMRI activation. For instance, peak plasma concentrations following administration of CBD (600 mg) administration ranged from 17.0 ng/ml (Winton-Brown et al, 2011 ;Bhattacharyya et al, 2010, Borgwardt et al, 2008Fusar-Poli et al, 2009) to about 55 ng/ml (Englund et al, 2013). Although cannabis effects peaked 120 min after CBD administration in the current study, and 60 min earlier than peak CBD concentrations, there was no indication that CBD attenuated cannabis effects at any point during the 2-h cannabis time course (Figures 1 and 2); note, we did not assess whether CBD altered the metabolism of THC, as there is little to suggest that this occurs in humans (Hunt et al, 1981;Englund et al, 2013;Agurell et al, 1981;Karschner et al, 2011a, b).…”

“…The broad and upper range of CBD doses were chosen to ensure pharmacological activity given its known poor oral bioavailability of o20% (Mechoulam et al, 2002). Timing of cannabis administration was designed to coincide with time-to-peak (T max ) plasma CBD concentrations estimated at 1-2 h (Agurell et al, 1981;Bhattacharyya et al, 2010;Winton-Brown et al, 2011;Englund et al, 2013).…”

Cannabidiol inhibits synaptic transmission in rat hippocampal cultures and slices via multiple receptor pathways

“…These data offer some clues into the mechanisms through which CBD may be reducing regional brain activity Bhattacharyya et al, 2010) and epileptiform activity (Jones et al, 2010) as reported in recent studies and suggest that further investigations into the actions of CBD in the CNS are required in order to fully elucidate its therapeutic potential.…”

Conformational Study of Cannabinoid Docking to Cannabinoid Receptor 1 (CB1) via Linear and Nonlinear Circular Dichroism

“…THC, the main psychoactive component of marijuana attributed with the euphoric effect [4,5], is also reportedly responsible for the stimulation of appetite [6,7] and reduction of pain [1] as well as increased anxiety, paranoia and impairment of memory, [8] among many other effects. While CBD is likewise credited with appetite stimulation and pain relief [9], it has been shown to have opposing psychological effects [10]. In fact, when administered together, CBD has been shown to reduce the psychotropic effects of THC [11][12][13], making it a potentially exceptionally useful therapeutic agent for psychological disorders.…”