A review article published in the British Journal of Pharmacology earlier this year suggests that cannabidiol (CBD), the major non-psychoactive component of cannabis, may have utility as an adjunct to treatment approaches for anxiety disorders such as PTSD and substance abuse disorders. This is mainly due to the way CBD interacts with learning and memory processes. But first, a look at CBD’s anti-anxiety effects and a brief overview of classical conditioning.
Animal studies have clearly established CBD’s anxiolytic effect using tests which measure defensive behaviors in response to a variety of threatening or unpleasant stimuli. Broadly, these anxiolytic effects occur at low and medium doses, but not at high doses. These anxiolytic effects have also been shown in human studies in which participants are exposed to anxiety-provoking stimuli, as well as in studies of people with anxiety disorders.
While CBD has many effects in the brain, only two of these mechanisms seem to be directly related to its anxiolytic effects. The first is the direct activation of serotonin 5-HT1A receptors in the periaqueductal gray, the bed nucleus of the stria terminalis, and the infralimbic cortex.
The second relevant mechanism of action is the indirect activation of cannabinoid CB1 receptors. CBD achieves these by interfering with the reuptake and metabolism of anandamide, one of the endocannabinoids produced by the body, resulting in an increase of serum and hippocampal anandamide levels.
Fear learning and classical conditioning
Classical conditioning refers to a kind of learning by association where a neutral cue or context (unconditioned stimulus or ‘US’) is repeatedly presented alongside a desirable or undesirable event (conditioned stimulus, CS). Eventually, the organism forms a strong association between the US and the CS such that the CS presented on its own now triggers the same reaction that the US does. This process is referred to as conditioning.
For example, if a small electric shock (US) is repeatedly applied to a rat at the same time that a neutral sound (CS) is played, the rat will eventually respond to the sound (CS) on its own as it would have to the shock.
This fundamental mechanism is at play in anxiety disorders as well as substance use disorders. For example, a veteran with PTSD may have a strong association between loud noises and a vital threat, such that fireworks, previously indicative of celebration, may now trigger intense anxiety and feelings of imminent danger. In a similar fashion, a person who has overcome a drug dependency may feel a strong craving or be more inclined to relapse if they are exposed to a person or environment that was strongly associated with their past drug use.
Once the association has been forged, it is encoded into long-term memory, a process called “consolidation.” Re-exposure to the CS retrieves the association from memory, creating a window within which the memory can be maintained or updated before reconsolidation takes place. This is the principle by which extinction therapy works—repeated or prolonged re-exposure to the CS can, over time, create a new association between the CS and the lack of US, which competes with the original association.
Thus, the process of classical conditioning provides several points for potential intervention: conditioning, consolidation, retrieval, and reconsolidation.
Treating anxiety-related and substance-use disorders
CBD appears to affect the formation and expression of fear memories in a way that may have clinical relevance. Animal studies have shown that administration of CBD at the time of retrieval diminishes the fear response. It also appears to impact the formation of the fear memory—when CBD was acutely administered to rats alongside the initial formation of a fear memory, these rats showed a diminished fear response during later retrieval compared to the group that did not receive CBD. However, the research is unclear about the effect of repeated CBD administration, with some studies showing that repeated administration actually facilitated learning while others showed that it had no effect.
CBD does seem to show clear promise in the extinction of fear memories. In rats that were undergoing contextual fear extinction sessions (that is, the extinction of fear associated with a specific room, chamber, or other context), CBD administered prior to the session displayed greater extinction of the fear memory compared to rats that did not get CBD. This approach was particularly effective for strong fear memories, while CBD appeared to impair the extinction of weaker conditioning.
In addition to its effects on extinction, CBD also seems to disrupt the reconsolidation of conditioning, regardless of whether the memories are new or old. However, studies showed that it needs to be administered immediately after memory retrieval to have this effect.
While there are many studies that have explored the interaction between CBD and fear memory processing, far fewer studies have evaluated the potential for CBD to affect addictive drug memory processing.
In one rat study which attempted to cause a heroin relapse by presenting cues associated with heroin, rats who had received CBD 24 hours beforehand were less likely to relapse, an effect which lasted up to 14 days following CBD administration. This finding suggests that CBD may be useful for preventing relapse to opiate addiction in humans.
This effect may not be limited to opiates, as similar but more modest findings have been replicated in a study of tobacco smokers. Smokers who were instructed to self-administer CBD when they had a craving reduced the number of cigarettes smoked compared to the group that did not administer CBD, but this effect did not extend beyond the time of CBD administration.
These effects of CBD on fear memory processing make it a good candidate for testing as an adjunct to psychological or behavioral therapies in treating PTSD and phobias. With regards to its potential as an adjunct to therapies for drug dependence, further studies will be required before a clearer and more consistent picture emerges as to its possible applications.
For interested readers, the review article can be found here.