Lately cannabidiol (CBD) has been hogging the therapeutic limelight; it’s an anti-inflammatory, an anti-tumor, and it helps inhibit psychotic behavior. THC, the psychoactive chemical most prized in the recreational community, has been deemed to have less potential for therapeutic use, in part due to the side effects that accompany dosage. For this reason, much clinical research has shifted toward CBD and away from THC. However, THC’s psychedelic, mindset-altering activity is exactly what lends it therapeutic benefits in situations involving memory and fear consolidation.

Fear memory consolidation occurs after a painful memory is acquired, and is the process through which that memory is stabilized in the brain. Although not all aspects are understood, we know that the consolidation process involves strengthening synapses the brain deems useful and paring down synapses the brain deems less useful. Aside from this process, memories are also converted from being dependent on the short-term memory region of the brain to being independent of this region and placed in a longer-term storage area. However, memories are also capable of being re-consolidated and forming new associations. To put all of this into practical terms, someone suffering from Post-Traumatic Stress Disorder (PTSD) stemming from military service may initially suffer injury while hearing an unrelated stimulus, such as a warning siren. The brain may then associate the pain and injury with that sound. Unfortunately, as the individual returns to normal society and hears similar sounds, such as ambulance sirens, those memories and fears may resurface, causing additional pain, aggression, and a host of other cognitive issues. Each time a siren is heard, the memory is retrieved and re-consolidated. Interruption of that re-consolidation would ideally allow the initial injury to be detached from the siren sound, enabling the individual to live more freely. Unfortunately, classical therapy is not observed to be highly effective at treating PTSD.

Observing that an abnormally high number of patients with PTSD also use cannabis, research groups have speculated that this connection is evidence of self-medication for those with deeply consolidated fears that need to be attenuated. While many studies focus on the therapeutic outcomes of patients using cannabis (as discussed in our first article about PTSD), one research group chose to take a more neuro-cognitive approach by forcing rodents to develop fear memories and then testing the lingering effects of those memories. To do this, researchers built a contraption of two rooms, Chamber A and Chamber B. Chamber A contained a gridded floor wired to deliver electric shocks to mice in the chamber, while Chamber B was designed to be visually reversed, with a gridded ceiling that did not deliver electric shocks. Researchers first let mice habituate to Chamber A, and then proceeded to shock the mice before returning them to cages. This represents the initial acquisition of a fear memory. After a length of time, the mice were placed back in Chamber A and observed (without foot shocks), then given THC at varying doses (or placebo without THC) and then placed back in Chamber A and observed. This process represents the fear memory being reactivated, as mice remember being in a room where shocks were applied. Finally, mice were placed in Chamber B. Placing the mice in Chamber B at the end allowed for a control to see how the mice behaved when not exposed to something that would cause the fear memory to resurface.

To test the effect of the lingering fear memory, trained, un-biased observers with no knowledge of the test groups watched videos of mice in the chambers and carefully recorded freeze times. Freeze times are the total cumulative lengths of times that mice stopped all motion (think of a deer in headlights, paralyzed with fear). The concept here is that mice with strong connections between being shocked and being in the shock room will freeze much more often, whereas mice that have dissociated the room from the shock will freeze less often. Through this setup, the research group found that administration of THC in substantial doses substantially decreased the freeze time of mice when re-exposed to the shock room, as compared with mice that received placebo injections of no THC. However, mice showed no significant difference in behavior in Chamber B (the no shock room), confirming that the freeze time behavior is specifically associated with the fear memory and is not an overall movement decrease.

Having confirmed the ability of THC to reduce fear reconsolidation, the group went on to perform several more varieties of the test to answer questions about the specific method through which these effects are achieved. In the first alteration, mice were applied THC during exposure to Chamber B (no shock room), as opposed to Chamber A. This produced no observable difference, indicating that to be effective, THC must be applied during the conditions that re-elicit the fear memory, in this case, being in the shock room. Should this effect be observable in humans, the equivalent would be that THC must be applied while the PTSD patient is re-hearing the siren sound. THC taken outside of this context may have no effect. After this test, researchers applied another variant where some of the mice were pre-treated with a cannabinoid receptor antagonist that blocks cannabinoid receptors from receiving THC. In this test, mice received no benefit from being treated with THC, confirming that whatever effects are occurring are occurring through the activation of cannabinoid receptors. Researchers then extended testing to 22 days after the initial shock application to test longevity of effects and found that the effects held over time and without re-administration of THC. This aspect is important, because it means that therapeutic effects are not limited to the period that THC is still in the bloodstream, provided it was administered at least once during the fear environment. Finally, researchers noted the lowest effective dose of THC and administered only 1/3rd of this amount (so less than should actually be effective) along with a dose of CBD. Surprisingly, this combination was as effective as larger doses of THC, indicating that there may be some synergistic effect of THC and CBD taken together. However, patients should note that the combination was CBD-heavy, unlike the high THC, low CBD content found in most cannabis strains.

This does not necessarily mean that THC will be incorporated into the treatment regimen of PTSD patients. As always, human tests are the ultimate analysis of whether the treatment will be effective in real life. However, it does represent a large step in fear memory and PTSD research. At the moment, no pharmacological treatments are available that disrupt memory reconsolidation and have no harmful side effects. THC or a combination of THC and CBD seem to be the perfect solution here. Moreover, at the very least, whether this specific chemical will end up being used, these experiments indicate that a chemical solution should be possible for future fear memory treatment.

 

 

Works Cited

Christina Stern, Lucas Gazarini, et. al. (2014) Delta-9-Tetrahydrocannibinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption. European Neuropsychopharmacology (2015) Published Online.