cbd vs ssri for anxiety

December 15, 2021 By admin Off

So, while these drugs may be effective for many patients, some do not respond favorably and actually seem to get worse with common side effects (not to mention many are highly addictive). Many patients do not see any results or cannot tolerate the harmful side effects these drugs include so we are seeing a big rise in non-pharmaceutical solutions, especially as new research on them emerges — including cannabis, and particularly cannabidiol.

We’ve seen Dr. Sanjay Gupta on CNN and recently on the Dr. Oz show explaining the science behind cannabis, how it works on the body, and why he thinks it is a promising plant medicine alternative for America. “For the past 40 years, we have been told that cannabis turns the brain into a fried egg, and now there is scientific evidence that it can do just the opposite… It can heal the brain when nothing else does.” Gupta writes to Sessions.

CBD has gained much popularity in recent years because of the amount of interest among not only consumers but clinicians and scientist as well. With over 20,000 plus scientific articles on the cannabis plant, there is much reason to believe that the medical uses for this plant are here to stay.

Some 40 million people in the United States suffer from anxiety disorder and about one-third of them get treatment for it.

There is much research to support that anxiety and depression can also be the result of inflammation and particularly inflammation in the gut. We hear the term “inflammation” a lot when dealing with chronic health conditions. Chronic, low-grade, systemic inflammation has been directly implicated in just about every chronic disease; brain conditions are no exception. This low-level inflammation can manifest as problems like anxiety, depression, and brain fog.

We all feel stress and anxiety at some points in our lives. To a certain degree, there is a healthy amount of stress that helps us take action or defend ourselves in certain situations. We evolved a defense system called our sympathetic nervous system aka “fight or flight” that allows us to do just that in dire situations.

Anandamide is a neurotransmitter that is produced when we meditate, go for a run, or eat chocolate and is another cannabis-like chemical that is part of the endocannabinoid system.

This is what helps the body have an alkaline balance. When our bodies are inflamed we have higher levels of acidity thus making CBD powerfully anti-inflammatory for the body.

This chemical calms down anxious feelings and makes extreme pain seem distant and irrelevant. Anandamide is not only elevated when we take CBD but it actually inhibits the enzyme that is responsible for breaking it down. Less FAAH means more anandamide is able to stay in the body longer, which means a lifted mood, more euphoria, and bliss. At the same time, a lack of anandamide could be linked to depression and anxiety.

Cannabinoids are chemical messengers of the ECS system and they modulate the way we make hormones, the way we run our neurotransmitters in the brain as well as our immune system. They are predominantly in the brain, the central nervous system, and the peripheral immune cells.

We all have what’s called the endocannabinoid system which is the largest neurotransmitter system in the body and part of the central nervous system in the body. It regulates every other neurotransmitter system including serotonin, dopamine, norepinephrine, and GABA. The endocannabinoid system (ECS) plays a very important role in the human body for our survival. This is due to its ability to play a critical role in maintaining the homeostasis of the human body (meaning it is constantly working to bring about a state of balance to our bodies and minds), which includes the brain, endocrine, and immune system, to name a few.

Anxiety in the U.S.

Anxiety for some may only last a day or so but for many, anxiety can be a regular feeling that can be debilitating at times and include panic attacks. We might see anxiety show up in physical ways such as shortness of breath, headaches, stomach aches, insomnia and over time maybe even weight loss (or gain), IBS (irritable bowel syndrome), acne, heart problems, hormonal issues, and disease. In today’s world, it’s hard to avoid stress — we’re all feeling it in one way or another. Whether it be from work, family, politics, or our lifestyle choices. When the stress piles on over an extended period, your body actually becomes accustomed to this way of feeling and in a way it becomes the norm.

Focusing on just one neurotransmitter does not make it likely that this drugs will exacerbate the disease. Additionally, in many cases, these drugs actually increase depression and suicidal thoughts suggesting they may not be the best option for some.

CBD looks to be a promising, safe supplement that can provide less inflammation, pain, anxiety, depression and more. Every case is different and no one person’s lifestyle or chemical makeup is alike; always consult your health care physician before getting off of medications or switching over.

This makes CBD a promising natural supplement for those suffering from underlying inflammatory issues, both mental and physical.

If this plant can be the answer to the opioid epidemic that took an estimated 45,000 lives in 2017, what can it mean for other diseases and mental health disorders?

CBD on the Brain and Body.

We will continue to learn more about cannabis and its medical use as well as the endocannabinoid system as we are only in the infancy of research. Wellness Co will be on the cutting edge of research as we aim to educate and provide as much new information as possible. If you want to know more about what we do, you can check the best tasting CBD oils here on our site, these are all CBD Hemp Extract from the USA.

Aptly named after Ananda, the Sanskrit word for “joy, bliss, or happiness,” anandamide binds to the CB1 receptor (the one in charge of your mood, appetite, pain sensitivity, and sleep cycle).

The dominant two receptors in our bodies are CB1 and CB2. CB1 is concentrated in the central nervous system but also found in other tissues as well, including liver, gut, uterus, prostate, adrenals, the cardiovascular system, and very high levels in several regions of the brain. CB2 is localized in the immune cells. CB2 is what controls inflammatory responses making it the more important one to pay attention to for therapeutic effects in general.

When you feel stress creeping into your life, there are steps you can take to come back to balance and to equilibrium. In fact, there is a part of our central nervous system in our bodies that’s entire job is to bring us back into homeostasis, the endocannabinoid system. Nutrition, mindset, and lifestyle all play a role in keeping our stress and anxiety levels at bay and our nervous system balanced, but we most often see people turning towards pharmaceutical medications.

This whole system regulates important activities such as sleep, immune, gastrointestinal, central and peripheral nervous system, reproductive, digestive, mood, memory, appetite, and other cognitive and physical processes.

These cannabinoids are all unique and interact with receptors in cells of the human body. THC has received most of the spotlight as the compound that “gets you high.” CBD is another compound of the 400 in the plant that is showing to have amazing benefits to the body without the psychoactive effect.

Fear generalization to context is commonly measured in a novel context during a baseline period which precedes auditory-cued memory testing with mice that had received paired conditioning. During a 3-min baseline preceding our auditory test, all treatment groups initially showed low levels of freezing which increased during the first minute and then plateaued for the remainder of the test (Fig. 3a). Average freezing levels across this entire period were near 40% for vehicle-treated mice, but dropped to about half of that for CBD and citalopram treated groups (Fig. 3b). This decrease was statistically significant for both treatment groups. Therefore, both CBD and citalopram, when administered prior to memory acquisition, inhibited generalization of fear association with a novel context.

PTSD is a disorder of learning and memory characterized by the generalization of fear memory and associated behavioral responses to inappropriate stimuli (Chen et al. 2014; Atwoli et al. 2015). PTSD affects over 350 million people worldwide, with an individual lifetime prevalence of 7.3% (Koenen et al. 2017; Hoppen and Morina 2019; Karatzias et al. 2018). Leading clinical therapies for PTSD include cognitive behavioral therapy, eye movement desensitization therapy, and reprocessing therapy. However, these approaches are minimally effective and consequently are often used in combination with pharmacotherapeutics (Gallagher 2017; Simpson et al. 2019; Garcia et al. 2019). This prominently includes the use of selective serotonin reuptake inhibitors (SSRIs) which were originally developed for depression. However, SSRIs produce gender-dependent variability in effects, can initially increase negative symptoms, require chronic treatment, are problematic to discontinue, and can produce severe negative side effects including depression, violent behavior, and suicide (Burghardt et al. 2004; Burghardt and Bauer 2013; Tawa and Murphy 2013; Soga et al. 2012; Soga et al. 2010; Clayton et al. 2006; Bezchlibnyk-Butler et al. 2000; Molero et al. 2015; Surawski and Quinn 2011; Healy et al. 2006). Thus, there is a need to develop alternative therapeutics for PTSD which would include the benefits of SSRIs without the harmful side-effects.

Cannabidiol (CBD) is currently being promoted as one such alternative candidate, with published evidence that it exerts anxiolytic properties which promote extinction of fear memories (Bitencourt et al. 2008; Loflin et al. 2017; Campos et al. 2016; Stern et al. 2018). CBD is reported to have low toxicity and is well tolerated in humans, although the volume of clinical research into its efficacy for treating PTSD is currently minimal (Iffland and Grotenhermen 2017). Despite the reported potential for CBD as therapeutic for PTSD, we recently showed that a single dose administered just prior to fear memory acquisition enhances the expression of fear in male mice, consistent with other research showing an anxiogenic effect when administered to rats (Uhernik et al. 2018; ElBatsh et al. 2012). This would suggest a counter indication for CBD as a treatment for PTSD. Moreover, very little work has evaluated the effects of CBD on fear learning and memory in females (Shbiro et al. 2019), and no work has directly compared the effects of CBD to SSRIs on fear learning and memory. It would, however, be very useful to know how CBD and SSRIs compare in affecting particular types of fear memory that model PTSD and other memory disorders; i.e., do these drugs affect multiple memory types the same way, or do differences exist that might guide safe and efficacious prescription for particular disorders but not others?

We previously found that CBD enhances contextual memory and its extinction when assessed 24 h following trace fear conditioning in male mice (Uhernik et al. 2018). In contrast, using an identical experimental design, we found that context-dependent memory and its extinction were decreased by CBD in this study involving female mice (Figs. 2 and 4). There are only three studies where CBD was administered before acquisition of contextual fear memory, two with male rats and one with male mice (ElBatsh et al. 2012; Levin et al. 2012; Uhernik et al. 2018). Interestingly, CBD was anxiogenic in one rat and the mouse study, but anxiolytic in the other rat study, with major differences between the rat studies being the duration of treatment and strain. Therefore, our results suggest a sexual dimorphism in the effect of CBD on contextual memory in mice. This is consistent with well documented sexual dimorphisms in contextual fear memory processing in general (Cossio et al. 2016; Farrell et al. 2013; Jasnow et al. 2006; Kobayashi et al. 2020; Dalla et al. 2009), and noted sexual dimorphisms in the distribution and function of the major receptor signaling pathways that support CBD signaling in rodents (Jimenez Naranjo et al. 2019; Liu et al. 2020; Inoue et al. 2014; Uphouse et al. 1991; Greaves et al. 2005). This result could be important for guiding the design and interpretation of fear memory experiments involving mixed genders and could have clinical relevance as discussed below.

Both drugs are potent modifiers of fear memory formation; however, there is considerable divergence in their targeting of different memory types which, overall, could support the use of CBD as an alternative to SSRIs for treating PTSD in females, but not males. A limitation of the study was that it compared data from experiments done at different times to evaluate sexual dimorphism. Overall, this suggests that more research is necessary to guide any therapeutic approach involving CBD.

Data analysis and statistics.

In summary, citalopram inhibited recall of generalized fear; however, CBD reduced both this and context fear when measured 24 h after conditioning. This divergence in effects is consistent with the current understanding of the pharmacology of CBD, which includes a broader range of neurological targets prominently including endocannabinoid signaling, G protein-coupled receptor 55 (GPR55), transient receptor potential vanilloid type 1 (TRPV1) channels, and serotonin 5HT1A receptors. In comparison, citalopram is known to primarily target serotonin signaling, and only mildly interacts with other neurotransmitter systems (Hyttel 1982; Preskorn 1997; Stahl 1998). Since PTSD involves both fear generalization and misrepresentation of contextual fear associations, our study suggests that CBD might provide a spectrum of effects that would be more comprehensive than citalopram for targeting processes involved in acquisition of memories that lead to PTSD. More important, CBD is not known to produce any of the negative side effects associated with SSRI’s, which comparatively, might make it more therapeutically desirable (Mir and Taylor 1997; Spigset 1999; Teicher et al. 1990; Fergusson et al. 2005; Ravinder et al. 2011; Salchner and Singewald 2002; Sánchez and Meier 1997). On the other hand, because CBD inhibited the formation of contextual memory, it could be considered detrimental as a blocker of this essential adaptive learning process. Citalopram did not have this effect.

Extinction of contextual memory also was significant over the full period of extinction training for each of the treatment groups. However, on the final day of extinction training, CBD-treated mice showed a significantly lower level of freezing in comparison to controls ( p = 0.001) while citalopram-treated mice were similar to controls ( p = 0.2), (Fig. 4b). Therefore, CBD significantly enhanced extinction of the contextual memory, but, citalopram did not affect this.

Adult female C57BL/6 mice were given trace-fear conditioning as described in the materials and methods section. Briefly, 30 or 60 min prior to conditioning, mice received intraperitoneal injections of either vehicle, CBD, or citalopram, respectively, with the time courses and doses chosen so as to be consistent with the previously published literature (Burghardt et al. 2013; Uhernik et al. 2018). Auditory-cued memory was assessed 24 h after conditioning in a novel context by measuring freezing responses to tone presentations and comparing results between mice that received paired versus unpaired conditioning. With this approach, a statistical difference indicates that an auditory-cued memory was present (Fig. 1).

Fear memory extinction training was conducted at 24-h intervals for 4 days following the first day of memory testing. It was completed by first exposing mice to the novel context for a 3-min baseline period, followed by seven 30 s presentations of the auditory cue which were spaced at 120 s intervals. In this period, we assessed generalized fear, and auditory cue-associated memory, respectively. Four hours after that, mice were returned to the original context for 5 min to assess contextual memory strength.

All experimental procedures were carried out in accordance with approved Colorado State University-Pueblo Institutional Animal Care and Use Committee protocols and guidelines. Female C57BL/6 mice (Charles River Laboratories) arrived at the age of 29 to 32 days old and were housed in groups of three under a 12 h dark-light cycle and given food and water ad libitum. Mice were weighed 24 h after arrival and weights were distributed across experimental groups to ensure similar group averages. All mice were acclimated for 10-18 days prior to the start of experimentation.

Overall, perhaps the most remarkable effect that we observed were those on extinction learning, given that extinction effects were assessed 5 days after the drugs were applied. This strongly implies that, as discussed above, the original memory and not the extinction process per se was the target of each drug. The specificity of extinction effects was also different between drugs. This is summarized simply in that CBD-enhanced extinction of auditory-cued, contextual, and generalized fear memory, but citalopram was only able to enhance extinction of the auditory-cued memory. This would suggest that CBD could be more favorable than citalopram for treating PTSD since the disorder involves the broader spectrum of memory types that was more completely targeted by CBD. On the other hand, generalized fear with citalopram showed a large decrease at 24 h, but no further extinction, consistent with the known divergence in effects for this drug over the time course ranging from initial administration to long term use (Berlanga and Flores-Ramos 2006; Bigos et al. 2009; Burghardt and Bauer 2013; Burghardt et al. 2013). This suggests citalopram might have a therapeutic application for fear learning and memory disorders involving a tailored acute pre-memory acquisition administration and would have a less effective or different indication involving chronic treatment. Notably, the final difference in freezing levels for auditory-cued extinction was not significantly different between CBD- and citalopram-treated mice, despite the divergent pharmacology described above.

Four hours following cue-associated memory testing, mice that had received paired conditioning were placed back into the original training context and freezing behavior was averaged across a 5-min period to assess contextual memory (Fig. 2). In this experiment, vehicle-treated mice showed moderate levels of freezing. Mice that had received CBD, on the other hand, showed significantly lower levels of freezing, indicating that treatment inhibited the formation or recall of the context association. In contrast, citalopram treatment did not produce a noticeable change in contextual memory strength.

The conditioning stimulus (CS) was always an audible 85db, 7 kHz, 30 s tone. The unconditional stimulus (US) was always a 1-s long 0.5 mA foot shock. Both stimuli were computer controlled and delivered by the fear conditioning system described above.

For extinction of auditory-cued memory, regardless of treatment, all three groups of mice showed significantly decreased freezing to the auditory cue by the fourth day of extinction training when analyzed within treatment groups across the 5-day period. However, the level of freezing was significantly reduced in both CBD and citalopram treated mice when compared across treatment groups within the final day of extinction training (Fig. 4a). This result shows that extinction learning was present for all groups, and that both CBD and citalopram were able to significantly enhance extinction learning for this memory type, when administered one-time prior to trace-fear conditioning. Notably, the difference in final levels of freezing was not significantly different between the CBD and citalopram treated mice.

Introduction.

Consistent with our previous study using male mice, a single pre-acquisition dose of CBD to females did not affect auditory cue-associated memory recall when assessed 24 h after trace fear conditioning (Fig. 1) (Uhernik et al. 2018). We saw the same lack of effect using citalopram in this study; however, this is contrary to reports showing an increase in auditory-cued fear following delay conditioning when citalopram was administered with the same timing to male rats (Burghardt et al. 2004; Inoue et al. 1996). This difference could be attributed to differences in processing memories formed with trace versus delay conditioning, the use of rats instead of mice, or to sex differences (Jurkus et al. 2016).

All fear conditioning was completed in context A, 24 h after habituation, and on the second day of experimentation. Each of the three conditioning groups was further divided into three treatment groups, vehicle, CBD, or CIT. Mice in the vehicle or CBD groups received an IP injection 30 min prior to conditioning whereas those mice that received CIT were injected 60 min prior to fear conditioning. This resulted in a final total of nine experimental groups containing 12 animals per group. Paired conditioning consisted of a 2 min baseline period followed by seven 30-s long presentations of the CS each paired with an US. A trace interval of 17 s was placed between presentations of the CS and US, and the seven CS-US pairs were separated by an inter-trial interval (ITI) of 2 min. Animals in the unpaired groups received seven presentations of the US at pseudo-random intervals. Non-conditioned animals received seven presentations of the CS with a 2-min ITI. All animals were exposed to the conditioning chamber for the same overall duration regardless of the conditioning group.

Both drugs in our study inhibited particular types of fear memory when given prior to conditioning, suggesting the mechanisms of action involved either the acquisition or early consolidation phases of fear memory. This would suggest an acute-phase clinical perspective for these drugs in reducing fear memory formation, perhaps as a prophylactic for people with known risk of developing a fear-memory-related disorder such as PTSD. However, while CBD is thought to be mostly metabolized by 24 h, citalopram has a plasma half-life closer to 35 h, suggesting that it could have also targeted the recall process (Deiana et al. 2012; Sangkuhl et al. 2011). Because the drugs were both likely metabolized at the time of memory testing, the pharmacokinetics also suggest that each drug targeted fear memory, rather than exerting anxiolytic effects during memory testing. This would not, however, rule out the possibility of an anxiolytic effect as part of the mechanism which affected memory formation.

Overall, these results are consistent with the majority of published reports which show that both CBD and SSRIs have anxiolytic properties (Bitencourt et al. 2008; Campos et al. 2016; Stern et al. 2018; Homberg 2012). Interestingly, citalopram has previously been shown to be more effective for treating depression in women than in men (Young et al. 2009; Berlanga and Flores-Ramos 2006; Dalla et al. 2010). While we do not have comparable data involving males and citalopram, this sex-dependent difference might suggest that the acute dose we used here might also share with CBD the sexual dimorphism in affecting fear generalization. This would be interesting to evaluate in the future and could support the development of preclinical and clinical studies with this drug, which is known to be underrepresented in studies involving females (Choleris et al. 2018; Tronson 2018).

Auditory-cued trace fear conditioning was conducted shortly after dosing female C57BL/6 mice, with either CBD or citalopram (10 mg/kg each), by pairing auditory tones with mild foot shocks. Auditory-cued, contextual, and generalized fear memory was assessed by measuring freezing responses, with an automated fear conditioning system, 24 h after conditioning. Each memory type was then evaluated every 24 h, over a 4-day period in total, to create an extinction profile. Freezing outcomes were statistically compared by ANOVA with Tukey HSD post hoc analysis, N = 12 mice per experimental group. Evaluation of sexual dimorphism was by comparison to historical data from male mice.

The reported sexually dimorphic effects of CBD and citalopram suggested that the female estrous cycle might impact fear memory recall and extinction in our studies. Therefore, our study design included a step to determine the stage of the estrous cycle, on each day, for each mouse, over the course of experimentation (see materials and methods). Mice were grouped, within treatment groups, into estrogen- and progesterone-dominated phases for each of the types of memory that we assessed: auditory cued, contextual, fear generalization, and extinction of each of these. In no case did we detect a statistically significant impact of the estrous cycle phase on the results presented above. Figure 5 shows the results of this analysis for auditory-cued memory recall.

Methods.

Our results showed very low levels of freezing among mice that received non-conditioning, indicating that treatments did not affect animal mobility in a way that might confound the interpretation that freezing is a measure of memory strength (vehicle vs. CBD p = 0.4 ; vehicle vs. CIT p = 0.15). On the other hand, mice that received paired or unpaired conditioning showed considerable levels of freezing which increased following the onset of each tone presentation and briefly persisted for a period following the offset of the CS. An auditory-cued memory was shown to be present in all treatment groups by comparing freezing levels between animals that received paired versus unpaired conditioning for each of the three treatment groups. Additionally, mice that received paired conditioning did not show measureable differences in freezing between either treatment group when compared to control. Therefore, neither CBD nor citalopram, when administered prior to memory acquisition, appeared to affect the formation, or recall of the auditory cue-associated memory when assessed 24 h following trace fear conditioning. It was interesting that mice, which received unpaired conditioning showed trends toward increased and decreased freezing behavior with CBD or citalopram, respectively (vehicle vs. CBD p = 0.06; vehicle vs. CIT p = 0.08). Because this freezing was in a novel context, and to an auditory cue that was not paired with the US during conditioning, it could be interpreted as representing fear generalization to the auditory cue.

Results of extinction training over a four day period following the original memory test in female mice. a. Extinction of the tone-associated memory was assessed in the novel context by recording freezing levels averaged across seven presentations of the auditory cue and comparing these levels within groups across days, and across treatment groups on the last day, with a t-test (* p = < 0.05). b. Contextual memory extinction was similarly assessed by averaging freezing levels over a five minute period in the original conditioning context (*p < 0.05). c. Extinction of generalized fear was similarly assessed by measuring freezing levels during a three minute baseline period in the novel context (* p < 0.05). The timeline for the experiment is shown in the inset above.

The female mice in our study were 39 to 50 days old when we began fear conditioning. This is past the range in which these mice are known to reach sexual maturity. Therefore, the lack of any estrous phase influences on the drug effects in our study suggest that hard-wired sexual dimorphisms in brain physiology with a developmental basis, rather than acute influences of sex hormone signaling to fear memory, was the source of the gender-dependent divergence in effects that we report here. This is consistent with well documented pre-pubescent gender-specific differentiation of contextual fear processes in rodents and humans, which of importance, are thought to provide a basis for sex differences in anxiety and stress disorders in people. Interestingly, this is also known to begin during sexual differentiation, early in development, of key brain areas that process fear learning and memory, including the hippocampus and amygdala (Colon et al. 2018; Koss and Frick 2017; Fish et al. 2020). On the other hand, while there are still many unknowns regarding acute sex hormone signaling to the fear learning processes which we studied with mice, there is some related research showing hormonal effects, which involve pro-estrous phase signaling in women. For example, an estradiol-dependent enhancement of brain activity in key areas that support fear memory acquisition and extinction has been shown in women (Velasco et al. 2019; Hwang et al. 2015; Peyrot et al. 2020). Moreover, a majority of relevant studies showing sex-cycle-dependent effects on fear learning and memory involved stress as a factor (Maeng and Milad 2015; Cover et al. 2014; Van Veen et al. 2009; Ter Horst et al. 2009; Antov and Stockhorst 2014; Garrett and Wellman 2009; Maeng et al. 2010). Perhaps the reason we did not observe effects of the estrous cycle in our studies is that we avoided involving stress as a factor in our experiments.

In contrast, we did not see an effect of citalopram on contextual memory or its extinction in this study (Figs. 2 and 4). While a majority of previous studies have shown increased fear and anxiety responses with acute dosing of SSRIs (Burghardt et al. 2004; Burghardt et al. 2007; Ravinder et al. 2011; Mir and Taylor 1997; Spigset 1999; Salchner and Singewald 2002; Sánchez and Meier 1997; Dekeyne et al. 2000), at least one study showed an anxiolytic effect of an acute dose on contextual memory recall, therefore, our result is not inconsistent with the published literature (Inoue et al. 1996). Moreover, we are unaware of any other study that assessed contextual memory recall after administering citalopram to female mice before trace conditioning, therefore, any discrepancy could be related to differences in experimental design and/or to known gender differences in the signaling pathways and brain circuitry that is targeted by citalopram (Berlanga and Flores-Ramos 2006; Burghardt et al. 2013).

Finally, generalized fear memory was significantly extinguished over the 4 day period of extinction training in both vehicle controls and CBD-treated mice, but not in the citalopram-treated group. Therefore, citalopram-treated animals did not show extinction of generalized fear with our protocol. This was likely a result of the greatly reduced original memory; however, this was also true for the CBD-treated animals which, despite a similar reduction in the memory measured 24 h post-conditioning, did show extinction of the memory (Fig. 4c). In addition, on the final day of extinction training, both CBD- and citalopram-treated mice showed significantly lower levels of freezing in comparison to control ( p = 0.005 and 0.04, respectively). Therefore, both CBD- and citalopram-treated animals showed reduced levels of fear generalization across the entire experimental period, however, the generalized fear memory was extinguished only in the CBD-, but not the citalopram-treated animals.

Auditory cue-associated fear memory was not affected with CBD or citalopram; however, contextual memory was reduced with CBD by 11%, p < 0.05, but not citalopram, and generalized fear memory was reduced with CBD and citalopram, 20% and 22%, respectively, p < 0.05. Extinction learning was enhanced with CBD and citalopram, but, there was considerable memory-type variability between drug effects, with freezing levels reduced at the end of training by 9 to 17% for CBD, and 10 to 12% with citalopram. The estrous cycle did not affect any outcomes.

On the fourth, fifth, and sixth days of experimentation, 24, 48, and 72 h after the first day of memory testing, respectively, mice underwent extinction training. During these 3 days, mice underwent the exact same testing protocols as described on day 3 described above.