Cannabidiol (CBD) combined with some THC has been shown to be effective for depression and a variety of related anxiety disorders like PTSD, SAD, GAD. Notably, PTSD and OCD are no longer classified as anxiety disorders in the recent Cannabidiol (CBD) is a phytocannabinoid constituent of Cannabis sativa that “post-traumatic stress disorder” or “panic disorder” or “obsessive compulsive. CBD constitutes about 40% of the active LTP and depression) in several brain areas.
vs anxiety, CBD PTSD? depression, for THC
However, if this is the case, what is the advantage of using CBD over agents that act directly on the CB1 receptor? The answer is simple: Agents that target the eCB system directly, such as THC, CB1 agonists, and FAAH inhibitors, have a biphasic effect, in which low doses are anxiolytic, but higher doses can be anxiogenic, in both preclinical models and humans.
In contrast, CBD, when administered in acute systemic doses in models of general anxiety, does not cause anxiety even at high doses. However, few studies have examined chronic dosing effects of CBD in models of generalized anxiety, and such studies are needed for the safe long-term use of CBD Blessing et al.
Trauma-related disorders may involve dysregulation of the learning process of aversive memories. This process is fundamental for the individual to survive, because through it we avoid potentially dangerous situations without having to respond in a way that damages mental health Quirk and Mueller, Consistent with this concept, neural circuits that support fear conditioning are related to circuits that are affected in clinical conditions such as PTSD Davis and Whalen, That the available drugs such as antidepressants and anxiolytics do not specifically target the memory process may be one of the reasons that pharmacological treatment of PTSD is so difficult Singewald et al.
Moreover, the available treatments have considerable side effects, which may limit tolerance or even decrease adherence to the treatment Shin et al. In this regard, interventions that act on the eCB system have shown promise since they can affect both the emotional e. Two important observations led to the consideration of cannabinoids for the treatment of PTSD: Consistent with these observations, studies have made use of treatment with cannabinoids in animal models of traumatic event exposure to reduce the appearance of PTSD-like behavioral responses.
These studies have demonstrated great potential of cannabinoids in the mitigation of maladaptive responses to trauma for a more detailed review, see Zer-aviv et al.
When administered after a traumatic situation, cannabinoids may interfere with the acquisition and consolidation of memories of the event, thus mitigating the risk of subsequent symptoms. However, intervention at this stage may be inadvisable because not all people exposed to a traumatic situation will later manifest PTSD. Alternatively, cannabinoids may reduce traumatic memory by affecting its retrieval or reconsolidation, or by stimulating the process of aversive memory extinction.
The latter mechanism may hold the most therapeutic promise, especially when taking into account exposure-based psychotherapies, which extinction mechanisms are thought to be engaged reviewed in Berardi et al.
Additionally, studies have shown CBD, in its isolated form, to be a constituent of Cannabis with enormous therapeutic potential not only for trauma-related disorders, but also for various other psychiatric and neurological disorders Campos et al. Among the advantages of CBD are its high efficacy, lack of psychotomimetic properties or anxiogenic effects caused by eCB transmission activation, inability to induce tolerance and dependence, and safety at high doses both in humans and in animals Bergamaschi et al.
However, an alternative view must also be considered, according to which the therapeutic effects of Cannabis result from the interaction of all the compounds present in the plant particularly THC and CBD rather than the isolated action of a single compound. In this review, we will focus on CBD effects in isolation. The fear-conditioning paradigm has been widely used in animals to better understand the processes of acquisition, consolidation, retrieval, reconsolidation, and extinction of aversive memories LeDoux, ; Maren and Quirk, Parallels can be drawn between the expression of fear and anxiety in humans e.
Many studies use variations of this model e. Briefly, this model involves the pairing of a neutral stimulus called CS with an aversive US, usually a mild foot shock.
After successive rounds of pairing or, in some cases, a single pairing , the animal learns that the CS precedes the US, leading to a series of physiological e. Intervention in the processes of acquisition and consolidation of aversive memories is not promising, since this approach can only be effective when closely following the traumatic event, that is, when it is not yet possible to know if the event will result in a disorder.
However, intervention in the processes of retrieval, reconsolidation, and, especially, extinction may be a more promising alternative. Briefly, when reactivated by re-exposure retrieval , an aversive memory enters a transitional state, where the original memory trace can be reconsolidated or extinguished. This process may be influenced pharmacologically e. Animal studies have shown that CBD can affect every stage of the process of aversive conditioning.
In addition, exposure to traumatic stress is essential for the development of PTSD, and CBD is effective in reducing both the cardiovascular responses and anxiogenic effects caused by stress Resstel et al.
For example, CBD lowered responses related to trauma when administered before the acquisition Levin et al. CBD also proved to be effective in reducing responses to aversive memories by blocking the process of reconsolidation Stern et al. However, the most promising alternative, suggested by exposure-based psychotherapies, may be through enhancement of the extinction process by CBD Bitencourt et al.
Before discussing the facilitating effects of CBD on the extinction of aversive memories, it is necessary to highlight the role of the eCB system in this process. The process of extinguishing an aversive memory requires the participation of CB1 receptors, which was discovered in a classic study by Marsicano et al. The authors showed that blocking the action of CB1 receptors, either by pharmacological antagonism or genetic deletion, in previously conditioned mice resulted in strongly impaired short- and long-term extinction in fear-conditioning tests the function of CB1 receptors in the process of extinction of aversive memories is detailed in Wotjak, ; Lutz, This finding raised a new question: Would potentialization of the eCB system facilitate the extinction process?
The answer was not surprising, and several studies were published showing that eCB system potentialization could in fact facilitate fear extinction in different behavioral tasks Chhatwal et al. Given that, according to Bisogno et al. The answer once again was affirmative, and since then studies have shown that CBD can facilitate the extinction of aversive memories not only in animals Bitencourt et al.
However, it is important to note that some studies suggest that the reduced expression of fear caused by CBD may result mostly from blocked reconsolidation of an aversive memory than its increased extinction Stern et al. Regardless of which stage of aversive memory processing CBD affects, it appears that, at least in animals, this compound interferes with memory processing in a way that potentially mitigates damaging responses.
In addition to the possibility of CBD affecting different processes involved in aversive memory, animal studies also show favorable effects of this compound in the control of other frequent manifestations of PTSD symptomatology, such as sleep disorders.
Studies in rats indicate that CBD may contribute to an increase in sleep duration and depth, and a decrease in anxiety responses induced by sleep disturbance Monti, ; Hsiao et al. However, a thorough review of CBD and anxiety lies beyond the scope of this paper. The interested reader may want to see recent reviews by Blessing et al.
Research has also been moving in this direction, as we will see in the next section. Confirming animal study results in humans is essential for the validation of any strategy that demands a pharmacological therapy. In a study published by Das et al. Using inhaled CBD at a dose of 32 mg , a study in a model of aversive conditioning showed that the compound caused a reduction in the skin conductance response as well as in the expectation levels for the CS during new exposure.
Consistent with results of animal studies, these findings show that CBD may be a pharmacological complement to be used in exposure-based therapy. An important consideration in relation to this study is that CBD facilitated the extinction of aversive conditioning only when administered immediately after, and not before, the process.
Therefore, understanding at which moment exposure-based therapy with CBD should start is one of several issues that still need to be resolved Das et al. A case report published in by Shannon and Opila-Lehman described a year-old child who developed PTSD after being sexually abused before the age of five.
The child showed significant relief of the symptomatology using CBD oil. Before the CBD therapy, the child underwent standard pharmacological treatment for the condition, which produced short-lasting partial relief, as well as significant side effects.
However, CBD oil given at a dose of 12—25 mg once a day appeared to relieve key symptoms, such as anxiety and sleep disturbance, while inducing minimal side effects.
Although CBD is considered safe Bergamaschi et al. However, it is not possible to analyze the proportion of CBD and THC in the plant used by the patients in these studies. Recent studies also point to a link between Cannabis use, possibly as a form of self-medication, and the occurrence of trauma-related events both in adolescents Bujarski et al.
The more severe the traumatic experience, the greater the plant consumption Kevorkian et al. These findings may reinforce the theory that the entourage effect may be more important to the therapeutic effects of the plant than any single compound used in isolation.
To confirm this theory, more studies are required for a review of Cannabis use in people with traumatic experiences, see Zer-aviv et al. The mechanisms of CBD action in behavioral responses related to trauma are still unclear. Understanding the mechanisms underlying CBD action, for example on the expression of aversive memories, is important because a better understanding of this phenomenon may lead to the possibility of more effective interventions in traumatic memories in PTSD. Several mechanisms of action have been proposed to explain the pharmacology of CBD and, as we shall see, they are far from universally accepted.
Based on this assumption and taking into account different studies showing that the activation of CB1 receptors decreases the expression of behaviors related to aversive memories in rats Chhatwal et al. A recent review by Hill et al. Furthermore, animal studies have confirmed the importance of the CB1 receptor in mediating the effects of CBD on behavioral responses related to potentially traumatic memories Bitencourt et al.
However, other research has shown that the answer will not be that simple. In a systematic search of the extant literature for original articles on the molecular pharmacology of CBD, we found a study by Ibeas Bih et al. The authors show that CBD can act through 65 discrete, specific molecular targets, including 10 receptors, 32 enzymes, 10 ion channels, and 13 transporters.
With regard to the possible modulation of the eCB system, a study published by Massi et al. Nevertheless, because FAAH activity appears to be increased by chronic restraint stress in animal models as well as by anxiety-like behaviors Hill et al.
In any case, a great deal of caution is needed when interpreting in vitro assays and, especially, when extrapolating in vitro results to the in vivo effects of CBD. This mechanism may be the most promising possibility to explain at a molecular level the inhibitory effects of CBD on behavioral responses related to the recall of traumatic events and it is worth further investigation.
However, controversy regarding the effects of CBD on serotonergic transmission remains. A study by Rock et al. In this study, the authors suggested that the 5HT 1A -mediated effects of CBD might involve allosteric interactions with the receptor binding site or interference with intracellular pathways Rock et al.
The possible interaction of CBD with the serotonergic receptor, also observed in the eCB system, has not been confirmed in vivo Ibeas Bih et al. Another molecular target, still less explored, that may mediate, at least in part, the effects of CBD on the expression of aversive memories, is the adenosinergic system. It has now been established that the blocking of the eCB system leads to an increase in the expression of fear responses, whereas eCB system stimulation causes a decrease in such responses.
Drawing parallels between eCB and adenosinergic signaling, adenosinergic receptor stimulation direct or indirect may represent an alternative treatment for trauma-related psychiatric disorders.
Moreover, indirect stimulation of the adenosinergic system may explain the effects of CBD on aversive memories. Given the precariousness of the extrapolation of in vitro results to in vivo effects, the potential role of the adenosinergic system in the CBD-induced inhibition of aversive memory expression requires further investigation. We are still far from reaching a consensus regarding the possibility of other molecular targets mediating the effects of CBD on aversive memories.
Precisely for this reason, great care must be taken when interpreting the existing literature as well as proposing new experiments. In addition to the behavioral changes induced by treatment with CBD, some of which possibly mediated by the CB1 receptor, studies have also shown that chronic CBD treatment may facilitate neurogenesis in the hippocampus, a structure well known for its important role in processing memories Wolf et al. Among the brain areas implicated in the effects of CBD, it is also important to highlight the amygdala, which is hyperactive in patients with PTSD and may be related to the severity of the symptoms Shin et al.
CBD attenuated the level of blood oxygenation in the amygdalae of healthy subjects exposed to different levels of anxiety Fusar-Poli et al. Reduction in the hyperactivity of the amygdala may also explain, in part, the therapeutic effects of CBD against the symptoms caused by PTSD Passie et al. The activity of the mPFC, a brain structure that plays an important role in the effects of CBD on the regulation of aversive responses Lemos et al.
Finally, CBD-induced reduction of trauma-related responses raises a wide spectrum of possibilities involving multiple pharmacological and neural circuit mechanisms. Understanding how these mechanisms work is just one more of the various challenges in the study of cannabinoids as potential treatment for neuropsychiatric disorders. Human and animal studies suggest that CBD may offer therapeutic benefits for disorders related to inappropriate responses to traumatic memories.
The effects of CBD on the different stages of aversive memory processing make this compound a candidate pharmacological adjunct to psychological therapies for PTSD. CBD also shows an action profile with fewer side effects than the pharmacological therapy currently used to treat this type of disorder.
In addition, even at high doses, CBD does not show the anxiogenic profile of compounds that directly activate eCB transmission. However, even in the face of evidence pointing to the modulation of the eCB system, more studies are needed to develop a better understanding of the neurobiological mechanisms involved in CBD responses. Although much remains to be discovered about the effects of CBD on PTSD symptoms many steps have already been taken in this direction, which may yield a formulation of CBD for the treatment of patients with trauma and stress-related disorders.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors would like to thank Eduarda C. RB and RT are also grateful to Professor Elisaldo Carlini, pioneer of cannabinoid research in Brazil, for his invaluable contributions in this field of research.
National Center for Biotechnology Information , U. Journal List Front Neurosci v. Published online Jul Author information Article notes Copyright and License information Disclaimer.
This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience. Received Dec 28; Accepted Jul 3. The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Abstract Post-traumatic stress disorder PTSD is characterized by poor adaptation to a traumatic experience. Introduction Post-traumatic stress disorder PTSD is a chronic psychiatric condition that may develop after experiencing a potentially traumatic event.
Open in a separate window. Cannabinoids and Trauma-Related Disorder Cannabis sativa contains over compounds called phytocannabinoids. Facilitated extinction of contextual fear memory Via CB 1 receptors Lemos et al.
Decreased acquisition of contextual fear memory Not shown Stern et al. Blockade reconsolidation of contextual fear memory Not shown Gazarini et al. Blockade reconsolidation of contextual fear memory Not shown.
Not shown Das et al. Not shown Shannon and Opila-Lehman, How Does It Work, Anyway? Conclusion and Future Perspectives Human and animal studies suggest that CBD may offer therapeutic benefits for disorders related to inappropriate responses to traumatic memories.
Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments The authors would like to thank Eduarda C. Cannabinoids modulate hippocampal memory and plasticity.
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