Cannabidiol (CBD) is a phytocannabinoid discovered in It is one of some identified cannabinoids in cannabis plants, accounting CBD is not scheduled under any United Nations drug control treaties, and in the World . Various strains of "medical marijuana" are found to have a significant variation in the. In honor of her progress, high-CBD cannabis is sometimes known as The company is also studying cannabinoid-based drugs as a treatment for autism The Guardian is editorially independent, meaning we set our own. These are the two components of cannabis that have been most studied by scientists. and physicians highlight CBD's potential as a treatment for a wide range of Thus, it stands to reason that “modulating endocannabinoid system activity.
killer weed stands cbd for
This viewpoint stands contrary to the idea of holistic medicine, where you take something in its entirety for medicinal purposes. The Cannabis sativa plant is one of the greatest present-day examples of this tug-of-war between Western medicine and traditional medicine. It has been found to have a variety of health-related benefits for the user. CBD is the second most well-known cannabinoid found in cannabis, and like most of the other phytocannabinoids, it is non-psychotropic.
These are the two most abundant and well-studied cannabinoids in marijuana, and both have been found in numerous published studies to have pain-relieving properties in humans. While they may be the most abundant, THC and CBD are certainly not the only compounds found in cannabis that are known to exert positive effects on human health.
In every cannabis plant, there is a unique mixture of hundreds of plant compounds, comprised of phytocannabinoids, terpenes, and flavonoids. Research suggests that these compounds too have an influence on our neurochemistry, and together they may work synergistically, producing better improvements in pain relief than anyone would produce on its own. This research supports the idea that it is best to use the whole cannabis plant, with CBD, THC, and the natural medley of additional compounds.
This harmony between the various plant chemicals found in marijuana is colloquially referred to as the entourage effect. The most well-studied compounds found in the marijuana plant that support the idea of the entourage effect are THC and CBD, which have been found to work differently together than when separate. Using these two compounds in concert has been shown to help mitigate side effects and enhance efficacy, with CBD plus THC showing more benefit for some conditions than THC alone.
It has also been found to extend the half-life of THC, which may help to extend the pain-relieving benefits. This has allowed the use of higher doses of THC in clinical trials for the treatment of pain caused by multiple sclerosis, peripheral neuropathic pain, intractable cancer pain, and rheumatoid arthritis. When used in concert, a greater efficacy in treating these types of pain have been observed. Every strain of bud that you can purchase at a dispensary will be labeled with its THC and CBD content, which can be helpful when choosing which strain to choose for pain relief.
CBD has been found to exhibit enhancements in treating pain both when used on its own and when used in combination with THC. When used alone, CBD is largely best for inflammatory pain, such as that caused by arthritis or injuries. In one animal study on arthritis pain, it was found that the topical application of CBD led to a reduction in inflammation and pain. Another animal study found that CBD helps to reduce neuropathic pain through the suppression of chronic inflammation.
CBD does not directly bind to the receptors found in the endocannabinoid system but rather works to modulate the effects of the endocannabinoids the cannabinoids found naturally in our bodies as well as working as a CB1 receptor antagonist.
The main mechanism by which CBD is thought to help mediate pain is by reducing inflammation , largely by blocking inflammatory mediators.
It is also believed to potentiate glycine receptors, which help to regulate pain at the spinal level. This suppresses both neuropathic and inflammatory pain. THC is used clinically for the treatment of pain and studies find it helps relieve central and neuropathic pain. It is also used to help reduce pain in cancer, AIDS, and fibromyalgia patients, for which resistance to other pain treatments have been found. The mode of action for THC is as a partial CB1 receptor agonist, which means that it will bind to these receptors but not fully which leads to the variability in effects documented when THC is present with other CB1 agonists, antagonists or both.
It has been found to impact the serotonergic, dopaminergic, and glutamatergic systems — an action which may contribute to its pain-relieving benefits. Additionally, THC has been found to act as an anti-inflammatory agent.
While human studies have found benefits from the use of THC, CBD, and whole-plant marijuana in relieving pain, much of the evidence for this use comes from user reports and surveys. When searching for the best cannabis strains for pain relief, you will first want to consider how much THC and CBD is found in the strain. This is because CBD can help to mediate the side effects of THC while also providing additional anti-inflammatory and analgesic properties.
One example would be if you are experiencing inflammation, yet you are wanting to go about your day normally, without the psychotropic effects of THC. Other times you may be in enough pain that you would like something that takes your mind off the pain while also offering pain relief.
In one survey , participants reported that indicas helped more than sativas when it came to headaches, joint pain, neuropathy, and spasticity. Users also reported indicas to be more helpful when it comes to sleep and sedation. Lastly, there are countless user reports on specific strains of weed that have been found to be powerful for relieving pain. While some of these strains are high CBD, indica strains, some strains of weed used for pain do not fall into this category.
It may be that the other cannabinoids, terpenes, and flavonoids have come together in a harmonious balance that leads to strong pain-relieving properties. There are limited studies examining the effect of CBD alone on pain in humans. When it comes to CBD only studies, the majority are preclinical or animal studies. That said, the research conducted thus far, along with countless user reports, suggests that CBD itself may be able to help relieve pain. Activation of cannabinoid receptors has been linked to the inhibition of pain.
The exact mechanisms of action are still being researched, however, CBD has been found to increase the levels of endocannabinoids in the body, specifically anandamide.
It is plausible that this increase in endogenous endocannabinoids could have an impact on pain. Another study suggests that CBD in rats induced suppression of chronic inflammation and neuropathic pain through potentiating glycine receptors. Here we will examine the limited scientific evidence, along with theories relating to the use of CBD for pain.
Neuropathic pain, also known as nerve pain, is a unique type of pain that is caused by injured, dysfunctional, or irritated nerves. This pain tends to be chronic and severe, and with no known cure or remedy, every individual is left to try numerous strategies to find something that works for them.
Some of the most common sources of neuropathy include diabetes, injury, cancer, infections, alcoholism, and autoimmune disorders. In an animal study , researchers found that oral supplementation of CBD led to improvements in neuropathic pain in rats.
Back pain is one of the most common forms of both acute and chronic pain. Acute back pain tends to be caused by an injury, such as by falling or lifting something heavy. Chronic back pain is that which lasts more than three months and is often caused by a ruptured or bulging disc, arthritis, osteoporosis, scoliosis, or nerve pain. Some back pain is partly caused by inflammation, and numerous preclinical and animal studies have found benefits of CBD for inflammation.
Through possible reductions in both nerve and inflammatory pain, CBD may help relieve back pain. When it comes to localized pain, topical CBD lotion or creams may be a great option. While human studies on the efficacy of CBD lotion are lacking, there are plenty of animal studies and personal accounts to support this use.
In one study , researchers found that rats with arthritis treated with transdermal CBD experienced reductions in pain-related behaviors and inflammation. Cannabis and CBD dosing for pain are highly individual. Studies have found a bell-shaped dose-response curve with cannabis extract, meaning that it slowly becomes more effective until it hits a certain point, and then the effectiveness decreases.
To further complicate matters, the effective dose found in human studies varies greatly from one condition and one study to the next. However, doses of Sativex, an oral spray that delivers 2. CBD dosage for pain has not been examined in any human studies. Like the Cannabis sativa extract, studies have found that exceeding the optimal dose of CBD can lead to a reduction in efficacy.
In a study examining the effect of CBD on anxiety, mg and mg were not effective, where mg was. For more details, see text. Following the identification of THC in the s [ 28 ], extensive research was devoted to the identification of its biological targets and endogenous counterparts.
In line with their metabotropic nature, CB receptors mediate their intracellular response through a number of changes affecting signaling cascades, such as inhibition of adenylyl cyclase, activation of G-protein-activated inwardly rectifying potassium channels GIRKs and phosphorylation of extracellular signal-related kinases ERKs [ 35 , 36 ].
The distribution pattern of CB 1 and CB 2 receptors is strikingly divergent, indicating diverse physiological functions: CB 1 is the most abundant metabotropic receptor in the brain, and is primarily distributed in the synaptic terminals of neurons across all the major structures that regulate emotional responsiveness, perception and memory, including prefrontal cortex, amygdala, septo-hippocampal system, striatum, thalamus, brainstem nuclei etc.
CB 1 receptors are typically located on presynaptic terminals [ 42 , 43 ], but they have also been identified in postsynaptic locations [ 44 , 45 ]. In general, CB 1 activation has been shown to inhibit the neurotransmission of other mediators, including glycine, acetylcholine, norepinephrine and serotonin [ 50 ], but the underpinnings of these phenomena have not been completely elucidated.
Additionally, CB 1 receptors have been implicated in short- and long-term synaptic depression, in relation to phasic or tonic endocannabinoid release for a review on these topics, see [ 51 ]. The function of CB 1 receptors may vary depending on the specific interactions that they entertain with other molecular targets.
The key role of CB 1 receptors as mediators of neurochemical homeostasis in the brain is maintained through a complex regulation of their expression. For example, these receptors are subjected to a rapid internalization via clathrin-coated pits following their binding with full agonists; on the other hand, the receptors are also recycled, with a process that requires endosomal acidification and dephosphorilation [ 54 ].
While CB 2 receptors are abundantly expressed in most peripheral organs and particularly in immune cells, where they regulate cytokine secretion and modulate cell trafficking [ 55 ], their distribution in the brain appears to be sparse and particularly confined to microglial cells; nevertheless, recent evidence has revealed the presence of CB 2 receptors in several areas of the brain [ 56 - 58 ]. Interestingly, a number of studies suggest that neuronal CB 2 receptors may be mainly located in postsynaptic terminals [ 58 , 59 ]; nevertheless, the functional role of these targets in the brain remains largely elusive and awaits further characterization.
The existence of cannabinoid receptors other than CB 1 and CB 2 has been postulated based on ample experimental evidence [ 60 - 62 ]. Interestingly, a number of investigations have pointed to GPR55 as a novel putative cannabinoid receptor [ 63 , 64 ]; nevertheless, evidence on the specificity of this receptor for endocannabinoid is still inconclusive [ 65 ]. Both anandamide and 2-AG are derivatives of arachidonic acid, an unsaturated C20 fatty acid with 4 double bonds, which also serves as the precursor for synthesis of other eicosanoids, including prostaglandins and leukotriens.
Anandamide is found in picomolar concentrations and acts as a high-affinity partial agonist for both CB 1 and CB 2 receptors. It is synthesized on demand by enzymatic hydrolysis of the membrane phospholipid N-arachidonoyl phosphatidylethanolamine NAPE , a process catalyzed by several phospholipases [ 66 - 68 ].
Following release and activation of CB receptors, anandamide is rapidly removed from the synaptic cleft by a carrier-mediated system [ 69 - 72 ] and subsequently hydrolyzed by the membrane enzyme fatty acid amide hydrolase FAAH [ 73 - 75 ].
Both these compounds do not activate CB1 receptors [ 76 ], although they may reduce or slow down anandamide degradation by competing with it for FAAH activity.
In comparison with anandamide, 2-AG is much more abundant occurring in nanomolar concentrations across most tissues and acts as a full agonist of both CB receptors. It is produced from 1,2diacylglycerol DAG by diacylglycerol lipase DAGL [ 77 ] and degraded mainly by the cytosolic serine hydrolase monoacylglycerol lipase MAGL [ 78 ], although other enzymes are known to contribute to this process [ 79 ].
The divergent neurochemical profiles of anandamide and 2-AG underscore their different physiological roles. Although our current understanding of the different functions entertained by each endocannabinoid is still rudimentary, the development of FAAH and MAGL inhibitors [ 80 , 81 ] has been instrumental to elucidate the implication of each mediator in synaptic and neurochemical regulation. While 2-AG is known as the retrograde mediator of DSI [ 82 , 83 ] and DSE [ 84 - 87 ], a number of studies suggest that anandamide may serve as an activity-dependent regulator of monoaminergic transmission [ 88 - 90 ].
Recent evidence points to a potential biological antagonism between anandamide and 2-AG [ 91 , 92 ]; on the other hand, emerging evidence points to a similar role of anandamide and 2-AG in the regulation of anxiety albeit in relation to different receptors and pain [ 93 ].
Other lipids have been indicated as putative endocannabinoids, including 2-arachidonoylglycerylether noladin ether [ 95 ] and O-arachidonoylethanolamine virodhamine [ 96 ] Fig. Additionally, recent evidence has identified that CB receptors may be modulated by peptidic ligands, such as hemopressin and its derivatives [ 97 , 98 ]. The employment of cannabis for its medicinal, relaxing and mood-enhancing properties has been documented across most ancient civilizations.
Originally introduced in Chinese pharmacopoeia during the third millennium BCE [ 99 , ], cannabis became a popular remedy throughout Asia and Europe in the following centuries [ 99 , ]. The inclusion of cannabis in the medical treatises by Dioscorides and Galen secured the herb a stable reputation in the Roman Empire and the Arabic world [ ]. Until the early 20 th century, the plant remained a valuable therapy for a large number of diseases [ ]; however, growing concerns about the psychoactive and narcotic effects of cannabis led to a progressive restriction and ultimate ban of its usage in the United States and several European countries [ , ].
Despite its illicit status, cannabis remains one of the most popular recreational drugs, particular among adolescents and young adults, in view of its mood-enhancing and euphoriant characteristics [ - ]. Most psychological and behavioral effects of marijuana and other hemp products are induced by THC through activation of CB 1 brain receptors.
In fact, although THC and most synthetic cannabinoids are known to activate both CB 1 and CB 2 receptors, their actions on anxiety-like behaviors and emotional regulation are efficiently countered by selective CB 1 receptor antagonists, such as rimonabant see next section [ ]. The studies on the psychological effects of cannabis and THC have unfolded a highly complex and often contradictory scenario, fostering a long-standing debate on the potential harms and benefits of its products.
An important aspect of this discussion particularly in consideration of its legal aspects and the potential therapeutic applications of hemp derivatives , revolves around the distinction between use and misuse of cannabis.
In particular, whereas the abuse and dependence liability of cannabis is generally well-recognized [ , ], the definition of these phenomena has been heavily criticized as reflective of political agendas rather than scientific bases. For instance, the diagnosis of substance abuse, according to the criteria listed by the DSM—IV TR, is based on the manifestation of at least one of four symptoms: The applicability of some of these standards to marijuana and other cannabis derivatives, however, has been questioned [ 99 ], also in view of their lower potential to induce physical harm in comparison with other legal substances, such as alcohol and tobacco [ ].
While the controversies surrounding cannabis are far from subdued and are often permeated and masked by conflicting ideological credos , standardized studies on cannabinoids have highlighted that the psychological and behavioral outcomes of this substance are highly variable and range from relaxation, euthymia and heightened sociability to panic, paranoid ideation and psychosis [ - ].
The latter interpretation is supported by the observation that anxiety-spectrum disturbances and traumas in early developmental stages are a strong predictor for later cannabis use disorders [ - ]; furthermore, several lines of evidence suggest that the anxiolytic effects of THC may partially account for the high prevalence of cannabis use in patients affected by PTSD [ - ] and OCD [ ].
Accordingly, recent clinical studies have shown that THC elicits therapeutic effects in OCD [ ] and trichotillomania, an impulse-control disorder characterized by compulsive hair-pulling [ ]. Nevertheless, prospective analyses show that cannabis use and dependence increase the risk for development of panic disorder [ ], suggesting that the effect of cannabis may vary with respect to the nosological entities within the spectrum of anxiety disorders.
Of note, chronic consumption of cannabis has been hypothesized to exacerbate depressive or anxious manifestations, and reduce the therapeutic efficacy of anxiolytic agents [ , - ]; an interesting theoretical implication of this finding is that long-term exposure to cannabinoid agents may lead to profound alterations of synaptic plasticity and neurochemical homeostasis and alter the pathophysiological trajectory of anxiety and mood disorders.
Thus, while cannabis may be initially used as a self-therapy for certain anxiety disorders, the prolonged exposure to this substance in vulnerable individuals may in turn alter or aggravate the clinical course of these conditions and render the patients refractory to standard treatments.
The ability of cannabis to either exacerbate or attenuate emotional reactivity is highly influenced by numerous factors, including its chemotype, as well as the influence of genetic, developmental and contextual variables. Unfortunately, little is still known about the susceptibility factors that govern the behavioral outcomes of cannabis in patients affected by anxiety-spectrum disorders. Indeed, several components have been shown to play a role in this link, including genetic background, age, gender, environmental stress and concurrent use of other drugs; a detailed analysis of these determinants is outside the scope of the present work, but the interested reader should refer to [ ].
Aside from the influence of vulnerability factors, the available evidence indicates that cannabis, THC and other CB 1 receptor agonists exercise a bidirectional influence on anxiety responses as a function of the dosage. The majority of users report that consumption of modest amounts of cannabis and CB 1 receptor agonists results in euphoria, relaxation, heightened perception, sociability and creativity, moderate to high doses have been reported to elicit phobia, agitation, panic, dysphoria, psychotic manifestations and cognitive impairments [ - , , - ].
In line with these premises, early studies showed a robust anxiolytic efficacy of low-dose nabilone in comparison with placebo [ , ]. The biphasic effects of cannabinoids on anxiety-related responses have been extensively documented in rodents. The bidirectional action of CB 1 receptors on anxiety responses may be related to the modulatory role of these targets on GABA and glutamate release across amygdala and other forebrain areas [ 41 , , ].
As these two major neurotransmitters affect anxiety in an opposite fashion, different doses of cannabinoids and synthetic CB 1 receptor agonists may indeed produce highly divergent effects, in relation to their ability to affect the homeostasis and the balance of GABA and glutamate for a review on these issues, see [ ].
Furthermore, CB 1 receptors have been shown to play critical roles in the regulation of most neurochemical substrates of anxiety, including the neurotransmitters serotonin, norepinephrine and acetylcholine, as well as stress hormones, colecystokynin and opioid peptides [ 50 , ].
In line with this concept, the infusion in the periaqueductal grey of arachidonylchloroethylamide ACEA , an anandamide synthetic analog with high CB 1 receptor selectivity, elicited anxiolytic-like effects in rats in an elevated plus maze, with a bell-shaped dose-response curve [ ], the highest doses being associated to no significant behavioral change.
Novel categories of compounds have been patented for potential efficacy as selective CB 1 receptor modulators, including sulfonyl-benzamides [ ] and tetrasubstituted imidazole derivatives [ ].
To the best of our knowledge, however, no findings on the action of these compounds in anxiety regulation have been reported to date. The majority of preclinical studies found that these compounds are anxiogenic at high doses [ , , , ] and ineffective at low doses [ , ]. The anxiogenic properties of CB 1 antagonists, were unequivocally confirmed by clinical data on the psychiatric side effects of rimonabant.
The significant increase in anxiety, depression and suicidality in patients under treatment with rimonabant [ - ], in particular, led to the withdrawal of the drug from the European market in October, As a consequence, several pharmaceutical companies announced the interruption of their clinical research on CB 1 receptor antagonists, including taranabant from Merck and otenabant from Pfizer , both in Phase 3 of development.
Some of the anxiogenic properties of rimonabant and analogs have been speculated to be due to their activity as inverse agonists; as a result, the therapeutic use of newly-developed neutral CB 1 antagonists has been proposed, with the hypothesis that these compounds would not elicit the untoward psychological effects observed with rimonabant and its analogs [ , ]; this idea is supported by recent findings, showing that unlike CB 1 receptor inverse agonists, the neutral antagonists of this targets fail to facilitate the acquisition or consolidation of fear [ ].
Few studies have actually evaluated the role of CB 2 receptor in anxiety and stress response. Some of these investigations indicated that the suppression of CB 2 receptor in the brain, through intracerebroventricular injection of antisense nucleotide sequences, elicited anxiolytic effects in rodents [ ]. In contrast, Garcia-Gutierrez and Manzanares [ ] recently described that the overexpression of CB 2 receptors reduced anxiogenic-related behaviors in the light-dark box and elevated plus maze.
These premises point to the possibility that CB 2 receptor ligands may also play a role in the modulation of anxiety disorders. This hypothesis, however, awaits further examination with proper pharmacological tools. Several lines of preclinical work have shown that CBD reduces the effects of THC on several behavioral functions [ - ].
In line with these data, CBD has been found to reduce the anxiety and improve the sensation of well being induced by an acute, high THC dose in healthy volunteers [ ]. In contrast with these data, a number of studies have shown that CBD pretreatment potentiated the behavioral effects induced by THC [ - ].
These actions may signify the ability of CBD to inhibit cytochrome Pmediated drug metabolism [ , ], which may increase THC blood and brain concentrations [ , ]. Of note, the anxiolytic action of CBD also appears to be bidirectional, as only low to moderate doses, but not high doses, have been associated with exert anxiolytic effects [ , ].
The anxiolytic action of CBD do not appear to be mediated by benzodiazepine receptors [ ], but rather by 5-HT 1A serotonin receptors in the bed nucleus of the stria terminalis [ ], a critical component of the amygdaloid complex involved in the regulation of stress response. Accordingly, CBD has been shown to reduce amygdalar responses to fearful stimuli [ ]; this mechanism may be essential for the anxiolytic effects of this compound in social phobia [ ].
Furthermore, CBD has been shown to elicit antipanic effects through the activation of 5-HT 1A receptors in the dorsal periaqueductal gray, a critical area for the modulation of emotional reactivity to stress [ , ].
The systemic administration of the endocannabinoid transport blocker AM Fig. The same compound was shown to attenuate marble burying a paradigm for compulsivity testing in mice, suggesting that this compound may have some potential efficacy for OCD [ ].
Interestingly, the anxiolytic effects of AM were shown to be contributed by both CB 1 and 5-HT 1A receptors [ , ], in a fashion similar to the potent CB 1 receptor agonist CP 55, [ ]. Additionally, AM has been suggested to act as a FAAH inhibitor [ ], although evidence in this respect is controversial [ 72 ]. Chemical structures of endocannabinoid degradation inactivators. Although the possibility of targeting the endocannabinoid carrier for the development of anxiolytic compounds is appealing and has been targeted by a patent proposing these compounds as a pharmacological support for psychotherapy [ ], the elusive molecular identity of the transporter itself has greatly limited the studies.
Furthermore, preliminary data indicate that AM elicits reward in animals and is self-administered by squirrel monkeys [ , ], raising the possibility that endocannabinoid transport blockers may be addictive. In addition to its anxiolytic-like properties, URB was found to exert also antidepressant-like effects in several animal models with high face and predictive validity, such as the forced swim, tail suspension and chronic mild stress paradigms [ 89 , , , ].
The anxiolytic action of FAAH inhibitors has been suggested to depend on the enhancement of anandamide in the dorsolateral periaqueductal gray [ ]; interestingly, however, only low doses of URB in the prefrontal cortex were found to elicit anxiolytic-like effects, through CB 1 receptor activation.
However, higher doses ceased to elicit anxiolysis, in view of their interaction with TPRV1 vanilloid receptors [ ]. Furthermore, the anxiolytic and antidepressant actions of FAAH inhibitors were observed only under conditions of high environmental aversiveness, but not under normal conditions [ , , ].
Importantly, the psychotropic effects of FAAH inhibitors are partially distinct from those associated with cannabinoids, in that they appear to fail to reproduce the hedonic and interoceptive states produced by CB receptor agonists [ 89 ] and to induce self-administration in squirrel monkeys [ ]. Taken together, these data suggest that FAAH inhibitors may be promising tools in the therapy of anxiety and mood disorders with a safer profile than cannabinoid direct agonists.
This idea has been recently endorsed by several authors in recent articles and patents, featuring novel categories of highly selective and potent FAAH inhibitors [ - ] [ ].
However, it should be noted that recent data have recently shown that URB induce a number of side effects in rats, including social withdrawal, working memory deficits [ ] and impairments in auditory discrimination and reversal of olfactory discrimination [ ]. The role of 2-AG in emotional regulation has been difficult to ascertain until the recent development of highly selective monoacylglycerol lipase MAGL inhibitors [ 35 , ]. Several lines of evidence have suggested that 2-AG plays a pivotal role in the pathophysiology of anxiety and defensive behaviors.
Recent evidence has shown that this compound exerts anxiolytic-like effects in the elevated plus maze and in marble buyring, at doses that do not affect locomotor activity [ 93 , , ]. Similarly to the effects described for FAAH inhibitors see above , the anxiolytic effects of this compound were observed in highly aversive or anxiogenic contextual settings [ ].
The neurobiological role of 2-AG in anxiety is still poorly understood, although several studies have shown that environmental stressors alter its biosynthesis and degradation in key brain structures controlling emotional regulation, including periaqueductal grey, amygdala and hippocampus [ , ]. Interestingly, recent evidence has shown that the anxiolytic properties of JZL appear to be mediated by CB 2 , rather than CB 1 receptors [ 93 ], pointing to a potential implication of this receptor in the role of 2-AG in anxiety regulation.
In light of the limitations of our current pharmacological armamentarium for anxiety disorders, the ability of cannabinoids to modulate emotional responses is extremely attractive for the development of novel anxiolytic agents [ ]. At the same time, great concern arises from the protean role of cannabinoids on the regulation of these responses, as well as their misuse liability and other side effects.
The identification of operational strategies for the employment of cannabinoids in the therapy of anxiety disorders is therefore a fundamental goal in psychiatry research. As outlined above, clinical evidence strongly suggests that acute administration of low doses of CB 1 receptor agonists results in anxiolytic effects, while excessive activation of these targets elicits opposite outcomes, following a reverse U-shaped dose-response pattern.
This concept indicates a potential evolution in the search for direct CB agonists, in sharp contrast with the previous trend aimed at the identification of high-affinity CB receptor activators. However, recent preliminary clinical studies have shown that this formulation did not significantly reduce anxiety in fact, it was reported to induce a mild, yet not significant increase of this symptom [ , ], and that CBD did not appear to elicit a significant opposition to the effect of dronabinol [ ], plausibly indicating that a higher concentration of this ingredient or lower relative amount of THC may be necessary to elicit anxiolytic effects.
A third, highly promising avenue for the development of cannabinoid-based anxiolytic therapies may be afforded by FAAH inhibitors.
Unlike endocannabinoid transport blockers and direct CB receptor agonists, these compounds exhibit a number of highly desirable properties for anxiolytic agents: The neurobiological bases of this phenomenon are not completely understood, and may be related to the involvement of other FAAH substrates, such as OEA or PEA; however, recent investigations suggest that the lack of 2-AG enhancement ensuing FAAH inactivation may contribute to the lack of reinforcing properties of URB [ ], potentially suggesting a different role of anandamide and 2-AG in the modulation of reward; this idea is actually consistent with the recent finding that 2-AG is induces self-administration in monkeys [ ].
A key problem concerning the potential application of cannabinoid-related agents and cannabinoids is the relatively little information about their long-term effects following chronic administration. Indeed, the subjective effects of cannabis have been shown to be typically different in chronic users as compared to occasional marijuana smokers [ , ]. Prolonged consumption of cannabis has been shown to induce affective sequelae, including alexithymia and avolition [ , - ].
Interestingly, tolerance has been shown to the effects of THC [ , ], while no information is available on endocannabinoid-related agents. Long-term administration of cannabinoids has been shown to result in a number of neuroplastic adaptive processes, including CB receptor down-regulation [ , ].
Some of these phenomena may indeed be critical in shaping the different emotional responsiveness to cannabis throughout life and reflect a potential pathophysiological loop which may compound the severity of pre-existing anxiety and affective disorders.
Finally, another important step for the employment of cannabinoid-based anxiolytic therapies will be the analysis of the vulnerability factors implicated in the differential responses and long-term sequelae induced by cannabis consumption. For example, numerous meta-analyses and longitudinal studies have established that cannabis consumption in adolescence is conducive to an increased risk for psychotic disorders [ - ].
This association is particularly significant in the presence of other genetic factors, such as the Val Met allelic variant of the gene encoding Catechol-O-methyltransferase COMT [ , ], one of the main enzymes for the degradation of the neurotransmitter dopamine.
Interestingly, it has been shown that the synergistic effect of COMT haplotype and cannabis in adolescence is more robust in conjunction with predisposing environmental variables, such as the exposure to urbanicity and psychosocial stress [ ].
Another gene that may modulate the behavioral responsiveness to cannabinoids is Nrg1 , which encodes for the synaptic protein neuregulin 1. Indeed, the heterozygous deletion of this gene ablates the development of tolerance to the anxiogenic effects of CB receptor agonists [ , ]. These findings suggest that the employment of a pharmacogenetic approach may be a critical screening instrument to identify which patients may be treated with cannabis for medical purposes without risks of neuropsychiatric side effects.
Notably, the role of genes in the mental sequelae of cannabis may also be contributed by epigenetic factors, in consideration of the recent finding that THC induces expression of histone deacetylase 3 [ ]. While studies on the biological determinants of different responses to cannabis are still at their preliminary stages, advances in this area may be essential to allow a personalized approach for the employment of cannabinoid-based therapies in anxiety and mood disorders.
National Center for Biotechnology Information , U. Author manuscript; available in PMC Jun Simone Tambaro and Marco Bortolato. Author information Copyright and License information Disclaimer. See other articles in PMC that cite the published article. Abstract Rich evidence has shown that cannabis products exert a broad gamut of effects on emotional regulation. According to the current classification of anxiety disorders in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders DSM-IV [ 2 ], the main diagnostic entities in this category are: Table 1 Current pharmacological strategies for the treatment of anxiety disorders.
Generalized anxiety disorder Benzodiazepines. Panic attack High-potency benzodiazepines. Post-traumatic stress disorder Selective serotonin reuptake inhibitors. Obsessive-compulsive disorder Tricyclic antidepressants. Open in a separate window. Table 2 Paradigms for testing of anxiety-like behaviors in rodents. Unconditioned anxiety Tests for social anxiety Maternal separation-induced ultrasonic vocalizations for pups. Tests based on antipredator defensive behavior Mouse defense test battery.
Other tests Novelty-induced feeding suppression. Conditioned anxiety Tests on conditional fear Fear- conditioned freezing. Operant conflict test Geiller-Seifter test conditioned suppression of eating. Chemical structures of the major phytocannabinoids. Synthetic cannabinoids In addition to phytocannabinoids, several classes of synthetic CB receptor agonists have been developed; among these families, the best characterized are the synthetic analogs of THC - such as the biciclic compounds CP 47,, CP 55,, CP 55, and the benxopyrans HU and nabilone Fig.
Chemical structures of the major endocannabinoids. Endocannabinoids Both anandamide and 2-AG are derivatives of arachidonic acid, an unsaturated C20 fatty acid with 4 double bonds, which also serves as the precursor for synthesis of other eicosanoids, including prostaglandins and leukotriens. CB 2 receptor ligands Few studies have actually evaluated the role of CB 2 receptor in anxiety and stress response.
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