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The online version of this article doi: Fear and anxiety are adaptive responses essential to coping with threats to survival. Yet excessive or persistent fear may be maladaptive, leading to disability. Symptoms arising from excessive fear and anxiety occur in a number of neuropsychiatric disorders, including generalized anxiety disorder GAD , panic disorder PD , post-traumatic stress disorder PTSD , social anxiety disorder SAD , and obsessive—compulsive disorder OCD. Notably, PTSD and OCD are no longer classified as anxiety disorders in the recent revision of the Diagnostic and Statistical Manual of Mental Disorders-5; however, excessive anxiety is central to the symptomatology of both disorders.
These anxiety-related disorders are associated with a diminished sense of well-being, elevated rates of unemployment and relationship breakdown, and elevated suicide risk [ 1 — 3 ]. Currently available pharmacological treatments include serotonin reuptake inhibitors, serotonin—norepinephrine reuptake inhibitors, benzodiazepines, monoamine oxidase inhibitors, tricyclic antidepressant drugs, and partial 5-hydroxytryptamine 5-HT 1A receptor agonists.
Anticonvulsants and atypical antipsychotics are also used to treat PTSD. These medications are associated with limited response rates and residual symptoms, particularly in PTSD, and adverse effects may also limit tolerability and adherence [ 7 — 10 ]. The substantial burden of anxiety-related disorders and the limitations of current treatments place a high priority on developing novel pharmaceutical treatments.
CBD has broad therapeutic properties across a range of neuropsychiatric disorders, stemming from diverse central nervous system actions [ 11 , 12 ]. In recent years, CBD has attracted increasing interest as a potential anxiolytic treatment [ 13 — 15 ].
The purpose of this review is to assess evidence from current preclinical, clinical, and epidemiological studies pertaining to the potential risks and benefits of CBD as a treatment for anxiety disorders.
In total, 49 primary preclinical, clinical, or epidemiological studies were included. Neuroimaging studies that documented results from anxiety-related tasks, or resting neural activity, were included. THC ratio , were included. Cannabis sativa , a species of the Cannabis genus of flowering plants, is one of the most frequently used illicit recreational substances in Western culture. The 2 major phyto- cannabinoid constituents with central nervous system activity are THC, responsible for the euphoric and mind-altering effects, and CBD, which lacks these psychoactive effects.
Preclinical and clinical studies show CBD possesses a wide range of therapeutic properties, including antipsychotic, analgesic, neuroprotective, anticonvulsant, antiemetic, antioxidant, anti-inflammatory, antiarthritic, and antineoplastic properties see [ 11 , 12 , 16 — 19 ] for reviews. Pharmacology relevant to these actions is detailed below. The primary mechanism by which eCBs regulate synaptic function is retrograde signaling, wherein eCBs produced by depolarization of the postsynaptic neuron activate presynaptic CB 1 Rs, leading to inhibition of neurotransmitter release [ 23 ].
Interactions with the TRPV1 receptor, in particular, appear to be critical in regulating the extent to which eCB release leads to inhibition or facilitation of presynaptic neurotransmitter release [ 25 ]. TRPV1 receptors are also expressed in the brain, including the amygdala, periaqueductal grey, hippocampus, and other areas [ 26 , 27 ].
The eCB system regulates diverse physiological functions, including caloric energy balance and immune function [ 28 ]. The eCB system is also integral to regulation of emotional behavior, being essential to forms of synaptic plasticity that determine learning and response to emotionally salient, particularly highly aversive events [ 29 , 30 ].
Activation of CB 1 Rs produces anxiolytic effects in various models of unconditioned fear, relevant to multiple anxiety disorder symptom domains reviewed in [ 30 — 33 ]. Regarding conditioned fear, the effect of CB 1 R activation is complex: CB 1 R activation may enhance or reduce fear expression, depending on brain locus and the eCB ligand [ 34 ]; however, CB 1 R activation potently enhances fear extinction [ 35 ], and can prevent fear reconsolidation.
Genetic manipulations that impede CB 1 R activation are anxiogenic [ 35 ], and individuals with eCB system gene polymorphisms that reduce eCB tone—for example, FAAH gene polymorphisms—exhibit physiological, psychological, and neuroimaging features consistent with impaired fear regulation [ 36 ].
Reduction of AEA—CB 1 R signaling in the amygdala mediates the anxiogenic effects of corticotropin-releasing hormone [ 37 ], and CB 1 R activation is essential to negative feedback of the neuroendocrine stress response, and protects against the adverse effects of chronic stress [ 38 , 39 ].
Accordingly, CB 1 R activation has been suggested as a target for anxiolytic drug development [ 15 , 43 , 44 ]. In addition to dose-dependent activation of TRPV1 channels, the anxiogenic versus anxiolytic balance of CB 1 R agonists also depends on dynamic factors, including environmental stressors [ 33 , 49 ].
In preclinical studies, 5-HT 1A R agonists are anxiolytic in animal models of general anxiety [ 51 ], prevent the adverse effects of stress [ 52 ], and enhance fear extinction [ 53 ]. They are expressed on serotonergic neurons in the raphe, where they exert autoinhibitory function, and various other brain areas involved in fear and anxiety [ 54 , 55 ].
Mechanisms underlying the anxiolytic effects of 5-HT 1A R activation are complex, varying between both brain region, and pre- versus postsynaptic locus, and are not fully established [ 56 ]. Initial studies of CBD in these models showed conflicting results: When tested over a wide range of doses in further studies, the anxiolytic effects of CBD presented a bell-shaped dose—response curve, with anxiolytic effects observed at moderate but not higher doses [ 61 , 90 ].
All further studies of acute systemic CBD without prior stress showed anxiolytic effects or no effect [ 62 , 65 ], the latter study involving intracerebroventricular rather than the intraperitoneal route. No anxiogenic effects of acute systemic CBD dosing in models of general anxiety have yet been reported.
As yet, few studies have examined chronic dosing effects of CBD in models of generalized anxiety. Anxiolytic effects in models used: Anxiolytic effects of CBD in models of generalized anxiety have been linked to specific receptor mechanisms and brain regions. The midbrain dorsal periaqueductal gray DPAG is integral to anxiety, orchestrating autonomic and behavioral responses to threat [ 91 ], and DPAG stimulation in humans produces feelings of intense distress and dread [ 92 ].
The bed nucleus of the stria terminalis BNST serves as a principal output structure of the amygdaloid complex to coordinate sustained fear responses, relevant to anxiety [ 93 ]. In the prelimbic cortex, which drives expression of fear responses via connections with the amygdala [ 94 ], CBD had more complex effects: As noted, CBD has been found to have a bell-shaped response curve, with higher doses being ineffective.
Stress is an important contributor to anxiety disorders, and traumatic stress exposure is essential to the development of PTSD. In a chronic study, systemic CBD prevented increased anxiety produced by chronic unpredictable stress, in addition to increasing hippocampal AEA; these anxiolytic effects depended upon CB 1 R activation and hippocampal neurogenesis, as demonstrated by genetic ablation techniques [ 81 ]. Finally, CBD, partially via CB 1 Rs, decreased defensive immobility and explosive escape caused by bicuculline-induced neuronal activation in the superior colliculus [ 89 ].
Several studies assessed CBD using contextual fear conditioning. Briefly, this paradigm involves pairing a neutral context, the conditioned stimulus CS , with an aversive unconditioned stimulus US , a mild foot shock. After repeated pairings, the subject learns that the CS predicts the US, and subsequent CS presentation elicits freezing and other physiological responses. By contrast, CBD microinjection in the infralimbic cortex enhanced conditioned freezing [ 70 ].
Finally, El Batsh et al. In this study, CBD was administered prior to conditioning rather than prior to re-exposure as in acute studies, thus further directly comparable studies are required. CBD has also been shown to enhance extinction of contextually conditioned fear responses. Extinction training involves repeated CS exposure in the absence of the US, leading to the formation of a new memory that inhibits fear responses and a decline in freezing over subsequent training sessions.
Further studies showed CB 1 Rs in the infralimbic cortex may be involved in this effect [ 82 ]. CBD also blocked reconsolidation of aversive memories in rat [ 76 ].
Briefly, fear memories, when reactivated by re-exposure retrieval , enter into a labile state in which the memory trace may either be reconsolidated or extinguished [ 97 ], and this process may be pharmacologically modulated to achieve reconsolidation blockade or extinction. Overall, existing preclinical evidence strongly supports the potential of CBD as a treatment for anxiety disorders. Activation of 5-HT 1A Rs appears to mediate anxiolytic and panicolytic effects, in addition to reducing conditioned fear expression, although CB 1 R activation may play a limited role.
While CBD predominantly has acute anxiolytic effects, some species discrepancies are apparent. In addition, effects may be contingent on prior stress and vary according to brain region. Further receptor-specific studies may elucidate the receptor specific basis of this distinct dose response profile.
Further studies are also required to establish the efficacy of CBD when administered in chronic dosing, as relatively few relevant studies exist, with mixed results, including both anxiolytic and anxiogenic outcomes.
In particular, results show potential for the treatment of multiple PTSD symptom domains, including reducing arousal and avoidance, preventing the long-term adverse effects of stress, as well as enhancing the extinction and blocking the reconsolidation of persistent fear memories. The anxiolytic effects of CBD in humans were first demonstrated in the context of reversing the anxiogenic effects of THC. CBD reduced THC-induced anxiety when administered simultaneously with this agent, but had no effect on baseline anxiety when administered alone [ 99 , ].
Further studies using higher doses supported a lack of anxiolytic effects at baseline [ , ]. By contrast, CBD potently reduces experimentally induced anxiety or fear. CBD reduced anxiety associated with a simulated public speaking test in healthy subjects, and in subjects with SAD, showing a comparable efficacy to ipsapirone a 5-HT 1A R agonist or diazepam [ 98 , ]. CBD also reduced the presumed anticipatory anxiety associated with undergoing a single-photon emission computed tomography SPECT imaging procedure, in both healthy and SAD subjects [ , ].
Finally, CBD enhanced extinction of fear memories in healthy volunteers: These rCBF changes were not correlated with anxiolytic effects [ ]. In a series of placebo-controlled studies involving 15 healthy volunteers, Fusar-Poli et al. Response activation is diminished in PTSD and other anxiety disorders, and increased activation predicts response to treatment [ ]. CBD produced no changes in predicted areas relative to placebo but reduced activation in the left insula, superior temporal gyrus, and transverse temporal gyrus.
The fearful faces task activates the amygdala, and other medial temporal areas involved in emotion processing, and heightened amygdala response activation has been reported in anxiety disorders, including GAD and PTSD [ , ]. CBD attenuated blood-oxygen-level dependent activation in the left amygdala, and the anterior and posterior cingulate cortex in response to intensely fearful faces, and also reduced amplitude in skin conductance fluctuation, which was highly correlated with amygdala activation [ ].
Dynamic causal modeling analysis in this data set further showed CBD reduced forward functional connectivity between the amygdala and anterior cingulate cortex [ ]. Epidemiological studies of various neuropsychiatric disorders indicate that a higher CBD content in chronically consumed cannabis may protect against adverse effects of THC, including psychotic symptoms, drug cravings, memory loss, and hippocampal gray matter loss [ — ] reviewed in [ ].
As THC acutely induces anxiety, this pattern may also be evident for chronic anxiety symptoms. Two studies were identified, including an uncontrolled retrospective study in civilian patients with PTSD patients [ ], and a case study in a patient with severe sexual abuse-related PTSD [ ], which showed that chronic cannabis use significantly reduces PTSD symptoms; however, these studies did not include data on the THC: Thus, overall, no outcome data are currently available regarding the chronic effects of CBD in the treatment of anxiety symptoms, nor do any data exist regarding the potential protective effects of CBD on anxiety potentially induced by chronic THC use.
Evidence from human studies strongly supports the potential for CBD as a treatment for anxiety disorders: Limited results in healthy subjects also support the efficacy of CBD in acutely enhancing fear extinction, suggesting potential for the treatment of PTSD, or for enhancing cognitive behavioral therapy.
Further studies are also required to establish whether chronic, in addition to acute CBD dosing is anxiolytic in human. Human experimental findings support preclinical findings, and also suggest a lack of anxiogenic effects, minimal sedative effects, and an excellent safety profile.
Overall, this review emphasizes the potential value and need for further study of CBD in the treatment of anxiety disorders. Disclosure forms provided by the authors are available with the online version of this article.
National Center for Biotechnology Information , U. Journal List Neurotherapeutics v. Published online Sep 4. Blessing , 1 Maria M. Steenkamp , 1 Jorge Manzanares , 1, 2 and Charles R. Author information Copyright and License information Disclaimer. This article has been cited by other articles in PMC. Abstract Cannabidiol CBD , a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders.
Electronic supplementary material The online version of this article doi: Cannabidiol, Endocannabinoids, Anxiety, Generalized anxiety disorder, Post-traumatic stress disorder. Introduction Fear and anxiety are adaptive responses essential to coping with threats to survival. CBD Pharmacology Relevant to Anxiety General Pharmacology and Therapeutic Profile Cannabis sativa , a species of the Cannabis genus of flowering plants, is one of the most frequently used illicit recreational substances in Western culture.
Table 1 Preclinical studies. Open in a separate window. Effective doses are in bold Receptor specific agents: Stress-induced Anxiety Models Stress is an important contributor to anxiety disorders, and traumatic stress exposure is essential to the development of PTSD. Summary and Clinical Relevance Overall, existing preclinical evidence strongly supports the potential of CBD as a treatment for anxiety disorders.
Table 2 Human psychological studies. Table 3 Neuroimaging studies. Evidence from Epidemiological and Chronic Studies Epidemiological studies of various neuropsychiatric disorders indicate that a higher CBD content in chronically consumed cannabis may protect against adverse effects of THC, including psychotic symptoms, drug cravings, memory loss, and hippocampal gray matter loss [ — ] reviewed in [ ].
Summary and Clinical Relevance Evidence from human studies strongly supports the potential for CBD as a treatment for anxiety disorders: Electronic supplementary material Below is the link to the electronic supplementary material.
Required Author Forms Disclosure forms provided by the authors are available with the online version of this article. Anxiety disorders in primary care: Suicide risk in patients with anxiety disorders: Quality of life in the anxiety disorders: Twelve-month use of mental health services in the United States: Cost of disorders of the brain in Europe An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder.
Remission rates in patients with anxiety disorders treated with paroxetine. Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. This means the nerve cells in your brain are better able to transmit messages to each other and therefore improve your mood and reduce your symptoms of anxiety.
Studies on marijuana have given contradictory results, with some findings saying it eases anxiety and others saying it makes it worse. And research on the use of cannabis , particularly by smoking it, suggests it may have some negative consequences. However, studies on CBD are much more promising as researchers have discovered it offers many health benefits yet without the harmful side effects of cannabis or even prescription drugs.
Although there needs to be more studies on how CBD can treat anxiety, such as the benefits and risks, studies to date show it can be a potential alternative solution. A study on sufferers of social anxiety disorder found CBD lowered their symptoms and improved their mood. Researchers discovered CBD changed the way they responded to their anxiety.
Brain scans showed changes in blood flow in regions of the brain which become active when they experienced feelings of anxiety.
In , researchers carried out an analysis of previous studies on CBD oil and anxiety. They concluded CBD oil has the potential to treat many types of anxiety, like social anxiety disorder, panic disorder, obsessive-compulsive disorder , generalized anxiety disorder, and PTSD.
However, researchers said data on the long-term use of CBD oil is limited and more tests need to be carried out on using it as a prolonged treatment. In , researchers published a case study which investigated if CBD could combat post-traumatic stress disorder symptoms and anxiety provoked sleep disorder. The subject, who was a child patient with a background of trauma, witnessed a reduction in anxiety and improved sleep. Have a fear of public speaking? In a study , researchers discovered CBD reduced social anxiety associated with public speaking.
And in , researchers found CBD oil had an anxiolytic and antidepressant effects on animals. In the study mentioned above about social anxiety and public speaking, researchers found a mg dose of CBD was effective in reducing anxiety. However, in other studies researchers have found doses as low as 40mg to be effective in lowering the symptoms of anxiety. We all have a different physiology which means CBD acts differently in each individual. For example, your height and weight can affect the correct dosage.
It will take time for CBD to affect you, so changes can take a while to notice. So you should stick with the same amount of CBD for at least a few days before increasing your dose. For example, you can take one dropper a day for a week so your body has enough time to adapt and you can see if your anxiety improves. And then, if needed, take two droppers a day for a week.
It can also help to divide your dosage into smaller doses throughout the day. CBD is made in a variety of strengths as well so pay close attention to this so you know how much you are taking. Vaping CBD is a great option for faster relief; when inhaled, CBD is absorbed better and much more quickly, ideal for use in stopping panic attacks. The best approach would be to take CBD oil orally for prevention on a regular basis, and then inhale CBD by vape when faster relief is needed.
7 Best CBD Oils For Anxiety [ 2019 Update ]
While CBD oil is not listed on the Controlled Substances Act (CSA), a person should consult their doctor before using it to treat anxiety. Preclinical and clinical studies show CBD possesses a wide regulate fear and anxiety-related behaviors, specifically the Reduction of AEA–CB1R signaling in the amygdala. Cutting-edge studies show that CBD can decrease anxiety. Anecdotal Vaping to treat anxiety from THC-based marijuana for pain. Jessie Gill.