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Effects of ipsapirone and cannabidiol on human experimental anxiety
Abstract
The effects of ipsapirone and cannabidiol (CBD) on healthy volunteers submitted to a simulated public speaking (SPS) test were compared with those of the anxiolytic benzodiazepine diazepam and placebo. Four independent groups of 10 subjects received, under a double-blind design, placebo or one of the following drugs: CBD (300 mg), diazepam (10 mg) or ipsapirone (5 mg). Subjective anxiety was evaluated through the Visual Analogue Mood Scale (VAMS) and the State-trait Anxiety Inventory (STAI). The VAMS anxiety factor showed that ipsapirone attenuated SPS-induced anxiety while CBD decreased anxiety after the SPS test. Diazepam, on the other hand, was anxiolytic before and after the SPS test, but had no effect on the increase in anxiety induced by the speech test. Only ipsapirone attenuated the increase in systolic blood pressure induced by the test. Significant sedative effects were only observed with diazepam. The results suggest that ipsapirone and CBD have anxiolytic properties in human volunteers submitted to a stressful situation.
... In the context of clinical research, Zuardi et al. (1993Zuardi et al. ( , 2017 reported an anxiolytic effect on acute cannabidiol treatment in volunteers undergoing a public speaking test. Furthermore, the anxiolytic effects of CBD mediated by limbic and paralimbic areas were observed through functional neuroimaging, as evidenced by Crippa et al. (2004). ...
... Wistar rats in a state similar to a panic attack Vehicle or CBD (25, 50, and 100 nmol) intra-VMH and NMDA (at 6 nmol) and AM251 (at 100 pmol) CBD causes panicolytic-like effects and decreased unconditioned fear-induced antinociception Khan et al. (2020) Clinical studies Study features Treatment Main findings Reference Placebo-controlled double-blind study (n=40) Placebo or CBD (300 mg), diazepam (10 mg) or ipsapirone (5 mg) CBD attenuated anxiety after test. Ipsapirona and CBD causes anxiolytic effect in humans volunteers Zuardi et al. (1993) Randomized, placebo, doubleblind study. ...
... CBD's highly reproducible and well-acknowledged effect is its efficiency in reducing anxiety (Blessing et al. 2015;Crippa et al. 2011). CBD attenuates the psychotomimetic and anxiogenic effects induced by high doses of THC (Zuardi et al. 1982(Zuardi et al. , 1993. It has been suggested that the anxiolytic effect of CBD can be mediated by either direct activation of 5-HT 1A receptors or indirect activation of CB 1 and TRPV1 via anandamide Guimaraes 2008, 2009). ...
... However, at 24 h, the CBD and control groups showed no time differences in the center zone. The anxiolytic properties of CBD have been reported by many other studies (Blessing et al. 2015;Campos and Guimaraes 2008;Crippa et al. 2011;Zuardi et al. 1993). Although we cannot rule out the possibility that CBD's anxiolytic properties decrease mice's social anxiety and enhance STFP memory in the immediate choice test, it is important to note that CBD also enhances STFP memory in the 24-hour test when CBD's anxiolytic effect faded away. ...
Rationale and objective
Rodents acquire food information from their conspecifics and display a preference for the conspecifics’ consumed food. This social learning of food information from others promotes the survival of a species, and it is introduced as the socially transmitted food preference (STFP) task. The cholinergic system in the basal forebrain plays a role in the acquisition of STFP. Cannabidiol (CBD), one of the most abundant phytocannabinoids, exerts its therapeutic potential for cognitive deficits through versatile mechanisms of action, including its interaction with the cholinergic system. We hypothesize a positive relationship between CBD and STFP because acetylcholine (ACh) is involved in STFP, and CBD increases the ACh levels in the basal forebrain.
Materials and methods
Male C57BL/6J mice were trained to acquire the STFP task. We examined whether CBD affects STFP memory by administering CBD (20 mg/kg, i.p.) before the STFP social training. The involvement of cholinergic system in CBD’s effect on STFP was examined by knockdown of brain acetylcholinesterase (AChE), applying a nonselective muscarinic antagonist SCO (3 mg/kg, i.p.) before CBD treatment, and measuring the basal forebrain ACh levels in the CBD-treated mice.
Results
We first showed that CBD enhanced STFP memory. Knockdown of brain AChE also enhanced STFP memory, which mimicked CBD’s effect on STFP. SCO blocked CBD’s memory-enhancing effect on STFP. Our most significant finding is that the basal forebrain ACh levels in the CBD-treated mice, but not their control counterparts, were positively correlated with mice’s STFP memory performance.
Conclusion
This study indicates that CBD enhances STFP memory in mice. Specifically, those which respond to CBD by increasing the muscarinic-mediated ACh signaling perform better in their STFP memory.
... SD symptoms (J. A. Crippa et al., 2018;Guimarães et al., 1990;Papagianni & Stevenson, 2019;Uhernik et al., 2018). In healthy humans and in patients with generalized social anxiety disorder, oral CBD reduced self-report measures of anxiety at baseline and during the Simulated Public Speaking Test. (Bergamaschi et al., 2011;J. A. Crippa et al., 2004;A. W. Zuardi et al., 1993). Similarly, patients being treated for PTSD had improved outcomes after eight weeks of adjunctive oral CBD (Elms et al., 2019). Clinical trials are now investigating CBD pharmacotherapies (García-Gutiérrez et al., 2020). ...
Rationale
Clinical literature indicates there may be a therapeutic use of cannabidiol (CBD) for stress-related disorders. Preclinical literature remains conflicted regarding the underlying neurobehavioral mechanisms, reporting mixed effects of CBD (increased, decreased, or no effect) on anxiety- and fear-related behaviors. Preclinical data demonstrated that CBD modulates hypothalamus-pituitary-adrenal (HPA) axis gene expression; it is unknown whether CBD changes HPA axis responsivity and how this relates to altered behavior.
Objectives
We aimed to evaluate whether acute or chronic CBD administration would alter physiological and behavioral measures of HPA axis responsivity in male or female mice.
Methods
C57BL/6 mice of both sexes were injected with vehicle or CBD (30 mg/kg, i.p.) daily for 26 days. Plasma corticosterone (CORT) levels were evaluated following dexamethasone suppression and adrenocorticotropin hormone stimulation tests after acute and chronic CBD exposure. After chronic CBD, mice were tested for anxiety-like behavior using an elevated plus maze (EPM) and associative fear learning and memory using a trace fear conditioning (FC) protocol.
Results
Compared to vehicle, CBD induced a state of HPA axis hyperactivation, an effect which was significant in males; it also normalized anxiety-like behavior in female mice classified as having HPA axis hypofunction and primed all female mice for enhanced conditioned responding. Significant sex differences were also detected: females had greater plasma CORT levels and HPA axis responsivity than males, exhibited less EPM anxiety-like behavior, and were more responsive during FC.
Conclusions
CBD potentiated physiological and behavioral markers of HPA axis function and normalized anxiety-like behavior in a sex-specific manner. This observation has implications for cannabinoid-based drug development targeting individuals with stress-related disorders involving HPA axis hypofunction pathology.
... An early study by Zuardi et al. (1982) reported that CBD acutely reduced the subjective anxiogenic effects of delta-9-tetrahydrocannabinol (THC) relative to placebo in eight healthy participants. In a second, placebo-controlled study, they reported that CBD reduced subjective anxiety in 10 healthy participants performing a public speaking task (Zuardi et al., 1993). A third study by this group (Bergamaschi et al., 2011) compared the effects of CBD and placebo on subjective stress-and anxietyrelated responses in participants diagnosed with social anxiety disorder (SAD) completing a public speaking task. ...
Background
Cannabidiol (CBD) impacts brain regions implicated in anxiety reactivity and stress reactivity (e.g., amygdala, anterior cingulate cortex (ACC), anterior insula (AI)); however, placebo-controlled studies are mixed regarding CBD’s anxiolytic effects. We previously reported that CBD expectancy alone can alter subjective, physiological, and endocrine markers of stress/anxiety; however, it is unclear whether these findings reflect altered brain reactivity. This study evaluated whether CBD expectancy independently alters amygdala resting-state functional connectivity (rsFC) with the ACC and AI following acute stress.
Method
Thirty-eight (20 females) healthy adults were randomly assigned to receive accurate or inaccurate information regarding the CBD content of a CBD-free oil administered during a single experimental session. Following a baseline resting state MRI scan, participants administered their assigned oil sublingually, engaged in a stress task (serial subtraction with negative feedback) inside the scanner, and underwent another resting state MRI scan. Amygdala rsFC with the ACC and AI was measured during each scan, and the subjective state was assessed at six time points. Outcomes were analyzed using ANCOVA.
Results
CBD expectancy (vs CBD-free expectancy) was associated with significantly weaker rsFC between the left amygdala and right ACC ( p = 0.042), but did not systematically alter amygdala-AI rsFC ( p-values > 0.05). We also replicated our previously reported CBD expectancy effects on subjective stress/anxiety in the scanner context.
Conclusion
CBD placebo effects may be sufficient to alter neural responses relevant to its purported anxiolytic and stress-relieving properties. Future work is needed to replicate these results and determine whether CBD expectancy and pharmacology interact to alter neural anxiety reactivity and stress reactivity.
... In 1993, a study using healthy volunteers submitted to experimental anxiety was published by (Zuardi et al. 1993) and reported a positive effect of CBD compared with placebo, an effect that was similar to the BZD diazepam. The putative anxiolytic properties of CBD were later characterized in patients with social anxiety with positive results (Bergamaschi et al. 2011;Linares et al. 2019). ...
Background
Anxiety disorders (ADs) are a complex group of mental disorders and majorly contribute to the global health-related burden. Symptoms and clinical management differ widely depending on the specific diagnosis. There is a need for new, more effective pharmacological treatments for these patients as many patients do not respond to treatment and treatment is not available for several types of AD. The increased interest in the potential effects of cannabidiol (CBD) on symptoms of AD has led to several preclinical and clinical studies that suggest that CBD may be effective in some patients with AD. However, it remains unclear whether and how CBD can be used in the clinical management of ADs due to a lack of sufficiently robust clinical evidence.
Comparative evaluation
This narrative review provides a critical analysis of the current state of the art for ADs and summarizes six recently completed and 22 currently ongoing clinical trials investigating the effects of CBD on ADs or anxiety. The aim was to examine whether the ongoing trials are likely to provide the necessary solid evidence, or whether new studies with more robust design parameters can help to overcome the prevailing lack of solid clinical data for this CBD indication. Most of the trials reviewed are considered exploratory and do not focus on specific types of clinical anxiety or ADs as the primary condition studied. Participant numbers, CBD dose, treatment duration, and CBD formulation vary widely among the studies, and all but two are single-center studies.
Conclusion
For an effective clinical management of ADs using CBD, there is a need for sufficiently powered and appropriately designed clinical trials (RCT, multicenter, defined doses and exposure monitoring, robust primary outcomes) investigating the effect of CBD in specific ADs, such as social anxiety disorder and panic disorder, or in post-traumatic stress disorder.
... There were no effects of CBD on sweat loss during exercise or hydration markers across trials, nor on any subjective outcome. CBD can elicit acute psychological effects, but these have been limited to outcomes like anxiety at present (66). The correlational direction between peak CBD concentrations and between-conditions differences in mean core temperature during exercise was opposite to what would be expected if greater CBD concentrations were exerting an effect on core temperature, i.e., those with a greater peak CBD concentration were more likely to have a greater core temperature in the CBD condition. ...
Purpose
Exertional heat stress can induce systemic endotoxin exposure and a pro-inflammatory cascade, likely impairing thermoregulation. Cannabidiol (CBD) is protective in pre-clinical models of tissue ischaemia and inflammation. Therefore, this study examined the effects of CBD ingestion on exercise-induced thermoregulatory and inflammatory responses.
Methods
In a randomised, double-blinded study, thirteen active males (age 25 ± 5 y; peak oxygen uptake [V̇O 2 peak] 50.4 ± 3.2 mL/kg/min) ingested 298 mg CBD or placebo 105 minutes before 1 h treadmill exercise (60-65% V̇O 2 peak) in 32 °C and 50% relative humidity. Core temperature, skin temperature, heart rate, subjective outcomes and sweat loss were assessed during/after exercise. Plasma osmolality, plasma volume changes and plasma markers of intestinal damage (I-FABP), monocyte activation (CD14) and inflammatory cytokine responses (IL-6, IL-8 and TNF-α) were assessed at baseline, pre-exercise, 20- and 90-min post-exercise.
Results
Core temperature (∆ 1.69 ± 0.48 °C [CBD] and 1.79 ± 0.53 °C [Placebo]) and I-FABP increased during exercise, with no differences between conditions ( p > 0.050). Mean (95% CI) CD14 was 1776 (463 to 3090) pg/mL greater 90 min post-exercise in placebo ( p = 0.049). Median (interquartile range) peak IL-6 concentration was -0.8 (-1.1, -0.3) pg/mL less in CBD ( p = 0.050), whilst the between-conditions difference in IL-6 area under curve was -113 (-172, 27) pg/mL·270 min ( p = 0.054).
Conclusions
CBD did not affect thermoregulation during exertional heat stress but appeared to elicit minor immunosuppressive effects, reducing CD14 and IL-6 responses, warranting investigation in humans under more severe heat strain and other pro-inflammatory scenarios.
Background: Emerging evidence supports cannabidiol (CBD) as a promising therapeutic compound for various health conditions, despite its approval as a medication (product for medical purposes) remaining restricted to a limited range of clinical indications. Simultaneously, the regulation of cannabis-derived products for medicinal and recreational use has expanded their global market availability to meet local community demands. This scenario presents a complex challenge for clinicians, researchers, and industry, as the global appeal of therapeutic uses of CBD is growing more rapidly than the scientific evidence supporting its safety and effectiveness. Outcomes: A narrative review was conducted to discuss the best evidence regarding the pharmacological profile of CBD, its efficacy, and safety within the context of regulation and perspectives on the development of new cannabinoid-based drugs. Key articles addressing the various facets of this issue were selected for comprehensive analysis. Conclusions: Clinicians and researchers may face unique challenges in understanding the pharmacological profile of CBD and the prospects for developing its clinical indications, given the heterogeneity of clinical terminologies and the quality and composition of cannabis-based medical products available on the market. More basic and clinical research that complies with regulatory agencies’ testing guidelines, such as good manufacturing practices (GMPs), good laboratory practices (GLPs), and good clinical practices (GCPs), is needed to obtain approval for CBD or any other cannabinoid as a therapeutic for broader clinical indications.
High doses of nicotine administered to rodents serve as a model for studying anxiety and test compounds' potential anxiolytic effects. At these doses, anxiety in rodents is accompanied by disruption of brain‐derived neurotrophic factor (BDNF). The endocannabinoids and nicotine modulate several central nervous system processes via their specific receptors, impacting locomotion, anxiety, memory, nociception, and reward. Cannabidiol (CBD), an active ingredient of Cannabis sativa L., is devoid of psychoactive actions and has gained attention for its anxiolytic, antioxidant, and anti‐inflammatory properties, among others. This work aims to examine the potential anxiety‐reducing properties of CBD in a well‐established experimental mouse model of anxiety‐like behavior induced by high doses of nicotine on male C57BL/6 mice. In this context, the open‐field behavioral test was specially conducted to assess CBD's effects on anxiety‐like behavior and locomotion. Brain neuronal plasticity, modulated by BDNF, along with a diverse array of blood's metabolic markers, was examined as a means of evaluating systemic toxicity under various treatments. Finally, oxidative stress was evaluated through the measurement of glutathione (GSH), superoxide dismutase (SOD), and malondialdehyde (MDA), while pro‐inflammatory cytokine assessments were conducted to evaluate redox status and immune system function. Our research suggests that CBD shows potential in reducing anxiety‐like behaviors induced by high doses of nicotine, by mitigating changes in BDNF protein levels in cerebral hemispheres and cerebellum. At the same time, CBD targets specific liver enzymes, maintains tissue's systemic toxicity (i.e., renal, kidney, and pancreatic), balances redox status (SOD, GSH, and MDA), and regulates the secretion of pro‐inflammatory cytokines (TNF‐alpha and IL‐6).
•Cannabidiol has multiple pharmacological targets.
•The prepulse inhibition test is a translational model of schizophrenia symptoms.
•Cannabidiol prevents the prepulse inhibition disruption induced by amphetamine.
•Cannabidiol induces an acute antipsychotic-like effect.
•Cannabidiol's antipsychotic-like effect seems dependent on 5-HT1A and TRPV1 activation.
Brain 5-HT receptors have been classified in at least six subtypes (5-HT1A, 1B, 1C, 1D, 2 AND 3; Peroutka, 1988), among which the 5-HT1A subtype has been the focus of intense research during the last few years. This receptor type is located both presynaptically on the 5-HT cell bodies (somatodendritic receptors), predominantly in the dorsal and median raphe nuclei and postsynaptically, predominantly in the limbic system (Verge et al., 1985; Weissmann-Nanopoulos et al., 1985). Activation of presynaptic 5-HT1A receptors with 5-HT1A ligands inhibits serotonergic neurotransmission (Hamon et al., 1988; Hjorth and Magnusson, 1988; Sharp et al., 1989a, b) and the physiological role of these receptors is probably to provide the brain with an autoinhibitory feedback system controlling 5-HT neurotransmission. At the postsynaptic level, activation of 5-HT1A receptors results in neuronal inhibition, the consequences of which are not well understood (e.g. Sprouse and Aghajanian, 1988; Martin and Mason, 1987).
Synopsis: Buspirone hydrochloride (HCl)1 is a new anxiolytic with a unique chemical structure. Its mechanism of action remains to be elucidated. Unlike the benzodiazepines, buspirone lacks hypnotic, anticonvulsant and muscle relaxant properties, and hence has been termed ‘anxioselective’. As evidenced by a few double-blind clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety assessed by standard rating scales similarly to diazepam, clorazepate, alprazolam and lorazepam. Like diazepam, buspirone is effective in patients with mixed anxiety/depression, although the number of patients studied to date is small. In several studies, a ‘lagtime’ of 1 to 2 weeks to the onset of anxiolytic effect has been noted; hence motivation of patient compliance may be necessary. Sedation occurs much less often after buspirone than after the benzodiazepines; other side effects are minor and infrequent. In healthy volunteers, buspirone does not impair psychomotor or cognitive function, and appears to have no additive effect with alcohol. Early evidence suggests that buspirone has limited potential for abuse and dependence.Thus, although only wider clinical use for longer periods of time will more clearly define some elements of its pharmacological profile, with its low incidence of sedation buspirone is a useful addition to the treatments available for generalised anxiety. It may well become the preferred therapy in patients in whom daytime alertness is particularly important.
The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by ?9-TCH in normal volunteers, and whether this effect occurs by a general block of the action of ?9-TCH or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg ?9-TCH, 1 mg/kg CBD, a mixture containing 0.5 mg/kg ?9-TCH and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by ?9-TCH, however this effect also extended to marihuanalike effects and to other subjective alterations induced by ?9-TCH. This antagonism does not appear to be caused by a general block of ?9-TCH effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of ?9-TCH.
The pharmacological interaction between cannabidiol (CBD) and (−)δ
9-trans-tetrahydrocannabinol (δ
9-THC) has been studied in rabbits, mice and rats by administering mixtures containing varying amounts of both substances. CBD blocked the following effects of δ
9-THC: catatonia in mice, corneal areflexia in rabbits, the increased defecation and decreased ambulation after chronic treatment and exposures of rats in an open field arena, and the aggressiveness of rats previously stressed by REM sleep deprivation. On the other hand, CBD potentiated the δ
9-THC-induced analgesia in mice and the δ
9-THC-impairing effect on climbing rope performance of rats.
These interactions are tentatively explained by postulating that CBD directly antagonizes the excitatory effects and/or indirectly potentiates the depressant effects of δ
9-THC.
5-HT has been implicated in the mechanisms of anxiety since the seminal studies of Graeff and Schoenfeld (1970) and Geller and Blum (1970). They showed that 5-HT receptor antagonists and inhibition of 5-HT synthesis prevented the ability of foot shock to suppress operant behaviour. The subsequent observation that the anxiolytic benzodiazepine oxazepam decreased 5-HT turnover lead to the suggestion that anxiolytic drugs work by inhibition of 5-HT function (Wise et al., 1972).