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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.
... Pre-clinical work suggests CBD likely has anxiolytic effects (Campos et al. 2012;Galaj et al. 2020;Hill et al. 2012;McPartland et al. 2015;Navarrete et al. 2021;Sales et al. 2018). Similar effects have been observed in human subjects research examining the effects of CBD on real-time ratings of anxious arousal in the context of laboratory-based social anxiety elicitation (e.g., Bergamaschi et al. 2011;Linares et al. 2019;Zuardi 1993;Zuardi et al. 2017), as well as symptom ratings in clinical (Berger et al. 2022; Masatka 2019) and vulnerable (Crippa et al. 2021) samples. As discussed in more detail below, the literature is not entirely uniform (e.g., Bolsoni et al. 2022) due to variability in outcomes assessed as well as dosing-related differences across studies. ...
... Second, in terms of administration schedule, CBD may be administered acutely (e.g., testing the effects of a single dose) or repeatedly over time. A laboratory in Brazil conducted a series of randomized, double-blind, placebo-controlled trials using a simulated public speaking task; results suggest acute doses ranging from 300mg to 600mg of oral CBD alleviate anxious arousal related to social anxiety relative to placebo (Bergamaschi et al. 2011;Crippa et al. 2011;Linares et al. 2019;Zuardi 1993;Zuardi et al. 2017). Moreover, studies in which participants administered CBD for periods ranging from 2 to 12 weeks suggest anxiolytic effects (Berger et al. 2022;Crippa et al. 2021;Masataka 2019). ...
... One possibility is that sample characteristics affect response to an acute CBD dose. For instance, laboratorybased work out of Brazil suggests 300mg of oral CBD is the "goldilocks" dose (relative to higher and lower doses) in terms of reducing state anxiety ratings in response to a social anxiety elicitation among healthy subjects (Linares et al. 2019;Zuardi et al. 1993Zuardi et al. , 2017, whereas 600mg of oral CBD had anxiolytic effects in a similar protocol among patients with social anxiety disorder (Bergamaschi et al. 2011). Further, 300mg of oral CBD did not affect anxiety elicited by recalling traumatic events among patients with post-traumatic stress disorder (Bolsoni et al. 2022). ...
Rationale
Evidence suggests cannabidiol (CBD) displays broad therapeutic potential in the context of anxiety; however, no study has examined the effects of CBD on worry, a defining, cognitive feature of anxiety. Additionally, no study has examined the effects of an acute, single dose of CBD compared to repeated CBD administration.
Objectives
Within a sample of 63 individuals with elevated trait worry, the current study aimed to assess the effects of an empirically-derived high dose of CBD (i.e., 300mg) compared to a commercially-derived dose of CBD (i.e., 50mg) versus placebo on worry severity and anxiety symptoms after an acute dose and after a 2-week administration period.
Results
Results indicated no effect of acute CBD dosing on worry severity or anxiety symptoms. Repeated CBD administration similarly did not impact worry severity; however, 300mg of CBD reduced anxiety symptoms across the 2-week administration period compared to placebo.
Conclusions
Taken together, these findings suggest 300mg of oral CBD does not attenuate cognitive symptoms of anxiety (i.e., worry), following both acute and repeated administration. Some evidence for repeated administration of 300mg on physical symptoms of anxiety was obtained. Findings from the current study suggest CBD’s modest anxiolytic effects may be specific to the physical aspects of anxious arousal.
... 27 Both substances are approved medicines used to treat refractory epilepsies (CBD) and spasticity associated with multiple sclerosis (CBD/THC), whereas many other medical uses are currently being investigated. 28,29 In the case of CBD, its anxiolytic [27][28][29] and antipsychotic [30][31][32][33][34] properties have been described in several trials. ...
... 27 Both substances are approved medicines used to treat refractory epilepsies (CBD) and spasticity associated with multiple sclerosis (CBD/THC), whereas many other medical uses are currently being investigated. 28,29 In the case of CBD, its anxiolytic [27][28][29] and antipsychotic [30][31][32][33][34] properties have been described in several trials. ...
... The dose used in the present study (600 mg) is described in the literature, along with higher doses (up to 1500 mg orally), as having antipsychotic potential. 27,28,30,78,79 In previous studies, oral administration of 600 mg of CBD reduced VAMS-indexed anxiety between 90 and 130 minutes after administration in volunteers with social anxiety 80 but not in healthy participants. 81 The doses described with anxiolytic potential are usually lower, between 300 and 400 mg orally. ...
Background:
Serotonergic hallucinogens and cannabinoids may alter the recognition of emotions in facial expressions (REFE). Cannabidiol (CBD) attenuates the psychoactive effects of the cannabinoid-1 agonist tetrahydrocannabinol. Ayahuasca is a dimethyltryptamine-containing hallucinogenic decoction. It is unknown if CBD may moderate and attenuate the effects of ayahuasca on REFE.
Procedures:
Seventeen healthy volunteers participated in a 1-week preliminary parallel-arm, randomized controlled trial for 18 months. Volunteers received a placebo or 600 mg of oral CBD followed by oral ayahuasca (1 mL/kg) 90 minutes later. Primary outcomes included REFE and empathy tasks (coprimary outcome). Tasks were performed at baseline and 6.5 hours, 1 and 7 days after the interventions. Secondary outcome measures included subjective effects, tolerability, and biochemical assessments.
Results:
Significant reductions (all P values <0.05) only in reaction times were observed in the 2 tasks in both groups, without between-group differences. Furthermore, significant reductions in anxiety, sedation, cognitive deterioration, and discomfort were observed in both groups, without between-group differences. Ayahuasca, with or without CBD, was well tolerated, producing mainly nausea and gastrointestinal discomfort. No clinically significant effects were observed on cardiovascular measurements and liver enzymes.
Conclusions:
There was no evidence of interactive effects between ayahuasca and CBD. The safety of separate and concomitant drug intake suggests that both drugs could be applied to clinical populations with anxiety disorders and in further trials with larger samples to confirm findings.
... Early studies showed that acute doses of CBD (60 mg (n = 40) or 1 mg/ kg (n = 8)) could reduce the anxiety produced by THC administration [39,40]. A series of studies went on to show that a single oral administration of CBD (300 mg) is able to reduce the acute anxiety caused by public speaking in a total of 157 volunteers (some of which received placebo or other CBD doses) [41][42][43]. Functional brain imaging studies in healthy (mostly male) volunteers showed that CBD (600 mg) attenuated the blood oxygenation signal in the amygdala and the anterior and posterior cingulate cortex while subjects (n = 15) were processing intensely fearful faces [59] and reduced prefrontal-subcortical neural connectivity when shown fearful faces (n = 15) [46], brain region imaging findings that could be translated into anxiolytic effects. Similarly, a single dose of 400 mg reduced anxiety in healthy males (n = 10) associated with neuroimaging changes in the limbic and paralimbic brain areas [45]. ...
... It is interesting that this study was mainly in female participants, and recent preclinical data suggest that the anxiolytic effects of CBD are more pronounced in males rats and vary greatly across the female rat hormonal cycle [61]. A single oral of CBD Healthy volunteers 1 mg/kg or 60 mg, single dose Blocked the anxiety and subjective alterations induced by Δ 9 -THC [39,40] 300 mg, single dose Reduced anxiety in response to public speaking n/a [41][42][43] 32 mg inhaled single dose Enhanced consolidation of explicit fear extinction n/a [44] 400 mg, single dose Decreased subjective anxiety and increased mental sedation with changes in the limbic and paralimbic brain areas n/a [45] 600 mg, single dose Disruption of prefrontal-subocritical connectivity during emotional processing Attenuated the blood oxygenation leveldependent signal in the amygdala and the anterior and posterior cingulate cortex while subjects were processing fearful faces Reduced resting blood pressure and blood pressure responses to stress Decreased gut permeability induced by aspirin~ 47 nM at 2 h [46][47][48] 600 mg, 7 days Reduced blood pressure response to stress, increased internal carotid artery diameter, reduced arterial stiffness and improved flow mediation dilatation n/a [49] (600 mg) also did not affect emotional processing or selfreported stress (to mental arithmetic) in healthy participants (12 male and 12 female) in a neuroimaging study [62]. And finally, a single dose of oral CBD (150, 300 or 600 mg across 61 healthy adults) did not alter the selfreported fear, panic or tachycardia induced by a 10% carbon dioxide-enriched air breathing challenge [63]. ...
The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial. The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes. In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.
... У той же час представлені результати свідчать про те, що CBD може мати анксіолітичні (протитривожнi) та антипсихотичні властивості, що дало початок ряду досліджень, які тривають і досі. Згідно з комплексними оглядами, гостре та хронічне введення CBD різними шляхами (перорально, інгаляційно, внутрішньовенно) здоровим добровольцям і пацієнтам з різними клінічними станами не спричинило значних побічних ефектів [36,37]. Ці результати підтверджують попередні спостереження досліджень на тваринах, згідно з якими CBD є безпечною сполукою для використання людиною в широкому діапазоні доз. ...
Background. Cannabidiol (CBD), found in Cannabis sativa (hemp), is a non-psychoactive phytochemical substance that has gained considerable popularity over the past decade. Cannabidiol is the main phytocannabinoid, its share in the plant extract can reach 40%. Cannabidiol does not have any of the psychoactive properties that tetrahydrocannabinol (THC) and has a significant advantage for clinical use. Studies of cannabidiol involve studies of cognitive, anxiety and movement disorders, and chronic pain, but there is a lack of high-quality evidence that cannabidiol is effective for these conditions, such as safety and precise dose ranges for each disorder.
Aim: to analyze the main achievements in the development of experimental and clinical use of cannabidiol.
Materials and methods. We conducted a search for scientific studies related to the therapeutic use of cannabidiol. The included studies were selected based on a search of the online databases PubMed, Web of Science, Scopus, Google Scholar for documents related to the history of research and use of cannabidiol (cannabis, cannabidiol, tetrahydrocannabinol, endocannabinoid system, cannabinoid receptors were used as keywords). The search was carried out by two independent authors and 158 sources were selected for analysis, of which 61 were used that met the search criteria.
Results. Based on the analysis of experimental and clinical studies, it was established that cannabidiol has various properties, including antiapoptotic, antioxidant, anti-inflammatory, antipsychotic and neuroprotective. In addition, basic and clinical studies of the effects of cannabidiol have been conducted in the context of many other health conditions, including its potential use in epilepsy, depression, neurodystrophic diseases, schizophrenia, and social phobia.
Conclusion. Therefore, cannabidiol is a non-psychoactive phytochemical compound that can help patients with a different clinical condition. Despite the achievements, further studies are needed to determine the administration regimen and dose, likely side effects with long-term use, particularly in clinical settings.
... Both diazepam and alprazolam reduce physiological indicators of stress, but fail to decrease self-report ratings of anxiety during this paradigm. [124][125][126] On emotion recognition tasks, 127 diazepam reduces attention toward emotional faces and decreases overall startle reactivity, but does not significantly affect facial expression recognition. 122 Lorazepam dampens amygdalar reactivity to faces expressing both positive and negative emotions. ...
Background and hypothesis:
Diminished social motivation is a negative symptom of schizophrenia and leads to severe functional consequences for many patients suffering from the illness. However, there are no effective medications available to treat this symptom. Despite the lack of approved treatments for patients, there is a growing body of literature on the effects of several classes of drugs on social motivation in healthy volunteers that may be relevant to patients. The aim of this review is to synthesize these results in an effort to identify novel directions for the development of medications to treat reduced social motivation in schizophrenia.
Study design:
In this article, we review pharmacologic challenge studies addressing the acute effects of psychoactive drugs on social motivation in healthy volunteers and consider how these findings may be applied to deficits in social motivation in schizophrenia. We include studies testing amphetamines and 3,4-methylenedioxymethamphetamine (MDMA), opioids, cannabis, serotonergic psychedelics, antidepressants, benzodiazepines, and neuropeptides.
Study results:
We report that amphetamines, MDMA, and some opioid medications enhance social motivation in healthy adults and may represent promising avenues of investigation in schizophrenia.
Conclusions:
Given the acute effects of these drugs on behavioral and performance-based measures of social motivation in healthy volunteers, they may be particularly beneficial as an adjunct to psychosocial training programs in patient populations. It remains to be determined how these medications affect patients with deficits in social motivation, and in which contexts they may be most effectively administered.
... Numerous studies have shown CBD has therapeutic efficacy for reducing anxiety in those with generalized social anxiety disorder (Bergamaschi et al. 2011;Crippa et al. 2011), anxiety following an impromptu speech (Zuardi et al. 1993(Zuardi et al. , 2017, and in clinical populations with anxiety (Shannon et al. 2019). For instance, CBD decreased anxiety scores within the first month in 79% of patients with anxiety and this improvement was sustained at the 3-month follow-up (Shannon et al. 2019). ...
Background
The aim of the current study was to examine patterns of medical cannabis use in those using it to treat anxiety and to investigate if the anxiolytic effects of cannabis were impacted by gender and/or age.
Methods
Patient-reported data ( n = 184 participants, 61% female, 34.7 ± 8.0 years) was collected through the Strainprint ® app. Tracked sessions were included if the method of administration was inhalation, treatment was for anxiety and the product used was dried flower. The final analyzed dataset encompassed three of the most commonly utilized dried flower products in anxiety sessions. Independent sample t -tests were used. The core analysis examined within subject changes overtime (pre-medication to post-medication) and interactions between time with two candidate moderators [gender (male, female) and age (18–29, 30–39, and 40 + years old)] by using analysis of variance (ANOVA). For significant main effects of interactions, post hoc tests were conducted using a Bonferroni correction. A secondary analysis examined differences in proportion of emotives endorsed as a function of gender or age using chi-square test of independence.
Results
Cannabis consumption resulted in a significant decrease in anxiety scores among both males and females (average efficacy of 50%) and efficacy was similar across the three cultivars. However, gender differences in efficacy were identified in two of the cultivars. All age groups experienced significant reductions in their anxiety post cannabis consumption; however, the 40 + year old group had significantly less efficacy than the other groups. The overall optimal dosing for the entire cohort was 9–11 inhalations for males and 5–7 inhalations for females, with some variation in dosing across the different cultivars, genders and age groups.
Conclusions
We found all three cultivars had significant anxiolytic effects and were well-tolerated. Some limitations of the study are the moderate sample size, self-reported diagnosis of anxiety, unknown comorbidities and experience with cannabis, whether other drugs or cannabis products were used, and restriction to solely inhaled administration. We suggest that the gender and age differences in optimal dosing could support both healthcare practitioners and patients initiate medical cannabis treatment for anxiety.
Objetivou-se identificar os níveis de adaptação das estratégias de regulação emocional e as probabilidades de associação entre a autorregulação emocional para tristeza, alegria e raiva, e estados afetivos de alunos de pós-graduação. Para isto, participaram 58 alunos de pós-graduação, mestrado e doutorado, de dois programas de uma Universidade Federal, os quais preencheram um questionário de caracterização e as escalas de Satisfação com a vida, de Afeto Positivo e de Avaliação das Estratégias de Regulação Emocional de Adultos. Os dados foram analisados quantitativamente, por meio de estatística descritiva com medida de tendência central, com o auxílio do software SPSS 20. Os resultados apontam que, apesar da diferença entre o número de participantes por programa, os alunos têm utilizado estratégias satisfatórias, visto que não houve pontuação mínima em nenhuma das subescalas – tristeza, raiva e medo. Quando associadas às categorias de estudo, verificou-se que a Satisfação com a Vida apresenta correlação positiva alta com a Alegria e com o Afeto positivo. Além disso, percebe-se que os discentes que apresentaram baixo sentimento de satisfação com a vida, não demonstram animação e engajamento em atividades do cotidiano. A ausência de estratégias adaptativas para emoções negativas tende a afetar diretamente no afeto positivo e no sentimento de bem-estar dos sujeitos. Sugere-se o desenvolvimento de novos estudos, com amostra ampliada e que acompanhe o processo formativo dos alunos, a fim de compreender as influências das estratégias utilizadas no desempenho acadêmico.
Introduction: Cannabidiol (CBD) is a nonintoxicating phytocannabinoid used in clinical treatments and sold widely in consumer products. CBD products may be designed for sublingual or oral delivery, but it is unclear whether either is advantageous for CBD absorption. This study compared CBD pharmacokinetics after providing CBD oil as sublingual drops and within orally ingested gelatin capsules, at a dose relevant to consumer products.
Materials and Methods: Eight males completed three conditions in a participant-blinded, randomized crossover design. Participants received the following combinations of placebo and CBD-containing (69 mg/mL) hemp oil in capsules and as sublingual drops: placebo capsules/placebo drops (Placebo), CBD capsules/placebo drops (CBD-Caps), and placebo capsules/CBD drops (CBD-Drops). Blood samples, blood pressure, and subjective scales were obtained/completed hourly for 6 h and at 24 h.
Discussion: Plasma CBD concentrations were not different between CBD-Caps and CBD-Drops (interaction effect p=0.76). Peak CBD concentration (28.0±15.6 vs. 24.0±22.2 ng/mL), time of peak CBD concentration (4±1 vs. 4±2 h), and area under the concentration curve (45.3±20.3 vs. 41.8±23.3 ng/mL·6 h) were not different between conditions (p≥0.25). Cardiometabolic outcomes (plasma glucose/triacylglycerol, heart rate, blood pressure), liver function (plasma alanine aminotransferase/aspartate aminotransferase), kidney function (plasma creatinine), and subjective feelings/symptoms were not different between conditions (p≥0.07).
Conclusions: Plasma CBD profiles were comparable between CBD-Caps and CBD-Drops, suggesting that there were not meaningful differences in routes of CBD absorption between conditions. This implies that CBD oil delivered sublingually is swallowed before oral mucosal CBD absorption occurs, which may have implications for research design, CBD product design, and consumer product choice.
Introduction:
Studies reveal that cannabidiol may acutely reduce blood pressure and arterial stiffness in normotensive humans; however, it remains unknown if this holds true in patients with untreated hypertension. We aimed to extend these findings to examine the influence of the administration of cannabidiol on 24-h ambulatory blood pressure and arterial stiffness in hypertensive individuals.
Methods:
Sixteen volunteers (eight females) with untreated hypertension (elevated blood pressure, stage 1, stage 2) were given oral cannabidiol (150 mg every 8 h) or placebo for 24 h in a randomised, placebo-controlled, double-blind, cross-over study. Measures of 24-h ambulatory blood pressure and electrocardiogram (ECG) monitoring and estimates of arterial stiffness and heart rate variability were obtained. Physical activity and sleep were also recorded.
Results:
Although physical activity, sleep patterns and heart rate variability were comparable between groups, arterial stiffness (~ 0.7 m/s), systolic blood pressure (~ 5 mmHg), and mean arterial pressure (~ 3 mmHg) were all significantly (P < 0.05) lower over 24 h on cannabidiol when compared to the placebo. These reductions were generally larger during sleep. Oral cannabidiol was safe and well tolerated with no development of new sustained arrhythmias.
Conclusions:
Our findings indicate that acute dosing of cannabidiol over 24 h can lower blood pressure and arterial stiffness in individuals with untreated hypertension. The clinical implications and safety of longer-term cannabidiol usage in treated and untreated hypertension remains to be established.
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).