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Cannabis, a cause for anxiety? A critical appraisal of the anxiogenic and anxiolytic properties

Cannabis has been documented for use in alleviating anxiety. However, certain research has also shown that it can produce feelings of anxiety, panic, paranoia and psychosis. In humans, Δ 9 -tetrahydrocannabinol (THC) has been associated with an anxiogenic response, while anxiolytic activity has been attributed mainly to cannabidiol (CBD). In animal studies, the effects of THC are highly dose-dependent, and biphasic effects of cannabinoids on anxiety-related responses have been extensively documented. A more precise assessment is required of both the anxiolytic and anxiogenic potentials of phytocannabinoids, with an aim towards the development of the ‘holy grail’ in cannabis research, a medicinally-active formulation which may assist in the treatment of anxiety or mood disorders without eliciting any anxiogenic effects.

Objectives

To systematically review studies assessing cannabinoid interventions (e.g. THC or CBD or whole cannabis interventions) both in animals and humans, as well as recent epidemiological studies reporting on anxiolytic or anxiogenic effects from cannabis consumption.

Method

The articles selected for this review were identified up to January 2020 through searches in the electronic databases OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO.

Results

Acute doses of CBD were found to reduce anxiety both in animals and humans, without having an anxiogenic effect at higher doses. Epidemiological studies tend to support an anxiolytic effect from the consumption of either CBD or THC, as well as whole plant cannabis. Conversely, the available human clinical studies demonstrate a common anxiogenic response to THC (especially at higher doses).

Conclusion

Based on current data, cannabinoid therapies (containing primarily CBD) may provide a more suitable treatment for people with pre-existing anxiety or as a potential adjunctive role in managing anxiety or stress-related disorders. However, further research is needed to explore other cannabinoids and phytochemical constituents present in cannabis (e.g. terpenes) as anxiolytic interventions. Future clinical trials involving patients with anxiety disorders are warranted due to the small number of available human studies.

Background

Cannabis spp. have over 500 phytochemicals documented, including well over 100 cannabinoids, which are unique to the genus [1, 2]. Until recently, cannabis and its components were largely restricted under international legislation due to the perceived lack of medical value and the substantial risk of misuse [2]. As a result, the pharmacology of most of the cannabinoids are largely unknown. However, one of the more potent psychoactive compounds, Δ 9 -tetrahydrocannabinol (THC), has been extensively isolated, synthesised and studied [3] since it was first isolated in 1964 [4]. Along with the emergence of literature on this compound, there has been a corresponding increase in the use of cannabis for medical purposes, with the most frequently stated reasons for its use being for the management of pain, anxiety and depression [5].

Cannabis remains the most commonly consumed illicit drug around the world [6], whilst clinical research is nascent, yet rapidly emerging. Research is urgently required due to the large variety of cannabis preparations that are available on both the licit and illicit drug markets (depending on jurisdictions) [1]. Furthermore, both community and laboratory-based studies have demonstrated that the relative quantities of cannabinoids in the plant may directly affect its pharmacological activity when consumed. For example, when taken together with THC, CBD may potentially offset some of the adverse effects of THC, such as memory impairment and paranoia [7, 8]. It has been demonstrated in rodents that high doses of CBD are able to negate some of the anxiogenic response created by THC [9].

Recreational use of cannabis is commonly reported to lead to a feeling of euphoria accompanied by a decrease in anxiety and an increase in sociability [10]. Conversely, it is also frequently reported that cannabis can produce feelings of anxiety, panic, paranoia and psychosis [3, 11,12,13,14,15,16]. It has also been demonstrated that changes in sociability depends on prior exposure and use of cannabis [17]. So why may this contradictory finding be present? Studies have indicated that the two predominant compounds in cannabis: CBD and THC, appear to have opposing actions, with the reported anxiolytic effect attributed to CBD and anxiogenic outcomes being attributed to the THC [18]. Nevertheless, a number of more recent publications have shown that this outcome of THC is dosage-dependent, with lower dosages having the opposite effect.

There is extensive research supporting the biphasic nature of cannabinoids in both anxiety [19,20,21,22,23,24,25] (Fig. 1) and behavioral responses including motor activity [26,27,28,29,30] and aggression [31]. Different doses of THC have been found to be biphasic in reward and motor activity [32], and memory and cognition [31, 33]. Whilst the majority of these studies have been conducted on rodents, human studies (covered in detail later) have also provided promising results. Several reports have also found that in animals [34,35,36,37], as well as in humans [37], THC acts differently according to whether it is administered by itself or concurrently with other cannabinoids or terpenes. It has been discussed in the literature that CBD, due to its anxiolytic properties, may have a protective effect against certain negative psychological effects from THC [7, 8]. Research has also shown that it may also be capable of antagonising at least some of the adverse effects related to THC [1, 38]. Recent research has indicated that when low-dose CBD (4 mg) is combined with THC the intoxicating effects of THC were enhanced, while high doses of CBD (400 mg) decreased the same effects [38]. Furthermore, the plethora of chemical constituents found in whole cannabis have been found to be more active than single, purified phytocannabinoids [4, 39]. This being said, cannabis terpenoids as potential synergistic contributors to the effects of phytocannabinoids has not yet been explored in sufficient detail [39].

Summary of biphasic anxiolytic/anxiogenic effects of cannabis

The plant’s anxiety-modulating action has largely been attributed to a biphasic interaction with the CB1 receptor. Rey et al. (2012) [40] found that the anxiolytic effects of low doses occur when they interact with the CB1 receptor on cortical glutamatergic terminals. Conversely, interaction with the CB1 receptor on the GABAergic terminals is responsible for anxiogenesis, something which takes place when higher doses are administered. Further, the use of a CB1 receptor antagonist has been found to fully reverse the effects of THC [41]. However, other non-CB1 receptors are also believed to be involved including serotonin 5-HT1A receptors [42] and the opioid system [20, 43, 44]. There has also been research in recent years to determine the neural site at which these interactions take place. These studies have largely involved injecting THC into various parts of the brain in animal models and observing any anxiolytic or anxiogenic effect [41]; or by observing the effects of oral doses on the brains of individuals under the influence of THC using functional magnetic resonance imaging (fMRI) [45]. Not surprisingly, it has also been found that an individual’s history of cannabis use plays a role in the response of an individual to cannabis intake [46], something which has been observed in both animal [20, 42, 43, 47] and human models [48].

Whilst other papers have reviewed the association of cannabis with anxiety prevalence [49], or explored the underlying potential anxiolytic or anxiogenic mechanisms of action [20, 41,42,43,44,45], or covered the current human clinical trial evidence in the area [16], no comprehensive integrated paper exists to date which critically appraises both the potential anxiolytic and anxiogenic effects of the plant across these research domains. This review seeks to fill this void by compiling a broad overview of the scientific literature on both the anxiolytic and angiogenic properties of both whole plant cannabis and isolates (e.g. THC, CBD, and other phytocannabinoids and terpenes) in both animals and humans. This systematic review covers animal models, epidemiological data and human clinical trials, concluding with a perspective for industry, clinicians, and the public about current recommendations for medicinal cannabis formulations which may provide anxiolytic activity with lesser risk of anxiogenic effects.

Method

To provide a comprehensive review of the area, both animal and human studies were sought for inclusion. In order to include as many relevant sources as possible, there were no exclusions based on types of animals or models (testing anxiety or mood paradigms) used in the studies. Human studies included in the review involved either epidemiological studies exploring the cross-sectional or longitudinal association between cannabis use and anxiety, or interventional studies using whole cannabis extracts or isolates (botanically-derived only) for any anxiety disorder, or to test an acute anxiogenic or anxiolytic effect. Synthetic cannabinoid analogues were excluded from this review.

Articles were identified using the electronic databases of OVID MEDLINE, Cochrane Central Register of Controlled Trials, PubMed, and PsycINFO up to January 2020, and only included articles in English. No time limits were set. Intervention studies (animal or human) could involve either acute or chronic administration of cannabis-based treatment. Studies testing major cannabinoids or whole plant interventions were included. Where the composition was unknown, studies where THC was administered via cigarette or inhaler were excluded for the clinical trial portion of this review. In addition, reference lists were searched for additional references. The main database search was split into three systematic search streams: animal models; epidemiological data; human clinical trials (see Fig. 2). An additional limit was set for epidemiological studies over the past five years (2016-2020), due to the breadth of current data. The term ‘significant’ was used for a p value of < 0.05.

Process of identification and screening of articles for inclusion

The following search terms were used to locate animal models as well as epidemiological and intervention studies:

“delta 9 thc OR THC OR tetrahydrocannabinol OR delta 9 tetrahydrocannabinol OR delta 9-THC OR D9-THC OR Delta [9] -THC OR Δ9-THC OR CBD OR canna* OR terpenes AND “anxi* OR anxiety disorder* OR anxiolytic* OR anti-anxiety OR anxiogenic OR social phobia OR social anxiety OR panic disorder OR post-traumatic stress disorder OR PTSD.

Our search revealed a total of 1095 studies with 66 being relevant for a full review of the articles for potential inclusion. A final review revealed a total of 35 studies eligible for inclusion (17 preclinical, 8 human, and 10 epidemiological).

Results

Epidemiological data

Our review of the data revealed 10 studies involving cannabis users consuming whole cannabis preparations or extracts for anxiety (see Tables 1, 2). Included in our review were cross-sectional studies with no demographic limitations. Three studies in particular demonstrated that such use is prevalent, with more than half of the participants in each survey confirming using cannabis for anxiety [50,51,52]. Further, these studies indicate that there is also a significant proportion of people who replaced some or all prescription medication with cannabis use [53, 54]. The majority of participants were recruited online, particularly through social media or through medicinal cannabis suppliers.

The three cross-sectional studies found that respondents reported that they used cannabis medicinally for anxiety, second only to pain [50, 52, 55], with close to half of all survey participants stating they use cannabis for anxiety [50,51,52, 56]. In a study of 1429 participants, Sexton et al. (2016) [50] found that over half (59.8%) of medical users reported using cannabis as an alternative to pharmaceutical prescriptions [50]. Similarly, a US study of 2774 participants found this to be 46% of users [53]. Additionally, one study of 2032 people found that nearly half of the respondents had substituted an anxiety medication prescribed to them by their physician, with medical cannabis [56], and 61% indicated that cannabis had completely replaced their prescribed medication. Likewise, another study consisting of 1513 participants found similar results, with 71.8% indicating that they had reduced their intake of anti-anxiety medications [54] (Table 2).

In a review of 5085 responses recorded in a smart-phone application, it was found that users of the app reported significantly lower anxiety levels following cannabis use [57] (Table 2). Further, only 2.1% experienced exacerbated symptoms, while only 4.4% reported no change in anxiety symptoms. An Australian study of 1748 participants found that fewer than 1% of respondents felt that the treated symptom, including anxiety, had worsened compared to 71 to 92% who felt it had improved [51]. Such results were further confirmed by Turna et al. (2019) [56] where 92% of the 2032 respondents reported that cannabis improved their anxiety symptoms. Despite this response, the scores of self-reported questionnaires indicate that symptoms remained moderately severe.

In a 3-year longitudinal survey of cannabis use by patients with a primary anxiety disorder diagnosis (N = 3723), it was found that remission rates from anxiety disorders were higher among cannabis nonusers (Table 2). However, these differences were not statistically significant in adjusted models [58]. Discrepancies in responses are further highlighted as men reported experiencing greater headache/migraine relief from medical cannabis than women, despite a larger proportion of women reporting using it for this reason. Of note also is that women were significantly more likely than men to report using cannabis to treat anxiety [59]. A summary caveat concerns that the epidemiological data should be considered within the limitation of survey respondents being a ‘captive’ sample who had an active interest in cannabis use.

Animal studies

Our initial search returned 1095 articles, with a further nine studies found through handsearching of the references. A total of 17 preclinical studies were found to be relevant for inclusion (Tables 3 and 4). The focus of the research concerned primarily CBD and/or THC.

With respect to CBD, both Schier et al. (2012) [60] and Blessing et al. (2015) [61] concluded that when it was administered acutely, anxiolytic-like effects were only present at low doses, yet has the advantage of not producing anxiogenic effects at higher dose (see Table 3). Schier et al. (2012) [60] also noted that chronic doses produced mixed results, with both anxiolytic-like and anxiogenic-like outcomes being observed. Lee et al. (2017) [62] observed predominantly anxiolytic-like responses in the studies analysed, which applied to both acute and chronic administration. Iffland & Grotenhermen (2017) [63] concluded that CBD may only be anxiolytic where stress had been induced before CBD administration.

There was also some variance in the results. For example, Valjient et al. (2002) [21] observed that only the highest dose of 5.0 mg/kg had an anxiogenic-like effect, and lowest dose of 0.03 mg/kg had an anxiolytic-like effect in male CD-1 mice. Conversely, Fokos et al. (2010) [64] observed the opposite in male Sprague–Dawley rats with the low dose of 0.5 mg/kg producing an anxiogenic-like effect and the high dose of 1 mg/kg producing an anxiolytic-like effect. In McLendon et al.’s (1976) [65] study of male Rhesus monkeys, all doses from 0.2 mg/kg to 1 mg/kg produced an anxiolytic-like response. Conversely, Rock et al. (2017) [66] observed an anxiogenic-like response for both dosages of 1.0 mg/kg and 10 mg/kg in male Sprague–Dawley rats.

This variance may partly be due to different animals being studied. While McLendon et al. (1976) [65] used monkeys in their study, this was the only study found to do so, with the rest of the reviewed studies using rodents. Studies also differed in design, including types of test employed, the size of the apparatus used, dosages administered, and the route of administration.

Elevated plus-maze (EPM)

Braida et al. (2007) [42] injected male Sprague–Dawley rats with a THC dosage of either 0.015, 0.075 or 0.75 mg/kg and then placed them in the EPM. It was found that THC exhibited a dosage-dependent effect with the highest dosage of THC corresponding to the maximum anxiolytic effect. Another approach involved male Sprague–Dawley rats being administered dosages ranging from 0.075 to 1.5 mg/kg [67]. It was found that even with the addition of a higher dosage compared to the previous study, the maximum anxiolytic effect was still found to occur when the rats were administered 0.75 mg/kg THC, which supports the idea that depending on the dose THC can produce both anxiolytic and anxiogenic responses. The study by Schramm-Sapyta et al. (2007) [68] was unique in that rats were used in their EPM instead of mice. These male CD rats were also divided into two age groups: adolescent and adult. The rats were injected with either 0.5 or 2.5 mg/kg THC. They concluded that while there was a significant effect of drug dose on the percentage of time spent in the open arms, there was no significant effect of age on this outcome. At the lower dose of 0.5 mg/kg though, THC was less anxiogenic in adolescents than in adult rats.

The next study sought to determine the brain regions involved in producing anxiogenic or anxiolytic effects by injecting THC ranging from 0.001 mg to 0.01 mg directly into various parts of the rat brain [41]. The results indicated that in certain regions, different dosages produce opposite effects. For example, when injected into the ventral hippocampus, the lower dose of 0.005 mg produced a significant anxiolytic-like effect, which switches to an anxiogenic-like response when 0.01 mg was injected. In contrast, low doses had no effect when injected into the prefrontal cortex, whereas the higher dose of 0.01 mg produced an anxiolytic like response and 0.025 mg produced an anxiogenic-like outcome. When injected into the basolateral amygdala, 0.001 mg THC induced a significant anxiogenic-like response whereas higher THC doses did not affect anxiety behavior.

In an alternative to the typical rat-model studies above, one study utilised male C57BL/6 JArc mice [69]. When CBD was administered acutely, there was no change in the percentage of time in the open arms or ratio of open-arm entries was observed. Neither was any change in the total number of EPM arm entries. In contrast, Schleicher et al. (2019) [70] found that in male and female C57BL/6J mice who were injected with 20 mg/kg CBD for 6 weeks there was a significant decrease in the time spent in the open arms [70]. Conversely Zieba et al. (2019) [71] found that acute administration of CBD increased time in open arms of EPM in male Fmr1 KO mice. The same mice were all given both doses with at least three days between tests. When given the higher dose (20 mg/kg), they were found to spend a longer amount of time in open arms compared to when they received the lower dose (5 mg/kg) (p < 0.005 and p < 0.05, respectively) [71].

In Long et al.’s (2010) [69] study of chronic administration, male C57BL/6JArc mice received 21 consecutive daily intraperitoneal injections of either THC (0.3, 1.0, 3.0 or 10.0 mg/kg) or CBD (1.0, 5.0, 10.0, 50.0 mg/kg). While there was a trend (p = 0.08) towards an effect of THC on time spent in the inner open arm, there was no effect on the open arm entry ratio. When CBD was administered, there was no effect on the open-arm entry ratio or percentage of time spent on open arms [69]. However, there was a similar trend (p = 0.09). towards an effect of CBD on time spent in the open arm section closest to the center zone of the EPM.

Like Schleicher et al. (2019) [70], Kasten et al. (2019) [72] also used C57Bl/6 J mice, but also included both sexes, and both adults and adolescents in their observations. The mice were injected with THC (1.0, 5.0 or 10.0 mg/kg), CBD (5.0, 10.0 or 20.0 mg/kg), and THC + CBD (10 mg/kg and 20 mg/kg respectively). Although there were no trends consistent across all categories, they did observe that while there was no significant effect of age there was a significant dose-related reduction in the time spent in open arms and open arm entries. Conversely it was observed that there was no interaction between the dose of CBD and the time spent on the open arms.

Another method saw male Sprague–Dawley exposed to either 10 days of chronic unpredictable stress or no stressor [64]. After this period, they were injected with either a low (0.5 mg/kg) or a high (1.0 mg/kg) dosage of THC, then being placed in an EPM. It was observed that in unstressed animals, the rats that were administered either 0.5 mg/kg or 1 mg/kg THC showed anxiolytic-like effects. In stressed animals, however, only the high dosage of THC induced an anxiolytic-like response, whereas the low dosage induced anxiogenic effects. These results directly contradict both the idea that THC is anxiolytic at low dosages, and anxiogenic at high dosages at least when stress is applied.

Light-dark (LD) box

Although the aim of the Valjent et al. (2002) [21] study was to determine the effect of THC and nicotine administered together, we were able to utilise their results in this review, as THC was first administered alone. This involved the acute administration of either 0.03, 0.1, 0.3, 1, 2.5 or 5 mg/kg to determine at what dosage THC would produce a clear anxiolytic-like response. It was found that anxiolysis occurred at a dosage of 0.3 mg/kg. This markedly changed to an anxiogenic effect when 5.0 mg/kg was administered and there was no change in the response relative to vehicle for all other dosages given. These findings were further confirmed when in the same year the low dosage of 0.3 mg/kg THC was again given to male CD1 mice and once again an anxiolytic-like response was observed [20]. This was done based on the conclusions of the previous study, and with the intention to induce this anxiolytic-like response. Alternative dosages of 0.3, 1, 3 or 10 mg/kg were also employed [69]. The timeframe also differed, with these given in 21 daily injections. This study implies that there is a clear correlation between increasing dosages of THC and time spent in the dark area of the LD box.

In contrast to the other studies, Schramm-Sapyta et al. (2007) [68] looked at acute THC administration in adolescent and adult male CD rats. The rats received either 0.5 or 2.5 mg/kg THC. It was observed that the time in the light compartment was significantly reduced proportionally to increasing dose by THC in both adolescents and adults. Conversely, Rock et al. (2017) [73] studied the effect of THC chronic administration on male Sprague–Dawley rats using dosages of 1.0 and 10 mg/kg. At the dosages chosen, THC decreased the amount of time spent in the light chamber of the LD box on days one and 21, suggesting an anxiogenic-like effect both acutely as well as chronically. Furthermore, at a dose of 10 mg/kg only, THC increased the latency to enter the light box, but only on Day 1. This latency to enter was increased with the addition of a prior stressor. Long et al. (2010) [69] found that THC given at a high dose of 10 mg/kg to male C57BL/6JArc mice significantly decreased the time spent in the light compartment. Contrarily, it was observed that when the low dose of 1 mg/kg CBD was administered this resulted in a significant increase in the time spent in the light compartment. However, when 20 mg/kg CBD was given over a period of 6 weeks, no change in anxiety related behaviour was observed [70].

Open field (OF) test

Long et al. (2010) [69] tested mice injected with THC in an OF test. The ratio of central to total distance travelled (distance ratio) and the time spent in the central zone were taken as measures of anxiety. It was noted that when the maximum dosage of 10 mg/kg was given, there was a significant decrease in the time spent in the central area and a decrease in the distance ratio. This was consistently demonstrated when THC was given daily over 21 days, with a significantly decreased overall distance travelled on day 15 and on day 21, the latter of which was also observed when doses of 1 mg/kg and 3 mg/kg were given.

Kasten et al. (2019) [72] found that 5 and 10 mg/kg doses of THC in adult mice reduced total locomotion. In the 5 mg/kg adult group this was significantly correlated with reduced time in the centre of the open field indicating an anxiogenic-like response. When 10 mg/kg CBD was given, reduced activity in the adult group was also observed, but this was not significantly correlated with anxiety-like metrics. In support of this Long et al. (2010) [69] observed that acute doses of CBD (1 and 50 mg/kg) produced an anxiolytic-like effect and Schleicher et al. (2019) [70], who injected male and female C57BL/6 J mice over a period of time, found that anxiety behaviour in the open field test was not affected. In contrast, Zieba et al. (2019) [71] found that in their male Fmr1 KO mice acute CBD treatment had no impact on anxiety related parameters in the open field test [71]. However, they did find that CBD given chronically at 50 mg/kg increased the time spent in the central zone of the OF test on day 15.

Social interaction

The social interaction test for rodents was first introduced by File and Hyde (1978) [74]. In this study experimental manipulation was used to increase anxiety and this was observed to result in a decrease in social interaction. This test has continued to be used as it is sensitive to both anxiolytic and anxiogenic effects [75] and is an accepted measure of anxiety-like behaviours.

Test male C57BL/6JArc mice and those who had received 0.3, 1, 3 or 10 mg/kg THC were placed in opposite corners of a grey perspex arena to test social interaction [69]. Mice were allowed to explore freely for 10 min during which time the authors recorded manually the frequency and total duration of the active socio-positive behaviours undertaken by the mouse who had received the dosage of THC. It was found that while THC decreased the combined frequency of the socio-positive behaviours, the total duration of all these behaviours remained the same. However, the duration was decreased at 10 mg/kg THC, indicating an anxiogenic-like response at this higher dose.

Malone et al. (2009) [9], pre-treated male Sprague–Dawley rats with either vehicle, 5.0 or 20 mg/kg CBD. These rats were then administered either vehicle, 1.0, 3.0 or 10 mg/kg THC. A significant CBD-THC interaction was observed, as well as a significant effect of CBD on the total time spent interacting. The overall trend was that rats treated with a combination of a low dose of CBD and THC interacted less than rats treated with just the THC. However, when the dose of CBD was increased, these rats interacted more than those treated with just the THC. This outcome suggests that while CBD is able to negate some of the anxiogenic response of THC, higher doses of CBD are needed to achieve this.

Cardiac conditioned response (CCR)

McLendon et al. (1976) [65] used pairing one of two tones with the delivery of a peripheral electric shock in male Rhesus monkeys to establish the cardiac conditioned response (CCR). The conditioned response is considered to be part of the complex of physiological and behavioural changes characteristic of anxiety and has been used to study anxiety in human [65, 76]. The effect of various dosages of 0.2, 0.5 or 1.0 mg/kg intravenous THC was given. The results revealed that THC blocked the CCR in a dosage dependent manner and this was consistent across trials and across animals. At the lowest dosage tested of 0.2 mg/kg a slight attenuation was consistently noticed with a reduction in the conditioned response of 5 to 6 beats per minute observed. At the next highest dosage of 0.5 mg/kg a reduction of 10 to 15 beats per minute was noted for each animal and at the highest dosage of 1 mg/kg, there was a resultant complete block of the CCR in every case.

As detailed in Table 4, our search revealed a range of studies of cannabinoids (primarily THC) in anxiety models beginning in 1976. Research over this period of 40 + years has revealed conclusions that are inconsistent. Generally, the results indicate that at lower dosages an anxiolytic response for THC is observed, with the opposite being true of higher doses (however as indicate above across differing animal modes, this finding is not always consistent).

Human studies

Of the initial 1095 articles detected in our initial search, 26 full text articles were assessed for eligibility. Of these, 17 met our initial inclusion criteria and an additional five were identified through handsearching of references. Of these, eight were found to meet inclusion criteria and are included in this review.

Acute human clinical trials

The anxiogenic properties of isolated THC has have been firmly established in humans and as demonstrated in Table 5, and no human studies provided any evidence of anxiolytic effects. However, the dosages administered varied widely in the studies described ranging from 2.5 mg [48, 77] to 30 mg [78]. In addition there were two studies which utilised mg/kg [79, 80]. While these two studies are able to be compared more easily with the animal studies, this difference in measurement means that they are not comparable to the other studies as the masses of the participants are not provided.

Evidence of THC’s potential anxiolytic effects in humans, was first published in 2004. The study sample size consisted of 22 healthy individuals who had previously used cannabis, but had never been diagnosed with a cannabis abuse disorder [77]. In a 3-day, double-blind, randomised procedure, 22 volunteers received 2.5 or 5 mg of THC. They were asked to score their feelings using the Visual Analog Scale for anxiety (VAS-A) [81]. The results showed a statistically significant increase in VAS-A scores of ‘anxious’. This was observed to occur in a dosage-dependent manner, yet there were no statistically significant changes in the VAS-A scores for panic.

In a follow up US study, the same methodology was applied to people who were frequent users of cannabis [48]. The researchers aimed to determine if this frequent use offers protection from or tolerance to the effects of THC. Thirty frequent users were compared to 22 healthy volunteers, who acted as the control. Once again, a correlation between the dosage given and the VAS scores for anxiety was observed with VAS anxiety scores transiently increasing in both groups. It was noted that those who frequently smoked cannabis displayed significantly smaller increases in anxiety than controls.

Converse to the anxiogenic effects of THC, CBD appears to have the opposite effect. In Bergamaschi et al. (2011) [82], participants with social anxiety disorder (SAD) and an additional 12 controls were blindly allocated to receive CBD or placebo 1.5 h before a simulation public speaking test. The Visual Analogue Mood Scale (VAMS), Negative Self-Statement scale, and physiological measures were taken at six time points during the test. CBD administration resulted in significantly reduced anxiety, cognitive impairment and discomfort, and significantly decreased hyper-alertness in anticipatory speech. Further, Crippa et al. (2011) [83], observed regional cerebral blood flow activity in the brain of participants with SAD who were given CBD or placebo. CBD was found to modulate blood flow in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus, and right posterior cingulate gyrus. In addition, participants who received CBD reported significantly lower subjective anxiety than those who received a placebo.

Another two studies utilised Spielberger’s State-Trait Anxiety Inventory (STAI) to measure anxiety [18, 84]. In the first, participants participated in five experimental sessions where they received 0.5 mg/kg THC with the STAI being conducted at the start of the first and last experimental session [80]. In the second study this was done at baseline and 1,2, and 3 h post administration with 10 mg THC [84]. In both cases, an increased STAI score was noted. Further, it was found that both the STAI and the VAMS scores were significantly increased following THC intake relative to intake of a placebo. When CBD was administered alongside THC, this anxiogenic effect appeared to be reduced [18]. When CBD was given by itself, there was no change in the STAI score compared to the baseline. However, a possible reduction in anxiety was evidenced in the results of the VAMS anxiety and tranquilization subscale [84] Compared with placebo, CBD administration did not significantly change any of the subject ratings.

Another similar study, used a differing assessment, the Subjective Drug Effects Questionnaire (SDEQ) [79]. Ten frequent and 10 occasional cannabis users received doses of 0.2, 0.4, and 0.6 mg/kg THC. THC was found to have a profound anxiogenic effect, with participants stating that they felt increasingly more tense, jittery and less in control as the dose was increased. Karniol et al. (1974) [78] also reported a strong anxiogenic reaction as a result of THC administration with subjects expressing that the feeling of anxiety sometimes reached a near panic state. Further, four of the five subjects gave this feeling as the maximum grade possible in this study. In this case, 30 mg of THC was administered. This study also administered various doses of CBD (15.0, 30.0, 60.0 mg) to participants. Anxiety was reported by only two of the 15 subjects. When CBD was administered with THC, the anxiogenic effects of the latter were reduced.

Discussion

Data synthesis

The overall pattern of human clinical data supports consistent anxiogenic effects from THC, while CBD shows a consistent anxiolytic effect. In combination with CBD, the anxiogenic effect of THC has been shown to be decreased. However, further investigation is needed to categorically affirm this effect. Based on this data, it would imply that cannabis preparations higher in CBD and lower in THC cannabis would be most successful in treating anxiety. However, some survey data does not support this, with a preference for high THC cannabis being of greater interest to consumers for addressing affective symptoms. Further to this, only a very small percentage in surveys reported severe or intolerable side effects of using cannabis for their symptoms [51]; and in general, whole cannabis tends to have a much higher THC:CBD ratio. The epidemiological data is in contrast to the findings of the clinical trials.

These discrepancies could be due to the fact that while a substantial number of patients cross-sectionally report using cannabis and related products to treat anxiety symptoms or disorders, it has not been firmly established whether this anxiety occurred before or as a result of the cannabis usage [16, 85]. As epidemiological research largely relies on anonymous surveys, the composition of the cannabis being used is unable to be confirmed. It is known however, that between 1995 and 2015 there has been a 212% increase in THC content in the marijuana flower [86]. It is also known that plants producing high levels of THC are incapable of producing much CBD [86]. Thus, recent studies looking at whole cannabis consumption in theory should provide a relatively reliable source of information regarding the anxiogenic and/or anxiolytic properties of THC. Our review also highlights the lack of data from jurisdictions where cannabis is not legal, as most of the included studies are based on surveys by those living in certain states in the US or Canada where medicinal use is legal. An important consideration to note when assessing the epidemiological data is that many studies are based on self-reported effects from participants who are purposively using cannabis for their anxiety, and thus due to the sample bias, conclusions must be tempered.

In respect to the animal model research, there is strong evidence suggesting that an anxiolytic effect occurs after the administration of a small acute dose of CBD [60, 61, 63]. Results however differed depending on whether CBD was acutely or chronically administered, as well as the animal model used. This was demonstrated by Rubino et al. (2007) [67] and Schleicher et al. (2019) [70], who both observed no change in anxiety behaviour in the open field test, but significant changes in behavior in the elevated plus maze.

As the present data indicates, no clear conclusion can be drawn from the preclinical studies of acute administration of THC. This could in part be due to the types of animal model being utilised. For example, Onaivi et al. (1990) [19] found that in an elevated plus maze, THC induced both in rats and in mice, an increased aversion to the open arms of the elevated plus maze; but this effect was approximately three times greater in rats than in mice. Thus, while the two predominant tests for rodents are the elevated plus maze and the light–dark box, the results are difficult to compare as rats and mice may react differently to the test paradigm. This suggests that physiological parameters such as the cardiac conditioned response used by McLendon et al. (1976) [65] might be a more accurate measure as it relies much less on human observation.

In humans, research has also shown that the anxiogenic effects of THC are greater among infrequent or non-users relative to frequent users [16], and high potency THC in cannabis products in particular, are thought to induce the development of psychotic-like symptoms or overt psychosis in vulnerable individuals. Similarly, intoxication by low-dose CBD has been found to be particularly prominent in infrequent cannabis users [38]. Further, it has been observed in early 1970s research that individuals who were anxious before receiving it became less anxious under the influence of cannabis (note that potentially far lower THC preparations would have been used). Conversely, non-anxious persons became more anxious [87]. In an animal model, Long et al. (2010) [69] found that differences were observed amongst mice depending on the day in which they were tested, which suggests that the length of time over which the treatment is given also effects the anxiolytic and anxiogenic properties. Kasten et al. (2019) [72] also observed inconsistencies across the groups investigated, with adolescent male mice performing differently to adult male mice, which in turn performed differently to adolescent female and adult female mice. This clearly shows that age, sex and background of exposure may have an impact on how an animal or human reacts to THC or CBD inoculation, something which was found by Cuttler et al’s. (2016) [59] epidemiological survey, where different results were reported depending on the sex of the person responding.

Differences in methodologies and limitations of data provided across the studies reviewed, further reduces our ability to draw strong conclusions. This includes the irregularities in doses given, where some studies used mg/kg and others mg only, and different administration methods being used. Most acute studies using THC employ an oral or inhalation route of administration [77]. Oral administration delays the onset of effects by 30 min to two hours, produces lower peak plasma levels, and prolongs the action of the THC compared to the inhaled or intravenous route [88, 89].

In summary, the human clinical studies using acute THC consistently produced an anxiogenic effect, while studies using CBD and epidemiological studies of whole plant cannabis in anxiety disorders showed an anxiolytic effect. This is surprising as the doses of CBD that have been shown to have therapeutic effects are far lower than what is commonly found in cannabis plant matter, such as that which is being used by the majority of participants surveyed in the epidemiological studies [38]. Furthermore, these findings have not been reliably replicated in animal studies, and further larger human RCTs are required for stronger validation.

Development of optimal anxiolytic cannabinoid therapies

Pharmacological treatment of anxiety relies on our understanding of the neurobiological interactions responsible [90]. While there are various different targets, the endocannabinoid system has, in recent years, increasingly been attributed with the control of stress, anxiety and fear. Endocannabinoids appear to modulate this system as well as the dopamine system, and hypothalamo-pituitary-adrenocortical axis [46, 91].

Though several classes of synthetic CB receptor agonists have been developed, these alternatives are high-potency CB1 receptor activators which elicit pronounced psychotropic effects, something which has seen them recently revoked across most Western countries. THC on the other hand, is a partial agonist at the CB1 receptor [38, 90], while CBD acts with low-affinity on the CB1 and CB2 receptors [38]. Cannabis, as a substrate of the CB1 and CB2 receptors in the endocannabinoid system, is therefore a prime substance for investigation.

However, research has been limited given the controversial legal history surrounding cannabis. Policies are rapidly evolving, and access to cannabis and cannabinoid products is increasing worldwide [38], with it now being decriminalised or permitted for medical purposes in many countries [92]. In Australia however, this change only took place in 2016. Prior to this it was considered a schedule 9 drug and so research into its medical use has been highly restricted [93]. As such this is still an emerging field.

With ongoing clinical research into the use of cannabis for anxiety, it is likely that optimised cannabinoid ratios of THC and CBD will eventually be better understood. Various software programs in use by the general public (e.g. Strainprint Technologies, Releaf etc.) may also be of value to researchers tackling this challenge. Apps such as these are able to track patient symptoms and collect data on the specific cannabis dosage form, cannabinoid ratios and particular cannabis products used for certain diseases, conditions or symptomatic relief.

These two constituents may only be part of the story, and continuing research into the pharmacological activity of the cannabinoids themselves may reveal that THC and CBD are not the only cannabinoids of clinical interest in anxiety. Notwithstanding the academic appetite for cannabinoid research, an often-overlooked phytochemical class, such as the terpenes/terpenoids, has also shown significant anxiolytic action. D-limonene and linalool, whilst not exclusively found in cannabis, have demonstrated anxiolytic activity; the former via the 5HT1A receptor [4, 94, 95]. As such, specific chemovars of cannabis with higher expression of these terpenes may be of greater clinical interest, particularly when paired with higher CBD concentrations. With such a complex chemistry extent in the Cannabis genus, it is plausible that many phytochemicals could be contributing to anxiolytic activity, likely interacting with numerous receptor types.  Further, as previously mentioned, some research has shown that the adverse effects of THC, may be dose dependent and are potentially decreased by low doses of CBD [38]. Hence, further research into these interactions would contribute greatly to this area.

Lastly, each individual using cannabis is also unique, making the study of pharmacogenomics an important aspect of ongoing cannabis research [96]. Variability in cannabinoid receptor genes, transporter genes and pharmacokinetic drug metabolism [97], such as that observed in the Cytochrome P450 system, are important factors for consideration. Further investigation of single nucleotide polymorphisms (SNPs), in particular of fatty acid amide hydrolase (FAAH), may potentially affect individual responses to CBD, and is another worthy research pathway in the future [96].

Conclusion

The results of this review suggest that there is tentative support based on epidemiological surveys and clinical studies showing that whole cannabis and CBD may have a beneficial role in anxiety disorders (for certain candidates in this population). In contrast, for isolated THC, acute human studies consistently show an anxiogenic effect. However, animal studies show that there may be potential for THC to be used as an anxiolytic, if given at the right dose for the patient, and that this may require gradual titration to ameliorate initial anxiogenic effects. Further to this, such an approach may be assisted via the co-administration of CBD, other cannabinoids or terpenes found in the cannabis plant which have yet to be studied substantially.

Further human studies are needed to establish consistency in the results, therapeutic thresholds, and dosage required for cannabinoid therapies to produce an anxiolytic effect in humans, and further research on cannabinoids and terpenes may yield a more optimised anxiolytic formulation.

Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems

Public and medical interest in cannabidiol (CBD) has been rising, and CBD is now available from various sources. Research into the effects of low-dose CBD on outcomes like stress, anxiety, and sleep problems have been scarce, so we conducted an online survey of CBD users to better understand patterns of use, dose, and self-perceived effects of CBD.

Methods

The sample consisted of 387 current or past-CBD users who answered a 20-question online survey. The survey was sent out to CBD users through email databases and social media. Participants reported basic demographics, CBD use patterns, reasons for use, and effects on anxiety, sleep, and stress.

Results

The sample (N = 387) consisted of 61.2% females, mostly between 25 and 54 years old (72.2%) and primarily based in the UK (77.4%). The top 4 reasons for using CBD were self-perceived anxiety (42.6%), sleep problems (42.5%), stress (37%), and general health and wellbeing (37%). Fifty-four per cent reported using less than 50 mg CBD daily, and 72.6% used CBD sublingually. Adjusted logistic models show females had lower odds than males of using CBD for general health and wellbeing [OR 0.45, 95% CI 0.30–0.72] and post-workout muscle-soreness [OR 0.46, 95%CI 0.24–0.91] but had higher odds of using CBD for self-perceived anxiety [OR 1.60, 95% CI 0.02–2.49] and insomnia [OR 1.87, 95% CI 1.13–3.11]. Older individuals had lower odds of using CBD for general health and wellbeing, stress, post-workout sore muscles, anxiety, skin conditions, focusing, and sleep but had higher odds of using CBD for pain. Respondents reported that CBD use was effective for stress, sleep problems, and anxiety in those who used the drug for those conditions.

Conclusion

This survey indicated that CBD users take the drug to manage self-perceived anxiety, stress, sleep, and other symptoms, often in low doses, and these patterns vary by demographic characteristics. Further research is required to understand how low doses, representative of the general user, might impact mental health symptoms like stress, anxiety, and sleep problems.

Introduction

In the past years, cannabidiol (CBD), one amongst hundreds of naturally occurring phytocannabinoids found in the Cannabis sativa plant, has received a lot of attention from scientific communities, politicians, and mainstream media channels. CBD is the second most abundant cannabinoid in the Cannabis sativa plant after delta-9-tetrahydrocannabinol (THC), but unlike THC, CBD is not intoxicating (Pertwee 2008). In many countries, including the UK, there is unsanctioned availability of products containing CBD, from oils and capsules to chewing gums, mints, soft drinks, gummies, and intimate lubrication gels.

CBD has not demonstrated any potential for abuse or dependency and is considered well tolerated with a good safety profile, according to a report released by the World Health Organization (WHO) (Geneva CANNABIDIOL (CBD) n.d.). Since January 2019, the European Union (EU) has classified CBD as a novel food, implying that before 1997, consumption was insignificant. Each country has implemented the regulation of CBD differently. In the UK, The Food Standards Agency (FSA) recommends limiting the daily dose of CBD to 70 mg (Cannabidiol (CBD) n.d.). However, researchers have used doses up to 1200 mg without serious side-effects (Davies and Bhattacharyya 2019). Conversely, few clinical trials involving children with treatment-resistant epilepsy who received either 10 or 20 mg/kg of CBD (Epidiolex) for 12 weeks recorded side-effects, such as a reversible rise in liver enzymes (Devinsky et al. 2018a; Thiele et al. 2018).

The popularity of CBD can be partly explained by an increasing number of preclinical and clinical studies indicating a range of potential health benefits. However, mass media interest also plays a significant role. Studies suggest CBD might help with mental health symptoms and neurological conditions like experimentally induced anxiety (Zuardi et al. 1993), generalised social anxiety disorder (Bergamaschi et al. 2011), social phobia (de Faria et al. 2020), and conditions like PTSD (Elms et al. 2019; Shannon and Opila-Lehman 2016) schizophrenia (Zuardi et al. 2006; Leweke et al. 2012; Morgan and Curran 2008; Schubart et al. 2011), addiction (Hurd et al. 2019; Hindocha et al. 2018; Galaj et al. 2020), and epilepsy (Devinsky et al. 2017; Devinsky et al. 2018b; Cunha et al. 1980). These mental health disorders are often co-morbid and include other symptoms CBD might help with, e.g. sleep and impaired cognition. There is also data to suggest CBD could help treat neurodegenerative diseases like Alzheimer’s disease (Watt and Karl 2017; Fernández-Ruiz et al. 2013; Esposito et al. 2006), Parkinson’s disease (Fernández-Ruiz et al. 2013; García-Arencibia et al. 2007), and chronic pain conditions including fibromyalgia (Van De Donk et al. 2019), either alone or with THC (Rog et al. 2005; Berman et al. 2004; Wade et al. 2003; Svendsen et al. 2004; Notcutt et al. 2004). Additionally, in more than 30 countries, health authorities have approved CBD, under the name Epidiolex, to treat two severe forms of treatment-resistant childhood epilepsy (Dravet and Lennox-Gastaut syndrome) (Devinsky et al. 2016; Silvestro et al. 2019). Sativex, a sublingual spray containing an equal amount of THC and CBD, is also approved to treat multiple sclerosis in more than 30 countries (Keating 2017).

When used in high doses, somnolence is a primary adverse effect (Machado Bergamaschi et al. 2011). Patients in CBD clinical trials were more likely to experience sedation (OR 4.21, 95% CI 1.18–15.01) and somnolence (OR 2.23, 95% CI 1.07–4.64) in comparison to placebo (Chesney et al. 2020). Despite this preclinical and experimental research, there is a lack of human clinical trials to establish the efficacy and appropriate CBD indications fully. The effective dose for most of the above indications is still to be determined. In much of the research, high doses of CBD are used (between 300 and 1200 mg), whilst at the same time, globally, millions of CBD users are using low dose CBD. Thus, a disconnect exists between clinical research and the current state of the market.

A cross-sectional study of 2409 cannabidiol users from the USA found that the top three medical conditions reported were chronic pain, arthritis/joint pain, and anxiety, followed by depression and insomnia (Corroon and Phillips 2018). A recent survey carried out by Wheeler et al. of 340 young adults, some of whom were CBD users, found the top reasons to be stress relief, relaxation, and sleep improvement. They found edible CBD products to be the most prevalent (Wheeler et al. 2020). Another study of 400 CBD patients in New Zealand observed an increase in overall quality of life, a decrease in perceived pain, depression, and anxiety symptoms, as well as an increase in appetite and better sleep (Gulbransen et al. 2020).

A national survey indicated that in the UK, 8–11% of the adult population had tried CBD by June 2019 (Andrew et al. 2019). Studies of Google searches have shown considerable increases in CBD interest, with 6.4 million unique searchers in the USA in April 2019 (Leas et al. 2019). Yet it is clear that scientists, physicians, and governments were not prepared for the rapid surge in CBD use.

The regulatory confusion, along with recent media hype, has made it hard for most people to understand the true nature of CBD. Being classified as both a medicine and a supplement in some forms, whilst an illegal substance in others leads to consumer and patient confusion and potential frustration. Therefore, this study aimed to understand users’ consumption patterns regarding dose, route of administration, and reasons for using CBD. We hypothesised that out of all reasons for using CBD, the top three would be anxiety, sleep disturbances, and stress.

Methods

We developed an anonymous online questionnaire to collect CBD users’ self-reported characteristics, preferred method/s, and reason/s for using CBD. The survey was hosted on Survey Monkey Inc. (San Mateo, CA, USA). Data was collected between 10 January 2020 and 18 March 2020. The 20 questions were designed as multiple-choice questions with the option to choose either one or more answers. For some questions, respondents could write an alternative response if no option matched. We collected demographic information (age, sex, and location), CBD use patterns, reasons for use, other medication use, perceived effects, and side effects. The full questionnaire is provided in the supplementary materials.

To access actual CBD users, we collaborated with four different CBD brands and retailers (TheDrug.Store, OTO CBD, With Pollen and Grass & Co.), based in the UK, who sent out the survey to their email databases. The survey was sent out to 14,743 unique email addresses. Two thousand five hundred thirty-four were opened and 475 clicked through to the survey. We also shared the survey with CBD user groups on social media channels like Facebook and LinkedIn. We did not collect any personal data or IP addresses. Ethical approval was not required since this research investigated non-sensitive information using anonymous survey procedures with participants not defined as “vulnerable”. In addition, participation was deemed unlikely to induce undue psychological stress or anxiety based on ethics committee guidelines (UCL REC n.d.).

Statistical analysis

All analyses were conducted in SPSS version 24 (IBM Corporation, Armonk, NY). Valid percentages are reported rather than absolute values for descriptive statistics to account for missing data. We only report data on those reporting using CBD themselves equivalent to 90% of the respondents (e.g., not for veterinary use, not those who had not tried it, and those reporting on behalf of other users). An analysis of non-responders can be found in supplementary materials. We conducted logistic regression models to investigate associations between sex (males [reference category] and females), age (recoded to < 34 years old [reference category], between 35 and 54 years old, and 55+) and location (UK [reference category], other). For CBD use patterns, we used separate models to compare those who did and did not report their primary use of CBD for self-perceived anxiety, stress, and sleep whilst controlling for sex, age, and location. We dummy-coded “time of day” as each category versus all others. We report adjusted odds ratios with 95% confidence intervals and p values with a defined cut-off of 0.05.

Results

The most significant findings were that many CBD users reported that CBD could improve sleep problems, stress, and anxiety and be used for general health and wellbeing. In the detailed results below, you can find the demographics of our survey population (Table 1), the CBD use patterns (Table 2), and logistic regression and OR’s for the different subgroups. The indications for CBD use are shown (Fig. 1), as well as how CBD affects sleep (Fig. 2), and other effects of CBD (Fig. 3). Using CBD for sleep was associated with taking it in the evening, and using CBD for anxiety or stress was associated with the sublingual route. Females had higher odds of using CBD for anxiety and men for post-workout. Details of the results can be found below.

Reasons for cannabidiol use amongst 397 adult cannabidiol users who were allowed to respond to more than one option leading to a total of 1622 responses. Y-axis represents percentage based on total responses

Perceived effects of cannabidiol on sleep amongst adult cannabidiol users responding to the question “how does cannabidiol affect your sleep?” Participants were allowed to select multiple options. Y-axis represents percentage of total responses (n = 522)

Other perceived benefits of cannabidiol amongst adult cannabidiol users. Respondents were asked what other benefits or effects they feel from using cannabidiol. Participants were allowed to select multiple options. X-axis is the percentage of total responses (n = 906)

Demographic characteristics

A total of 430 people started the survey, of whom 15 (3.48%) did not respond to any questions, and 28 (6.5%) reported they did not use CBD themselves (analysis of these non-users can be found in the supplementary materials). Non-CBD-users skipped most questions and had sociodemographic characteristics similar to those of CBD users. Three hundred eighty-seven (90%) reported using CBD themselves. The majority of users were females from the UK (see Table 1). In regards to other medication use, there were a total of 467 responses. 39.4% of respondents reported not taking any other medication, 14.7% “painkillers”, and 14.7% “other” (40% anxiolytics and antidepressants). No other medication was reported by more than 10% of responses.

Logistic regression on location purchased (CBD shop or other) found that those who lived outside of the UK (aOR 2.286, [95% CI 1.35–3.86], p = 0.002) and males (aOR 1.75, [95% CI 1.06–2.88], p = 0.02) had greater odds of purchasing CBD from an “other” location. Each of the primary disorders was included in the model individually, and did not significantly alter the model and were not associated with location purchased.

CBD use patterns

The majority of users take CBD sublingually for 3–6 months (see Table 2). Those 35–54 years old (aOR 1.67 [95% CI 1.02–2.72], p = 0.04) and those 55+ (aOR 2.01, [95% CI 1.11–3.64], p = 0.02) had greater odds of using CBD daily in comparison to less than daily. There were no associations with self-perceived anxiety, stress, or sleep improvement. Females had lower odds of using CBD for greater than 1 year versus less than 1 year (aOR 0.54, [95% CI 0.38–0.88], p = 0.013) suggesting females had used CBD for less time. No associations emerged for self-perceived anxiety, stress, or sleep. There were no sex or age associations for the frequency of use, duration of use, or number of times per day. Females had a greater odds of responding that they take CBD when they need it versus males (aOR 1.79, [95% CI 1.036–3.095], p = 0.037). However, no other associations with age and sex on time of day emerged.

Compared with people not using CBD for anxiety, those who did self-medicate used CBD multiple times a day (aOR 3.44, [95% CI 1.70, 7.00], p = 0.001). Moreover, compared with those not using CBD for self-perceived stress, those who were self-medicating also used CBD multiple times a day (aOR 1.97, [95% CI 1.034–3.77], p = 0.039). Those using CBD for sleep improvement had greater odds of using CBD in the evening (aOR 3.02, [95% CI 1.86, 4.93], p ≤ 0.001) and lower odds of using CBD in the morning (aOR 0.157, [95% CI 0.07–0.38], p ≤ 0.001). Those using CBD for self-perceived anxiety had lower odds of using CBD in the evening (aOR 0.56, [95% CI 0.14–0.45], p ≤ 0.001). No associations emerged between those who did and did not use CBD for self-perceived stress on the time of day they used CBD.

CBD dose and route of administration

Route of administration did not vary by sex. There were lower odds of those aged 55+ of vaping CBD (aOR 0.176, [95% CI 0.04–0.80], p = 0.025) as well as lower odds of those aged 35–55 (aOR 0.245, [95% CI 0.10–0.59], p = 0.002) and 55+ (aOR 0.115, [95% CI 0.025–0.520], p = 0.005) in comparison to 18–34 years old for drinking CBD. Self-reported anxiety (aOR 1.78, [95% CI 1.08–2.92], p = 0.023) and those using CBD for sleep improvement (aOR 1.945, [95% CI 1.152–3.285], p = 0.013) were associated with the sublingual route. Stress was not associated with route of administration.

Reasons for use of CBD

42.6% endorsed using CBD for self-perceived anxiety, followed by 37.5% for stress, 37% for general health and wellbeing, and 37% for improving sleep (see Fig. 1). 24.6% reported use for self-perceived insomnia. Overall, 42.5% of respondents said they were using CBD for some sleep issue, either to improve sleep or for self-perceived insomnia. In the supplementary materials (see Table 2), we show reasons for use broken down by sex, age, and location.

In adjusted logistic models, more males (47.4%) were using CBD for general health and wellbeing than females (30.7%; aOR 0.464, [95% CI 0.30–0.72], p = 0.001). More females were using CBD for self-perceived anxiety (47.9%) than males (34.2%; aOR 1.595, [95% CI 1.021, 2.49], p = 0.04), and for self-perceived insomnia (females 28.6%, males 17.8%; aOR 1.871, [95% CI 1.125–3.112], p = 0.015). More males (14.1%) than females (7.1%) were using CBD for post-workout sore muscles (aOR 0.462, [95% CI 0.236–0.905], p = 0.024).

Self-perceived anxiety

One hundred sixty-five of 387 (42.6%) endorsed using CBD for self-perceived anxiety. In response to the question “how does CBD affect your anxiety levels”, participants responded that they felt less anxious (141/163 (86.5%)), followed by “no difference (I still suffer from the same degree of anxiety)” (21/163; 12.8%), and one person (0.6%) noted greater anxiety. Moreover, participants were asked how often they thought about problems when they were supposed to be relaxing, compared with before they started taking CBD. We found that just 96/163 (58.9%) of respondents thought about their problems less than before, followed by “it hasn’t changed (I still think a lot about problems” (55/163; 33.7%), followed by “it hasn’t changed (I did not think about problems a lot before)” (11/163; 6.7%), followed by (1/163; 0.6%) of respondents reporting thinking about problems more than before.

Amongst those who reported experiencing anxiety, adjusted logistic models comparing those who responded that CBD reduces their self-perceived anxiety with those who responded that they still suffer from anxiety found no associations with age, sex, or location. Similar results emerged for “thinking about problems”.

Self-perceived stress

One hundred forty-five of 387 (37.5%) of respondents endorsed the use of CBD for self-perceived stress. Amongst those using CBD for stress, in response to the question “how does CBD affect your stress level”, participants responded that they felt less stressed (130/141; 92.2% followed by it does not affect my stress levels (I still feel stressed) (11/141; 7.8%). No respondent said that it increased their stress level. Adjusted logistic models comparing those who responded that CBD reduces their stress versus those who responded that they still have stress found no associations with age, sex, or location.

Self-perceived sleep problems

As we initially designed the study to address sleep, we asked detailed questions regarding this. Improving sleep (125/387; 32.3%) and self-perceived insomnia (95/387; 24.5%) were the fourth and fifth-ranked endorsed reasons for using CBD, overall 42.5% endorsed sleep as a reason for use. Respondents said that CBD helped them sleep (see Fig. 2). As we restricted this analysis to respondents who selected using CBD for sleep improvement, there was considerable overlap between using CBD for sleep improvement and self-perceived insomnia. Regarding questions about the time it takes to fall asleep, 48.2%(73/124;) said CBD led them to fall asleep faster, followed by 29/124 (23.4%) who said it did not make a difference and still have a hard time falling asleep, followed by 22/124 (17.7%) who said it did not make a difference because they did not have a problem falling asleep beforehand. Age, sex, and location were not associated with the speed of falling asleep.

Other reported benefits

We asked participants to report on other effects they experience. From a total of 960 responses, the most prevalent effect was calm (21.3%), followed by decreased pain (19.5%) (see Fig. 3). One per cent reported feeling euphoric/high. In examining the “other” responses, 27/960 (9.3%) reported that they did not feel any benefits from the use of CBD.

Sex was associated with sexual enhancement where males reported experiencing more sexual enhancement (9.9%) than females (2.9%) (aOR 0.274, [95% CI 0.11–0.70], p = 0.007). There were no other associations between sex and other CBD benefits. Those aged 55+ (23.1%; aOR 3.8, [95% CI 1.63–8.87], p = 0.002) and those aged 35–54 years old (16.8%; aOR 2.72, [95% CI 1.258–5.876], p = 0.011) reported taking less of their other medications in comparison to those aged under 34 years old (9.9%). Those ages 55+ reported experiencing more “no positive experiences” (14.3%) in comparison to those under 34 (2.7%; aOR 5.31, [95% CI 1.45–19.41], p = 0.012).

CBD side-effects

A total of 388 responses were made, of whom 277/388 (71%) were logged as not experiencing any side-effects. Dry mouth was experienced by 44/388 (11%), and 13/288 (3%) experienced fatigue. All other side-effects were reported less than 2% (e.g. dizziness, nausea, upset stomach, rapid heartbeat, diarrhoea, headache, anxiety, psychotic symptoms, sexual problems, trouble concentrating). No respondents reported vomiting, fainting, liver problems (raised liver enzymes in blood test), or seizures. Adjusted logistic models show no associations of age, of sex with “no side effects” or fatigue. Location of the participants was associated with dry mouth, those who lived outside of the UK had greater odds of experiencing dry mouth (aOR 2.44, [95% CI 1.25–4.75], p = 0.009). No other side-effects were analysed due to the small number of respondents citing other side-effects.

Discussion

This study aimed to investigate CBD use patterns in the general population regarding the route of administration, dose, and indications for use. We found that the main indications for using CBD were self-perceived anxiety, stress, general health and wellbeing, sleep, and pain.

User characteristics and reason for use

More than half of the users were using a daily dose below 50 mg via a sublingual route of administration. Most were using CBD daily, sometimes multiple times per day. We found that respondents who use CBD for self-perceived anxiety and stress tend to use it several times per day, whilst respondents endorsing using CBD for sleep take it in the evening, indicating that user patterns vary according to the symptoms. A recent review suggests half-life is between 1.4 and 10.9 h after oromucosal spray and 2–5 days after chronic oral administration (Iffland and Grotenhermen 2017). In the light of these findings, it may be that people are dosing CBD several times per day to maintain stable plasma levels throughout the day if managing symptoms of stress and anxiety, whilst only using CBD at night if managing sleep problems.

We found that 69.7% of users had been using CBD for less than 1 year. Moreover, only 4.1% had used CBD for more than 5 years, reflecting both that it is a fairly new phenomenon and an increasing interest in CBD in the UK, compared with the USA. A similar American survey reported that 34.6% had used CBD for less than 1 year and 53.2% more than 5 years (Corroon and Phillips 2018). At the time of writing, CBD is legal in all but three, out of fifty, American states, and many of these allow the products to contain THC. In the UK and Europe, non-prescription CBD products are not allowed to contain any THC (< 0.01%). These differences might create a divergence between European vs American consumers’ experiences, and stresses the urgency for internal and external regulation, and education about cannabinoids in Europe.

We found age and sex differences in the reason for CBD use. Most of the sample was female, but males had greater odds of using CBD for general health and wellbeing and post-workout for sore muscles. In contrast, females were more likely to use CBD for self-perceived anxiety and insomnia, reflecting the higher prevalence of both symptoms amongst women (McLean et al. 2011; Li et al. 2002). We also found more females using CBD for fibromyalgia, possibly reflecting the much higher prevalence of fibromyalgia amongst women (Yunus 2002). A recent study compared the subjective effects of 100 mg oral versus vaporised and smoked CBD and found that women reported experiencing more subjective effects of CBD than men (Spindle et al. 2020), which may reflect why women were using CBD for more chronic symptomology. There were also significant age differences, with more people under 34 years old using CBD for general health and wellbeing than older age groups, which might be explained in part by the fact that disease burden generally increases with age. More young people use CBD to reduce self-perceived stress and anxiety, aligning with studies finding young people are more troubled by symptoms of anxiety than older people (Brenes et al. 2008).

In the present study, we found that the largest proportion of respondents used CBD to help with mental health symptoms like perceived anxiety, stress, and sleep problems. This finding aligns with a previous CBD survey that found that anxiety and insomnia were amongst the top 6 reasons for using CBD (Corroon and Phillips 2018). However, Corroon et al. found that the two main reasons for using CBD was arthritis/joint pain and chronic pain, whereas these ranked number six and seven amongst reasons from our respondents. This result may reflect the younger demographics of our sample compared with Corroon et al.

With few variations, the reasons for use in our study were somewhat similar to the results from another study of 400 patients in New Zealand, who were all prescribed sublingual CBD oil with doses ranging from 40 to 300 mg/day (Gulbransen et al. 2020). This study found that the patients had an increase in overall quality of life, including improved sleep and decreased self-perceived anxiety levels and reduced pain scores.

Route of administration, dosing, and side-effects

Younger respondents were more likely to use novel routes of administration, e.g., vaping or drinking. This trend correlates with data showing that more people have tried vaping (in general) amongst younger age groups (Vaping and e-cigarette use by age U.S 2018). Only 9.3% reported vaping CBD in our sample, compared with 19% in the study by Corroon et al. (Corroon and Phillips 2018). The fast onset of vaporised CBD might explain why inhaled CBD is popular for self-perceived anxiety and stress.

Corroon et al. found a more even distribution between various application methods with the most popular being sublingual CBD (23% vs 72,6% in our study sample). Our approach of recruiting respondents through email databases of non-vape CBD brands may explain why the sublingual administration route is much more frequent in our study than in the American survey.

The bioavailability of CBD varies by route of administration (Millar et al. 2019), but is generally low, between 10 and 31% (Millar et al. 2018). Oral routes have the lowest bioavailability due to first-pass metabolism, whilst inhaled routes have the highest bioavailability (Ohlsson et al. 1986). The bioavailability of sublingual CBD is between 13 and 19% (Mechoulam et al. 2002), and greater than the oral route, thus exerting effects at much lower doses, making it more efficient for users. Investigating plasma levels of low-dose sublingual CBD users, and correlating them to the subjective experience, might give important insights into the optimal dose for treating these low-level mental health problems like self-perceived stress, anxiety, and sleep problems.

Most people were using less than 100 mg (72.9%) per day. Due to the high price and the lack of medical supervision, it is not surprising that non-medical CBD users are taking much lower doses than those used in clinical studies, and those prescribed for specific medical conditions (Davies and Bhattacharyya 2019; Szaflarski et al. 2018). It is important to highlight that 16.8% reported using more than 100 mg per day, and 10.2% did not know how much CBD they were using. The use of high doses CBD is concerning in light of the current FSA recommendation of restricting the dose to 70 mg CBD per day (Cannabidiol (CBD) n.d.), and it stresses the importance of better public information and communication and improved packaging and guidance from brands to consumers.

Amongst our study sample, almost 11% experienced having a dry mouth, most likely indicating levels of THC in the product, as this is a common side effect of THC rather than CBD (Darling and Arendorf 1993; LaFrance et al. 2020). People living outside of the UK had higher odds of experiencing a dry mouth, which might be explained by the different legislation regarding permitted THC content and CBD quality between countries. This differentiation leads to some concerns about product safety, consistency, and ultimately trust amongst CBD consumers. A recent study of 29 CBD products showed that only 11% contained within 10% of the advertised CBD concentration, 55% of the products had traces of controlled substances such as THC (Liebling et al. 2020). There is still a need for external and internal control within the CBD industry to ensure consumer safety is prioritised.

CBD and self-perceived stress

37.5% of respondents reported using CBD for perceived stress, with 92.2% reporting reduced stress levels, making it the third-highest ranking reason for CBD use amongst our sample. Yet, no studies are looking directly at how CBD affects perceived stress levels. This might in part be because stress, apart from post-traumatic stress disorder, is not classified as a disease according to international disease classification (WHO | Burn-out an “occupational phenomenon”: International Classification of Diseases 2019). With more than 12.8 million working days lost because of work-related stress, anxiety, or depression in the UK (Hse 2019), the relationship between CBD and stress is an area of interest for further research. A recent study surveying social media for comments about perceived therapeutic effects of CBD products revealed that the most frequently discussed symptoms, which are not addressed in the research literature, are indeed stress and nausea (Tran and Kavuluru 2020).

CBD and self-perceived anxiety

Self-perceived anxiety was the top-ranked reason for the use of CBD with 42.6% reporting they take CBD for this reason. Of these, 86.5% reported they felt less anxiety. There are biologically plausible reasons for the use of CBD in anxiety. Pharmacological research suggests CBD is a partial 5-HT1a receptor agonist which supports anxiolytic and stress-reducing properties (Russo et al. 2005; Resstel et al. 2009), the activation of which has been associated with anxiolytic, antidepressant, and antipsychotic effects (Zuardi et al. 1993; Bergamaschi et al. 2011; de Faria et al. 2020; Vilazodone for major depressive disorder | MDedge Psychiatry n.d.; Newman-Tancredi and Kleven 2011). CBD also modulates specifically configured GABAA receptors that may be relevant to anxiolytic effects (Bakas et al. 2017; Deshpande et al. 2011). CBD is anxiolytic under experimental conditions in animals, healthy humans and in those with generalised social anxiety disorder (de Faria et al. 2020; Elms et al. 2019; Newman-Tancredi and Kleven 2011) although large clinical trials have not been conducted. Crippa et al. administered an oral dose of 400 mg CBD or placebo, in a double-blind procedure. They found it significantly lowered feelings of anxiety, accompanying changes in limbic areas, in subjects with social anxiety disorder (SAD) (Crippa et al. 2011). Similar results were seen in a small randomised trial using a public speaking test with 600 mg CBD vs placebo (Bergamaschi et al. 2011).

CBD and self-perceived sleep problems

In our survey, sleep was the second-highest-ranking reason for CBD use. We found that 42.5% used CBD to help with sleep, which is higher than for previously published data on adult CBD users, where it was the fifth-highest reason (Corroon and Phillips 2018). It is well-known that a lack of sleep can cause a variety of physical and mental health effects including raised levels of cortisol(Leproult et al. 1997), anxiety (Babson et al. 2010), and mood disturbances (Brazeau et al. 2010), and both short and long duration of sleep is a significant predictor of death (Cappuccio et al. 2010). A recent controlled study of 300 mg CBD found no effect on any sleep indices (Linares et al. 2018), whilst observational and cross-sectional studies showed improvement in sleep outcomes (Corroon and Phillips 2018; Gulbransen et al. 2020). Preclinical studies have shown mixed results with some doses showing an increase in total sleep time (Chagas et al. 2013) and another study indicating that CBD causes increased wakefulness (Murillo-Rodríguez et al. 2006). Thus, the research on CBD and sleep thus far is mixed. However, as sedation and somnolence are regarded as common adverse effects of CBD in a meta-analysis of clinical trials where high doses are used (Chesney et al. 2020), it may not be surprising that CBD at low doses improved sleep quality and duration.

Given the low quality of CBD available on the market, it may be that these individuals were not taking CBD, or that CBD is not efficacious in sleep, so many individuals report better sleep by virtue of the placebo effect, fuelled by marketing (Haney 2020). Another reason may be that CBD is acting on other aspects of stress and anxiety that indirectly reduce sleep problems. Still, in this survey, participants directly attributed improved sleep to CBD. This points to the need for RCTs, as the effect of expectations (i.e. the result of the placebo effect), particularly with compounds advertised as cure-alls (Haney 2020). Suggesting that the placebo effect may contribute to the purported impact of CBD does not reject the potential medical value of CBD, but it does mean we must be wary of the results of observational studies (Haney 2020).

Strengths and limitations

Our measures were retrospective self-reported symptoms, rather than contemporaneous reports or object assessments, and thus prone to recall bias. This approach may lead to over- or under-estimation of benefits and harms. In reporting anxiety symptoms, it should be noted that many anxiety measures are self-reported, and scales are often an accurate measure of anxiety. Stress itself is not often measured, but scales assessing self-reported stress are reliable (Morgan et al. 2014). Regarding sleep problems, our measures do not accurately correspond with objective measures of sleep such as actigraphy (Girschik et al. 2012), which has implications in the epidemiology of sleep, including in the present study. Future research should use validated measures of anxiety, stress, and sleep. However, it should be noted we included responses to gain an insight where CBD may not help, with about 20% responding that CBD did not help with sleep or anxiety and about 10% saying CBD did not help with stress. There is also a risk of selection biases regarding our recruitment method from email databases of current users and social media recruiting. As we had a self-selected sample, we do not represent the general population or even the overall population of CBD users. It is more likely that respondents with a positive experience have responded to this survey, and continue to use CBD. Still, users with a negative experience may have stopped using CBD and therefore were not reached by this survey, which might further contribute to the selection biases.

Conclusion

The survey demonstrated that CBD is used for a wide range of physical and mental health symptoms and improved general health and wellbeing. A majority of the sample surveyed in this study found that CBD helped their symptoms, and they often used doses below 50 mg. Out of the four most common symptoms, three were related to mental health. Self-perceived stress, anxiety, and sleep problems constitute some of society’s biggest health problems, but we lack adequate treatment options. Further research is needed into whether CBD can efficiently and safely help treat these symptoms.

Availability of data and materials

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.