Naturalistic examination of the anxiolytic effects of medical cannabis and associated gender and age differences in a Canadian cohort

Abstract

Background

Anxiety disorders contribute globally to a total of 24.6 million years lived with disability (World Health Organization 2017). They are associated with a poor quality of life across various domains such as general health, physical health, body pain, mental health, as well as impairments in role and social functioning (Mendlowicz and Stein 2000; Barrera and Norton 2009; Hoffman, Dukes, and Wittchen 2008). Anxiety disorders encompass a number of conditions and symptoms that can range from mild to severe (“Mental Health – Anxiety Disorders – Canada.Ca” n.d.; Anxiety Canada n.d.; “What Are the Five Major Types of Anxiety Disorders? | HHS.Gov” n.d.). Although there are currently various anxiolytic pharmaceuticals available to patients, approximately a third will not respond to them (known as “treatment-refractory anxiety”) and only ~ 50% will fully recover (Garakani et al. 2020). Additionally, not all patient groups can tolerate the available pharmaceuticals. Benzodiazepines for instance, can be effective for some anxiety disorders but run the risk of tolerance, misuse, abuse and/or are riskier for older patients due to the risk of falling (Garakani et al. 2020). Thus, there is a need for new and effective treatments to aid these patients. With an increase in public awareness and scientific investigation, there is increasing interest in, and evidence for, the use of medical cannabis in patients who have not found success with existing anxiolytics.

Treatment of anxiety is among the top three endorsed motives for medical cannabis use (Wadsworth, Leos-Toro, and Hammond 2019; Walsh et al. 2013). In a real-world evidence study, 85% of patients with anxiety self-reported some improvement in their condition and had increased quality of life following six weeks of medical cannabis treatment (Cahill et al. 2021). Of those who rated cannabis as being helpful for their anxiety, 32% selected high cannabidiol (CBD) products, 28% selected high tetrahydrocannabinol (THC) products, and 8% selected balanced THC:CBD products (Cahill et al. 2021).

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, 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). CBD-dominant treatments appear particularly beneficial in patients with moderate to severe anxiety (Rapin et al. 2021).

THC also has reported anxiolytic effects. Nabilone (a synthetic THC analog) has been shown to decrease anxiety in patients in two different studies (Fabre and McLendon 1981; Skrabek et al. 2008). Furthermore, a systematic review performed on 83 studies found that THC alone or in combination with CBD improved anxiety symptoms among individuals with comorbid medical conditions (Black et al. 2019).

While the above indicates cannabinoids show efficacy as anxiolytics, it is still not clear what specific THC:CBD ratio nor dose is most effective at treating anxiety and there continues to be gender differences reported for cannabinoid pharmacology (Tseng, Harding, and Craft 2004; Sholler et al. 2021; Spindle et al. 2020; Lunn et al. 2019) and anxiety pathophysiology (Toufexis et al. 2014; Kessler et al. 1994).

Females may be particularly vulnerable to anxiety disorders (Bandelow et al. 2014). Females are more likely than males to meet the criteria for anxiety disorders (McLean et al. 2011; Kessler et al. 1994, 1995) and less likely than males to respond to selective serotonin reuptake inhibitors for anxiety (Simon et al. 2006). This increased vulnerability is believed to be a result of female reproductive hormones and brain structure differences (Lebron-Milad and Milad 2012; Reimer et al. 2018).

Investigation into possible gender-related differences in the efficacy of medical cannabis have been limited, despite a significant proportion of females using medical cannabis (Government of Canada 2021) and doing so to treat anxiety (Moltke and Hindocha 2021; Cuttler, Mischley, and Sexton 2016). However, the available evidence does point to pharmacological differences amongst males and females in response to cannabis. Males are more likely to report memory improvement, to feel enthusiastic, experience an altered sense of time, experience munchies, less likely to have a desire to clean, and experience a loss of appetite(Cuttler, Mischley, and Sexton 2016) while females are more likely than males to report medical cannabis related adverse events (Aviram et al. 2021). When able to self-titrate, women smoked less cannabis and subsequently had lower THC plasma concentrations, while experiencing the same acute effects as males (Matheson et al. 2020). Nadulski et al. reported females had higher peak plasma concentrations (C_max) and quicker time to peak plasma (T_max) concentrations for THC, 11-hydroxy-THC (11-OH-THC) and CBD in comparison to males after orally ingesting a cannabis extract (Nadulski et al. 2005). Spindle et al. found female participants had higher plasma and oral fluid C_max for THC and its metabolites after eating THC brownies (Spindle et al. 2020) while Sholler et al. found females had a significantly greater C_max for 11-OH-THC than males post vaporized cannabis (Sholler et al. 2021).

Given that hepatic metabolism can be negatively impacted by aging (Klotz 2009; Tajir and Shimizu 2013), it is also possible age may play a role in how patients respond to medical cannabis. Taylor et al. found moderate-severe hepatic impairment significantly altered the pharmacokinetics of CBD and its metabolites’ and concluded CBD dosages should be modified for these patient groups (Taylor et al. 2019).

Thus, the goal of the current study was to examine changes in anxiety following medical cannabis use and how this may be impacted by gender or age. A secondary objective was to examine self-titration patterns over time and determine how dosing may be impacted by gender, age, and/or cultivar.

Methods

Results

The impact of medical cannabis as a function of gender

Changes in anxiety (pre- to post-medication) and interactions with gender are shown in Table 2 and Fig. 1. An ANOVA revealed a significant main effect of Time [F(1, 1019) = 2987.12, p < 0.001] and significant Time × Gender interaction [F(1, 1019) = 4.02, p < 0.05]. Post hoc tests revealed a significant decrease in anxiety scores pre- to post- medication among both males and females and an overall average efficacy of 50%.

Table 2

Anxiolytic effects and emotives of cannabis consumption as a function of gender. The asterisk denotes p < 0.05 for the comparison between males and females. One participant logged 7 sessions and reported their gender as “unknown.” Their data was included in the total but not in either the male or female categories

		Total (n = 184)	Males (n = 70)	Females (n = 113)	t or χ2	p-value
Number of logged sessions		1028	399	622
Average efficacy (M ± SD; %)		50.03 (± 0.23)	50.29 (± 0.23)	49.86 (± 0.23)	t = -0.29	p = 0.77
Optimal dose (number of inhalations)		5–7, 11–13	9–11	5–7
Percent reporting positive emotives (%)		94.8	100*	91.3	χ2 = 4.99	p = 0.03
	Top 1 specific positive emotive (%)	Relaxed (80)	Relaxed (83)	Relaxed (78)	χ2 = 0.68	p = 0.41
	Top 2 specific positive emotive (%)	Comfortable (57.5)	Comfortable (57.4)	Comfortable (57.5)	χ2 = 0.00	p = 0.99
	Top 3 specific positive emotive (%)	Happy (44.0)	Happy (50.0)	Happy (40.0)	χ2 = 1.31	p = 0.25
Number of different positive side effects selected (out of 17)		17	17	17
Average number reported positive emotives (M ± SD)		4.54 ± 2.91	4.65 ± 3.08	4.45 ± 2.79	t = -0.37	p = 0.71
Percent reporting negative emotives (%)		12.7	11.1	13.8	χ2 = 0.20	p = 0.65
	Top 1 specific negative emotive (%)	Anxious (8.2)	Anxious (5.6)	Anxious (10.0)	χ2 = 0.85	p = 0.36
	Top 2 specific negative emotive (%)	Dizzy (4.5)	Dizzy (3.7)	Dizzy (5.0)	χ2 = 0.13	p = 0.72
	Top 3 specific negative emotive (%)	Headache (3.7)	Nauseous (3.7) Paranoid (3.7)	Headache (5.0) Paranoid (2.5) Nauseous (2.5)	Nauseous χ2 = 0.16 Paranoid χ2 = 0.16 Headache χ2 = 0.89	Nauseous p = 0.69 Paranoid p = 0.69 Headache p = 0.35
Number of different negative side effects selected (out of 6)		6	6	6
Average number of reported negative emotives (M ± SD)		2.00 ± 1.32	1.83 ± 1.30	2.09 ± 1.38	t = 0.37	p = 0.71
Percent reporting neutral emotives (%)		63.4	59.3	66.3	χ2 = 0.68	p = 0.41
	Top 1 specific neutral emotive (%)	Thirsty (36.6)	Thirsty (33.3)	Thirsty (38.8)	χ2 = 0.41	p = 0.52
	Top 2 specific neutral emotive (%)	Sleepy (29.1)	Sleepy (20.4)	Sleepy (35.0)	χ2 = 3.34	p = 0.07
	Top 3 specific neutral emotive (%)	Hungry (24.6)	Hungry (20.4)	Hungry (27.5)	χ2 = 0.88	p = 0.35
Number of different neutral side effects selected (out of 12)		12	10	11
Average number of reported neutral emotives (M ± SD)		3.49 ± 1.61	3.44 ± 1.54	3.53 ± 1.66	t = 0.26	p = 0.80

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Fig. 1

Mean (± SD) self-reported anxiety pre- and post-medication (A) and mean (± SD) percent efficacy (B) among males and females. The asterisk denotes p < 0.05 between pre- and post-medication (A)

The optimal dose needed to experience anxiety-relieving effects was 9–11 inhalations for males and 5–7 inhalations for females.

Approximately, 94.8% reported a positive post-medication experience from using cannabis in the treatment of anxiety (Table 2). Males reported significantly more positive emotives than females. The top three positive emotives reported were relaxed, comfortable and happy. 12.7% reported a negative post-medication experience and the top three were anxious, dizzy, and headache. 63.4% reported neutral post-medication experiences and the top three were thirsty, sleepy, and hungry.

Discussion

As approximately a third of patients diagnosed with anxiety will not respond to the standard treatment options (known as “treatment-refractory anxiety”) and only ~ 50% will fully recover (Garakani et al. 2020), this study examined patient-reported data from Strainprint^® on the three Aurora Cannabis dried flower products most commonly consumed during anxiety related sessions. The anxiolytic effects of these different cultivars and the impact of gender and/or age on outcomes and dosages was examined.

Overall, cannabis administration significantly decreased anxiety. We identified some gender and age differences in efficacy, optimal dosing and proportion of emotives reported across the three cultivars. However, both genders and all age categories experienced significant anxiolytic effects and tolerated cannabis well.

Overall, an average reported efficacy of ~ 50% was reported after consuming cannabis and there were no gender-related efficacy differences. This was surprising given that Cuttler et al. previously reported females had a greater reduction in anxiety following cannabis than males (Cuttler, Spradlin, and McLaughlin 2018).This difference could be the result of variations between the two patient cohorts that were not captured in the data collected such as type and severity of anxiety, any other comorbidities, race, ethnicity and other medication use. Our male cohort also reported significantly more positive emotives than females, but no gender differences were observed for neutral and negative emotives. As females have shown to be more susceptible to medical cannabis-related adverse events than males (Aviram et al. 2021) this was a surprising finding. Nonetheless, from this data, it is clear that cannabis is an effective anxiolytic and well tolerated by both genders.

The overall optimal dosing for females was less than males, indicating females may need less cannabis to achieve the same anxiolytic effect. This is supported by the larger literature as when individuals are able to self-titrate, women smoked less cannabis and subsequently had lower levels of THC in the blood, while experiencing the same acute effects as males (Matheson et al. 2020). It is possible these differences are a result of variation in muscle mass and fat distribution between the genders (Fattore and Fratta 2010a). However, females reported higher levels of cannabinoids in blood and oral fluid post-consumption of a THC brownie in comparison to males though some of the males in the cohort weighed less than some females (Spindle et al. 2020). Similarly, controlling for body weight and peak blood concentrations did not impact the significant sex differences in subjective effects reported in another study (Sholler et al. 2021). Thus, further investigation is required to fully elucidate why cannabinoid dosing differs between the genders as it appears it is not solely the result of differences in muscle mass and fat distribution.

The specific efficacy and optimal dosing of the three cultivars and how these items may be impacted by gender were examined. While no gender-related efficacy differences were identified for THC sativa, males experienced significantly higher efficacy with THC indica than females and females had significantly higher efficacy than males with CBD. While it was surprising to find gender differences in one high THC cultivar and not the other, females have been reported to prefer consuming CBD over THC (Moltke and Hindocha 2021). While we noted gender differences in two of the cultivars, the efficacy was similar across the three, indicating no THC:CBD ratio was significantly more beneficial than another. Furthermore, we identified some gender differences in optimal dosing with males requiring less inhalations than females to achieve efficacy with THC sativa but requiring more inhalations than females for CBD.

The wider scientific literature supports our finding that all three cultivars provided significant anxiolytic effects as there is evidence for both CBD (Shannon et al. 2019; Rapin et al. 2021; Crippa et al. 2011; Bergamaschi et al. 2011) and THC (Fabre and McLendon 1981; Kamal et al. 2018; Skrabek et al. 2008; Cahill et al. 2021) to reduce anxiety. CBD has been shown to be an agonist at both cannabinoid receptors (CB; CB₁ and CB₂) and the serotonin-1 A (5HT_1A) (Breuer et al. 2016; de Gregorio et al. 2019; Resstel et al. 2009) receptor while THC’s partial agonism at CB₁ has been well documented (Petitet et al. 1998; Pertwee 2008). Given that both cannabinoids interact with CB₁ receptors, these gender differences in efficacy and optimal dosing may be tied to gender-dependent differences in CB₁ receptor expression and binding site density throughout the brain (Fattore and Fratta 2010b; Rubino et al. 2011). For instance, under healthy conditions, estradiol has been shown to increase CB₁ receptor binding site density in the amygdala but reduced it in the hypothalamus (Riebe et al. 2010) and females have lower CB₁ receptor binding density than males in numerous brain regions tied to anxiety (van Laere et al. 2008). Additionally, in response to chronic stress, CB₁ receptors were downregulated in the hippocampus of male rodents but upregulated in females (Reich, Taylor, and McCarthy 2009).There are also documented gender differences in terms of serotonin signaling and 5HT_1A receptor expression (Toufexis et al. 2014; Goel, Innala, and Viau 2014). 5HT_1A receptor expression is regulated by estrogen and this interaction has been hypothesized to influence why females experience higher rates of mood disorders (Toufexis et al. 2014). Thus, these gender-based signaling differences provide some insight as to why the genders experienced differences in efficacy with the THC indica and CBD. However, why no gender differences were observed with the THC sativa cultivar is unclear. Therefore, further investigation is required to understand the mechanistic differences in the anxiolytic effects of cannabinoids between the genders.

We also found all age groups experienced significant anxiolytic effects with cannabis. The 30–39-year-old group reported a higher number of optimal inhalations than other groups, which may be the cause of the higher average efficacy and positive emotives observed in this group. Those 40 + reported a significantly lower efficacy for cannabis compared to those under 40. However, those 40 + were more likely to report positive emotives than 18–29-year-olds. Because polypharmacy is more prevalent in older populations (Rotermann et al. 2014) it is possible that this population experienced some drug-cannabis interactions that contributed to altered efficacy and side effects (Anderson and Chan 2016; Rong et al. 2018; Cital et al. 2021; Geffrey et al. 2015). While the 40 + group’s average age was only 46, data from Statistics Canada show consistent trends that as adults age, they are more likely to be prescribed medications than their younger counterparts; of those 18–39 years, 38% were prescribed medications versus 56% of those aged 40–59 years (Statistics Canada 2021). Furthermore, a number of studies have shown that older populations respond less effectively than younger populations to anxiety treatments (Wetherell et al. 2013; Carl et al. 2020) as well as brain activation patterns differ between older and younger populations in response to threat-related cues (Gold et al. 2020) that could explain the age differences we identified.

While data captured via the Strainprint^® app has been included in numerous peer-reviewed publications and the ability for patients to capture their experiences in real time is a strength of this method, especially given the cyclic nature of anxiety, this study is not without limitations. Firstly, using the Strainprint^® app rather than the use of validated questionnaires typically used in observational studies is a limitation of this study. Furthermore, participants self-reported their anxiety and the diagnosis was not confirmed by a healthcare practitioner. Additionally, due to the nature of this naturalistic study, we are unable to confirm if any pharmaceuticals and/or other cannabis products were being consumed in addition to the products participants logged sessions on, the average use of cannabis per month, the historical use of cannabis, the race and ethnicity of participants nor any diagnosed comorbidities. The ability to access medical cannabis could also have been a barrier due to an inability to find a physician to authorize medical cannabis. While Aurora Cannabis does offer a compassionate program for lower income patients and there is the option to claim medical cannabis as a medical expense on federal income taxes, widespread insurance coverage for medical cannabis is still lacking in Canada. Thus, without widespread insurance coverage, the costs of cannabis will continue to be a barrier for many to access this medicine. We also only focused on inhaled dried flower sessions, excluding other formats, which limited our sample size. As it has been reported females prefer ingestible formats (Cuttler, Mischley, and Sexton 2016), it is possible further gender differences may have been identified if we had included ingestible products. There have also been reports that bioavailability of inhaled cannabis significant differs between those who are heavy and light consumers; bioavailability for heavy consumers was reported as 23 ± 16% (Lindgren et al. 1981) and 27 ± 10% (Ohlsson et al. 1986) versus bioavailability for light consumers at 10 ± 7% (Lindgren et al. 1981) and 14 ± 1% (Ohlsson et al. 1986). Other studies have shown significant differences in THC and 11-OH-THC C_max between males and females post inhalation of cannabis (Chiang et al. 1982; Sholler et al. 2021). Thus, while dosing was reported as number of inhalations, it is possible the concentration of cannabinoids delivered differed between participants based upon comfortability with smoking or vaping and/or due to their gender, even if the number of inhalations were similar.

Overall, cannabis was effective in relieving anxiety and well-tolerated at the doses consumed, independent of CBD and THC ratios. While one cultivar was not significantly more effective than the others, we did identify some gender and age differences in optimal dosing across the three cultivars. We suggest that the outlined THC:CBD ratios and optimal inhalations may be used as a starting point for patients and healthcare practitioners looking to use cannabis as an anxiolytic in order to mitigate the trial-and-error aspect of initiating medical cannabis treatments. Additionally, we recommend the above dataset be used as the foundation for future clinical trials to fully elucidate the efficacy of cannabis for the management of anxiety under more controlled conditions.

Acknowledgements

Abbreviations

Authors’ contributions

Dr. Minhas was involved with directing the data analysis which was performed by Strainprint® and both Dr. Minhas and Dr. Lunn were involved with drafting the manuscript.

Funding

No grant funding was utilized for this project. The analyzed dataset was purchased by Aurora Cannabis Inc from Strainprint®.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Declarations

Footnotes

References