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. Author manuscript; available in PMC: 2022 Aug 7.
Published in final edited form as: Drug Alcohol Depend. 2021 Apr 20;223:108718. doi: 10.1016/j.drugalcdep.2021.108718

Investigating sex differences in acute intoxication and verbal memory errors after ad libitum cannabis concentrate use

Laurel P Gibson a,*, Charleen J Gust a, Jarrod M Ellingson b, Sophie L YorkWilliams a, Cristina Sempio c, Jost Klawitter b,c, Angela D Bryan a,d, Kent E Hutchison a,d, L Cinnamon Bidwell a,d
PMCID: PMC9357512  NIHMSID: NIHMS1826066  PMID: 33866072

Abstract

Background:

An innovative naturalistic at-home administration procedure was used to investigate sex differences in subjective drug effects and verbal memory errors after ad libitum use of high potency state legal market Δ9-tetrahydrocannabinol (THC) concentrate.

Methods:

Regular concentrate users were randomly assigned to ad libitum administration of one of two cannabis concentrate products (70 % or 90 % THC) that they purchased from a dispensary. 65 participants (N = 34 men, N = 31 women) were assessed in a mobile pharmacology lab before, immediately after, and 1 -h after ad libitum concentrate use. Plasma cannabinoids (THC, 11-OH-THC, CBD), subjective drug effects, and verbal memory errors were assessed at all three time points.

Results:

Although men and women exhibited similar plasma 11-OH-THC levels across time (p = .10), sex differences were found in plasma THC and CBD after legal market concentrate use, with men displaying significantly higher levels of plasma THC and CBD immediately after cannabis concentrate use (plasma THC [ng/mL]: Mmen = 489.88, Mwomen = 135.08, p < .001; plasma CBD [ng/mL]: Mmen = 1.14, Mwomen = 0.53, p = .04). Despite this, sex differences in subjective effects and verbal memory errors did not emerge, although women reported a steeper decrease in drug liking after use (p = .04).

Conclusion:

These data provide the first look at sex differences after acute naturalistic cannabis concentrate use, and suggest much higher THC exposure in men versus women, but similar acute drug and impairment effects across the sexes. Further studies are needed to determine the mechanisms (e.g. tolerance, cannabinoid metabolism, smoking topography) behind these findings.

Keywords: Marijuana, Abuse liability, Cannabinoids, Sex, High-potency, Memory

1. Introduction

As of 2020, 11 U.S. states and the District of Columbia have legalized cannabis for recreational use. An additional 36 states have legalized cannabis for medical purposes, although medical cannabis laws are highly restrictive in 14 of these states (e.g., low THC CBD oil only). Four more states are poised to legalize recreational cannabis in 2021 after voters in these states approved statewide cannabis legalization ballot initiatives in the November 2020 election. A burgeoning legal cannabis market has prompted an increase in the availability of and demand for high potency products such as cannabis concentrates (McCormick et al., 2017; Stogner and Miller, 2015). State legal market concentrates, cannabis products made from extracting cannabinoids and terpenes from the cannabis plant (Raber et al., 2015), typically have THC levels around 60–69 % (Orens et al., 2014; Raber et al., 2015; Smart et al., 2017), although it is not uncommon for the THC content of these products to exceed 90 % (Bidwell et al., 2018a). In comparison, the average potency of state legal market flower products is typically around 16–21 % THC (Orens et al., 2014; Smart et al., 2017; Vergara et al., 2017).

Although there is concern that higher potency cannabis products may lead to heightened levels of intoxication and impairment (Volkow et al., 2014), there is a paucity of data on the risks associated with high potency products, including state legal market concentrates (Stogner and Miller, 2015). Despite findings that cannabis users self-titrate in order to consume less cannabis when using higher potency forms (Cooper and Haney, 2009; Hartman et al., 2015; Ramesh et al., 2013), blood cannabinoid levels and subjective intoxication are greater after high potency cannabis use (Cooper and Haney, 2009), which may be indicative of greater cannabis-associated risks (Volkow et al., 2014).

Men use cannabis more frequently and in higher quantities than women (Calakos et al., 2017; Cuttler et al., 2016), and early data suggest that cannabis concentrates are no exception (Cuttler et al., 2016). However, results from epidemiological studies suggest that this gender gap in overall cannabis use is decreasing (Cooper and Craft, 2018). Interestingly, although the prevalence of use is lower, women develop cannabis use disorder (CUD) at a faster rate as compared to men (a finding known as the “telescoping effect”; Ehlers et al., 2010), report higher levels of abuse-related effects after using cannabis (Cooper and Haney, 2014), report greater severity of some cannabis withdrawal symptoms compared to men (Ehlers et al., 2010; Schlienz et al., 2017), and are more likely to have a comorbid mood or anxiety disorder, raising concerns about the impact of high potency product use by women (Khan et al., 2012). Finally, prior work suggests sex differences in plasma cannabinoid levels and subjective cannabis intoxication at lower potencies (Nadulski et al., 2005; Wardle et al., 2015), highlighting the importance of understanding how intoxication may differ between men and women after acute concentrate use.

Findings regarding sex differences in plasma cannabinoid levels are predominantly from preclinical (animal) studies (Cooper and Craft, 2018). In humans, evidence is equivocal. For example, while an early study found no significant differences between men and women in plasma THC levels after oral or intravenous THC administration (Wall et al., 1983), a later randomized controlled trial found that women had higher levels of plasma THC, 11-OH-THC, and THC-COOH than men after administration of oral cannabis (Nadulski et al., 2005). In both studies, doses were matched across men and women, however, they utilized cannabis with differing modes of administration and with lower potencies than concentrates (e.g., 10 mg of orally administered THC; Nadulski et al., 2005), and thus it is unclear whether these findings generalize to cannabis concentrates.

Studies of sex differences in subjective intoxication have produced similarly mixed findings. Wardle et al. (2015) found that women reported higher levels of subjective intoxication than men after administration of oral THC capsules. However, another study found that among non-users and relative to women, men reported greater levels of cannabis-induced “high” after consuming 2.5, 5, and 10 mg THC capsules (Haney, 2007). In comparison, the same study failed to find sex differences in subjective intoxication after administration of oral THC in high doses (20 and 40 mg). Similarly, two studies which matched men and women according to current cannabis use found that there were no significant differences between men and women’s “high” ratings after smoking cannabis flower (Cooper and Haney, 2007; Cooper and Haney, 2014). However, the latter study found that after smoking cannabis, women reported greater levels of effects associated with abuse liability (i.e., “take again”, “good”) compared to men (Cooper and Haney, 2014). Sex differences in subjective intoxication may be less apt to emerge with smoked forms of cannabis, as it is easier to self-titrate or modify smoking patterns in order to reach a desired “high” when using smoked rather than oral forms of cannabis. Such differences may also depend on the dose, as one study found that women reported greater subjective intoxication at low doses of oral THC while men reported greater subjective intoxication at high doses of oral THC (Fogel et al., 2017).

Numerous studies suggest that cannabis also produces acute cognitive impairment during intoxication. The negative impact of cannabis on memory, inhibitory control, and attention are among the most robust cognitive effects found in acute cannabis administration studies (Ranganathan and D’Souza, 2006). However, the vast majority of the literature on sex differences in the cognitive effects of cannabis has focused on the effects of chronic, rather than acute, cannabis use among recreational users (Crane et al., 2013; Pope et al., 1996, 1997). Studies testing for sex differences in cognitive performance after acute cannabis use are scarce; however, one study found that after being administered 5 mg of a sublingual THC spray, spatial working memory performance was improved in women but not in men (Makela et al., 2006).

Importantly, the extant literature on sex differences in responses to cannabis does not include samples using high potency concentrates. In order to more fully assess the potential harms of cannabis consumption, it is imperative that researchers begin to prioritize ecological validity by examining the effects of products that are commercially available and widely used. Furthermore, to date, no studies have explored possible sex differences in the acute effects of cannabis following any form of ad libitum administration. Such studies are necessary in order to understand the effects of cannabis in a naturalistic, rather than controlled, research setting. Lastly, although concentrate extraction methods primarily focus on extracting THC, other minor cannabinoids can be measured in small quantities. Thus, in addition to THC and 11-OH-THC, the present study will examine plasma concentrations of cannabidiol (CBD) after acute concentrate use in order to expand the literature on sex differences in plasma cannabinoid levels.

Using novel, federally compatible, observational methods, this is the first study to look at sex differences in the effects of high potency commercially-available cannabis concentrates (70 % or 90 % THC) after ad libitum use. Subjects administered their products in their own residences and completed assessments of subjective drug effects, as well as verbal memory errors, in a mobile laboratory immediately before, immediately after, and 1 -h following at-home cannabis administration. Plasma cannabinoids were assessed at all three time-points. The larger study from which these data are drawn examined the associations of naturalistic concentrate administration with blood THC exposure, subjective intoxication, and neurobehavioral impairment (Bidwell et al., 2020). The current paper extends those initial results by focusing on sex differences in key cannabis-related outcomes in relation to concentrate use. Given (a) the previous mixed findings on sex differences in the acute effects of cannabis, and (b) the dearth of research on high potency cannabis concentrate products in general, these analyses were considered exploratory in nature.

2. Methods

2.1. Participants

This study was approved by the University of Colorado Boulder Institutional Review Board and was carried out in accordance with the Declaration of Helsinki. These methods have been reported previously in Bidwell et al. (2020). Participants were recruited using social media posts and mailed flyers. Participants were compensated up to $150 for their time and effort ($50 for completing the baseline appointment, and $100 for completing the experimental appointment). Due to federal restrictions, funds were not provided for the purchase of state legal market cannabis.

Eligibility screening was completed via telephone by trained research staff. Inclusion criteria were: (1) between 21 and 70 years of age; (2) cannabis use at least four times in the past month; (3) experience with the highest potency of cannabis that could be assigned in the study (i.e., 90 % THC); (4) no other non-prescription drug use in the past 60 days; (5) no daily tobacco use; (6) two or fewer drinking occasions per week, with three or fewer drinks per occasion, at the time of screening; (7) not pregnant or trying to become pregnant; and (8) no current or history of a psychotic or bipolar disorder. Sixty-five participants (34 men, 31 women) met these criteria, had complete data for the baseline and experimental appointments, and were included in analyses.

2.2. Appointments

The present study consists of four assessment time points: one during the baseline appointment (baseline) and three during the experimental appointment (pre-use, acute post-use, and 1 -h post-use). Primary outcome measures (i.e., plasma cannabinoid levels, subjective drug effects, verbal memory errors) were collected at all four time points.

2.2.1. Baseline appointment

The first appointment was conducted at the Center for Innovation and Creativity (CINC) where participants provided informed consent, were screened via urinalysis for pregnancy (if female) and the presence of alcohol, sedatives, cocaine, opiates, and amphetamines. Participants also completed measures of demographics, lifestyle, substance use, mental health, and medical history, completed measures of subjective drug effects and verbal memory errors, and provided a baseline blood draw.

Participants were then randomly assigned to potency condition using a random assignment table generated by the study statistician, given directions to a study-partnered local dispensary, and instructions to purchase 1 g of their assigned cannabis concentrate product (e.g., “concentrate A” or “concentrate B”), which was either 70 % THC (< 1% CBD) or 90 % THC (< 1% CBD) concentrated hash oil. The THC potency of all study products was labeled according to testing in an International Organization of Standards (ISO) 17,025 accredited laboratory. 16 women and 18 men were randomly assigned to “concentrate A”, while 15 women and 16 men were randomly assigned to “concentrate B”. No effects of potency (70 % vs. 90 % THC) were found on any outcome in the primary study (Bidwell et al., 2020) and the proportion of men and women in each potency condition was similar (p = .91). Thus, the 70 and 90 % potency groups are combined in the current report. In order to verify that participants purchased their assigned study product, participants were instructed to bring a receipt of their cannabis purchase to the experimental appointment.

2.2.2. Experimental appointment

To familiarize themselves with their concentrate product, participants were free to use the product ad libitum during the five-day period between the baseline and experimental appointment. On the fifth day, the experimental appointment took place in a mobile laboratory outside of the residence of each participant. Participants were instructed to abstain from using cannabis that day prior to their appointment. The experimental appointment involved assessments at three time points: (1) pre-use, (2) acute post-use, and (3) 1 -h post-use. Participants first completed primary outcome measures (described below) prior to using cannabis (pre-use) and then returned to their residence to use their study product ad libitum. A short time later (M =13.49 min, SD = 7.44), they returned to the mobile lab while acutely intoxicated (acute post-use) and completed the same outcome measures (Note: On average, men returned to the mobile laboratory 4.54 min earlier than women (p = .02). This effect was driven by a female outlier who was away from the van for 47 min. The patterns of significant and non-significant findings presented below do not change after removing this outlier). Participants stayed in the mobile lab until one hour after using their product (1-h post-use) and completed the measures for the last time. While in their residence, participants weighed their concentrate both before and after use with a study provided electronic scale to provide a measure of amount (grams) of cannabis concentrate used during the ad libitum administration.

2.3. Primary outcome measures

2.3.1. Blood cannabinoids

Thirty-two mL of venous blood was collected by a certified phlebotomist through venipuncture of a peripheral arm using standard, sterile phlebotomy techniques and plasma was separated from erythrocytes. The concentrate extraction process results in the presence of low levels of other cannabinoids such as cannabidiol (CBD) which can contribute to or alter the effects of THC (Zuardi et al., 1982). Therefore, quantification of THC, 11-OH-THC, and CBD was conducted using validated high performance liquid chromatography/mass-spectroscopy (HPLC-MS/MS) (API5500) in MRM mode. The blood draw at the pre-use time point was used to confirm same-day cannabis abstinence.

2.3.2. Subjective drug effects

Participants’ subjective cannabis intoxication was assessed using the 12-item Addiction Research Center Inventory-Marijuana (ARCI-M) effects scale (Haertzen and Hickey, 1987; Huestis et al., 1992). Three additional items assessed cannabis intoxication: “mentally stoned” (5-point scale), “physically stoned” (5-point scale), and “feel high” (10-point scale). Responses were averaged to create a composite intoxication score (α = .69) (Bidwell et al., 2020). A modified version of the Profile of Mood States (POMS) questionnaire assessed state affect (Bidwell et al., 2020; Shacham, 1983). POMS items were rated on a 5-point Likert scale ranging from not at all (1) to extremely (5) and averaged to create subscales of Tension (“nervous”, “anxious”, “unable to relax”, “shaky/jittery”; α = .80) and Vigor/Elation (“joyful”, “euphoric”, “elated”, “cheerful”; α = .83). Drug liking was assessed with a single item (“do you like any of the effects you’re feeling?”) ranging from not at all (1) to a lot (5) (Morean et al., 2013).

2.3.3. Verbal memory errors

Verbal memory errors were assessed via the International Shopping List Test (ISLT; Thompson et al., 2011). At each time point, a trained research assistant read a list of 12 everyday shopping items (e.g. bread, apples) three times at the rate of one word per two seconds. Each time after the list was read, participants were immediately instructed to recall as many words as possible, in any order (training phase). Then, participants were instructed to recall the list a final time after a 30-minute delay (recall phase). To minimize practice effects, the items included in each list were randomly generated from the ISLT database and did not repeat across participants or administration time points. Consistent with previous research (Bidwell et al., 2018b, 2020), the ISLT was scored as the number of errors (repetitions or incorrect words) during recall at the 30 min delay. Note: Participants also completed tasks of working memory and inhibitory control from the NIH toolbox (List Sorting Working Memory Test Age 7+ v2.1 and Flanker Inhibitory Control and Attention Test Age 12+ v2.1; Weintraub et al., 2013). However, as detailed in Bidwell et al. (2020), acute impairment after concentrate use was only demonstrated on verbal memory errors. Therefore, in the current report, we only examined sex differences in verbal memory errors assessed by the ISLT.

2.4. Baseline substance use variables

2.4.1. Timeline follow back (TLFB)

Participants completed a calendar-assisted, researcher administered TLFB (Sobell and Sobell, 1992) that queried their drug use over a 30-day retrospective timeframe. The current study includes TLFB measures of cannabis flower use, cannabis concentrate use, orally ingested cannabis use, tobacco use, and alcohol use.

2.4.2. Marijuana dependence scale (MDS)

Cannabis use disorder symptoms were assessed using the Marijuana Dependence Scale (MDS; Stephens et al., 2000), an 11-item self-report measure developed based on dependence criteria found in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).

2.4.3. Alcohol use disorders identification test (AUDIT)

As cannabis use often overlaps with other substance use (Degenhardt et al., 2001a,b; Roche et al., 2019; Qato et al., 2020), participants completed the self-report AUDIT (Saunders et al., 1993). The range of possible scores is 0–40, with a score of 8 or more indicating harmful or hazardous drinking.

2.5. Statistical analyses

We conducted analyses of plasma cannabinoids, subjective drug effects, and verbal memory errors (across the three experimental time-points: pre-use, acute post-use and 1 -h post-use) separately using mixed-effects models estimating random intercepts for each participant. In each model, we included linear and quadratic change over time as fixed effects. Additionally, in each model we included contrast-coded sex (women = −0.5, men = 0.5) as a fixed effect. Grams of cannabis used, potency condition, and the baseline measure of the relevant outcome variable were included as covariates. Interaction effects tested whether the linear and quadratic change over time varied by sex. In models were both the linear and quadratic effect were significant, we focused on the higher-order quadratic effect. In models where the time X sex interaction was significant, we conducted simple effects tests to determine sex differences at the acute post-use and 1 -h post-use time points.

We conducted all analyses in RStudio version 3.6.1 (www.rstudio.com) using the lme4 package version 1.1–25 (Bates et al., 2007), which implements maximum likelihood (ML) estimation. We set an a priori significance threshold of p < .05 (two-tailed). Note: All beta coefficients (B) presented below are unstandardized.

3. Results

3.1. Demographic information

A total of 69 participants completed baseline and experimental measures. One participant did not identify their sex and was excluded from analyses. An additional three participants were excluded due to very low THC levels acutely post-use (THC < 20 ng/mL vs. study mean =320.67 ng/mL), resulting in a final sample of 65 participants (women = 31, men = 34). At baseline, there were no significant differences in demographic characteristics or cannabis use frequency metrics between men and women, but there were differences in anxiety, and age of onset of cannabis use (see Table 1).

Table 1.

Sample Demographics and Baseline Characteristics by Sex (± standard deviations).

Women Men
(n = 31) (n = 34) p-value
Demographics
Age 27.77 ± 10.91 28.71 ± 10.10 .72
Marital Status (% married) 16 % 9% .39
Education (% bachelors or higher) 48 % 41 % .57
Employment (% full time) 39 % 59 % .11
Race (% White) 81 % 76 % .62
Body Mass Index (BMI) 23.49 ± 4.63 24.58 ± 3.02 .26
Cannabis History and Current Use
Age of Onset of Regular Cannabis Use 19.28 ± 7.73 16.36 ± 2.32 .04
Days of Flower Use a (past 30 days) 17.93 ± 9.29 13.41 ± 11.67 .09
Days of Concentrate Use a (past 30 days) 14.67 ± 9.68 18.00 ± 12.21 .23
Days of Edible Use a (past 30 days) 3.47 ± 7.16 2.50 ± 5.83 .55
Cannabis Dependence (MDS Total) 3.23 ± 2.29 2.97 ± 2.04 .63
Other Substance Use and Psychological Factors
Days of Alcohol Use a (past 30 days) 7.87 ± 6.44 10.15 ± 5.90 .14
Days of Tobacco Usea (past 30 days) 1.94 ± 4.93 1.24 ± 4.95 .57
AUDIT Totalb 5.42 ± 3.58 7.71 ± 5.58 .06
Depression (BDI Total) 7.77 ± 7.14 5.18 ± 4.80 .09
Anxiety (BAI Total) 8.42 ± 6.62 3.35 ± 3.64 < .001
Cannabis Use During Experimental Appointment
Grams Used During Exp. Apptc 0.11 ± 0.13 0.12 ± 0.16 .92
Milligrams of THC consumed 95.94 ± 132.41 84.21 ± 128.31 .73
Mode of ad libitum administration
 Glass rig/tube 90.32 % 94.12 % .57
 Hash pen 9.68 % 5.88 % .57
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Abbreviations: MDS, Marijuana Dependence Scale; AUDIT, Alcohol Use Disorders Identification Test; BDI, Beck Depression Inventory; BAI, Beck Anxiety Inventory.

a

Using a 30 Day Timeline Follow-back.

b

Mean AUDIT scores for both genders were below the threshold for hazardous or harmful drinking.

c

Participants brought our scale into their home to measure the amount of study cannabis used during the experimental appointment.

The amount of cannabis concentrate used during ad libitum administration did not differ between men and women (See Table 1). See Table 2 for means and standard deviations of the outcome variables.

Table 2.

Means (± standard deviations) of self-reported subjective effects and cognitive performance before and after using cannabis concentrates.

Women (n = 31)      Men (n = 34)
Measure Pre-Use Acute Post-Use 1-Hour Post-Use Pre-Use Acute Post-Use 1-Hour Post-Use
POMS Tension 0.35 ± 0.41 0.42 ± 0.60 0.23 ± 0.33 0.33 ± 0.36 0.33 ± 0.41 0.20 ± 0.32
POMS Vigor 0.98 ± 0.67 1.46 ± 0.92 1.07 ± 0.89 0.98 ± 0.63 1.65 ± 0.78 1.4 ± 0.91
Intoxication 0.19 ± 0.55 3.64 ± 0.98 2.41 ± 1.05 0.20 ± 0.61 3.49 ± 1.06 2.50 ± 1.04
ARCI-M 2.81 ± 1.85 6.39 ± 2.3 4.84 ± 2.66 1.94 ± 1.72 5.32 ± 2.37 4.35 ± 2.44
Drug Likinga N/A 4.10 ± 0.92 3.21 ± 1.15 N/A 4.03 ± 0.80 3.61 ± 1.00
ISLT Verbal Memory Errors 1.28 ± 2.93 1.83 ± 2.12 2.71 ± 2.73 0.62 ± 1.30 1.09 ± 1.40 2.09 ± 2.63
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Abbreviations: POMS, Profile of Mood States; ARCI-M, Addiction Research Center Inventory -Marijuana Effects Scale; ISLT, International Shopping List Test.

Note. Men reported marginally greater drug liking 1 -h post-use (p = .09). No other significant sex differences in subjective effects emerged.

a

The “Drug Liking” item from the Drug Effects Questionnaire (DEQ) was not administered at the pre-use assessment time-point.

3.2. Plasma cannabinoid levels

Unadjusted mean plasma cannabinoid levels grouped by sex across the three experimental assessment time points are presented in Fig. 1. Analyses of plasma cannabinoids across time without covariates are included in the supplementary materials.

Fig. 1.

Fig. 1.

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Unadjusted mean plasma concentration of metabolites THC, 11-OH-THC, and CBD (ng/mL) across the three experimental assessment time points: pre-cannabis concentrate use, acute post- cannabis concentrate use, and 1 -h post- cannabis concentrate use. (Fig. 1a. Among both men and women, plasma THC levels exhibited a significant quadratic effect of time. Men displayed higher plasma THC levels acutely and a steeper decrease in plasma THC over time. Fig. 1b. Among both men and women, plasma 11-OH-THC levels exhibited a significant quadratic effect of time. Men and women displayed similar plasma 11-OH-THC levels at both post-use time points. Fig. 1c. Among both men and women, plasma CBD levels exhibited a significant quadratic effect of time. Men displayed higher plasma CBD levels acutely and a steeper decrease in plasma CBD over time). Results suggest the existence of sex differences in plasma cannabinoid levels after cannabis concentrate use.

Note: Error bars are standard errors.

3.2.1. Plasma THC levels

THC exhibited a significant quadratic effect of time controlling for sex, grams used, condition, and baseline THC levels (B = 98.84, SE = 11.87, p < .001), such that levels peaked at the acute post-use assessment and dropped an hour after use. There was a significant quadratic time X sex interaction, B = 111.24, SE = 23.74, p < .001, with men displaying a steeper decrease in plasma THC levels from acute post-use to 1 -h post-use. A simple effects test indicated that men had higher THC levels than women at the acute post-use assessment (p < .001) but not at the 1 -h post-use assessment (p = .96).

3.2.2. Plasma 11-OH-THC Levels -THC levels

11-OH-THC exhibited a significant quadratic effect of time controlling for sex, grams used, condition, and baseline 11-OH-THC levels (B = 1.86, SE = 0.41, p < .001), such that levels peaked at the acute post-use assessment and dropped an hour after use. The quadratic time X sex interaction term was not significant, B = 0.72, SE = 0.83, p = .38; across time, men and women exhibited similar levels of 11-OH-THC, B = 3.04, SE = 1.79, p = .10.

3.2.3. Plasma CBD levels

CBD exhibited a significant quadratic effect of time controlling for sex, grams used, condition, and baseline CBD levels (B = 0.17, SE = 0.04, p < .001), such that levels peaked at the acute post-use assessment and dropped an hour after use. The quadratic time X sex interaction term was significant, B = 0.19, SE = 0.08, p = .02. A simple effects test indicated that men had higher CBD levels than women at the acute post-use assessment (p = .04) but not at the 1 -h post-use assessment (p = .72).

3.3. Subjective effects

3.3.1. Vigor

Vigor exhibited a significant quadratic effect of time controlling for sex, grams used, condition, and baseline vigor (B = 0.15, SE = 0.03, p < .001). The quadratic time X sex interaction term was not significant (B = 0.01, SE = 0.05, p = .83); across time, men and women experienced similar levels of vigor (B = 0.12, SE = 0.15, p = .44).

3.3.2. Tension

Tension exhibited a significant quadratic effect of time controlling for sex, grams used, condition, and baseline tension (B = 0.03, SE = 0.01, p = .03). The quadratic time X sex interaction term was not significant (B = −0.02, SE = 0.03, p = .53); across time, men and women experienced similar levels of tension (B = 0.02, SE = 0.09, p = .86).

3.3.3. Intoxication

Intoxication exhibited a significant quadratic effect of time controlling for sex, grams used, condition, and baseline intoxication (B = 0.75, SE = 0.04, p < .001). The quadratic time X sex interaction term was not significant (B = −0.08, SE = 0.08, p = .36); across time, men and women experienced similar levels of intoxication (B = −0.05, SE = 0.17, p = .77).

3.3.4. Arci-m

ARCI scores exhibited a significant quadratic effect of time controlling for sex, grams used, and condition (B = 0.80, SE = 0.08, p < .001). The quadratic time X sex interaction term was not significant (B = −0.14, SE = 0.17, p = .40); across time, men and women reported similar ARCI-M scores (B = −0.80, SE = 0.47, p = .10).

3.3.5. Drug liking

Drug liking exhibited a significant linear effect of time controlling for sex, grams used, and condition (B = −0.34, SE = 0.06, p < .001), such that drug liking decreased over time. The time X sex interaction term was significant (B = 0.26, SE = 0.12, p = .04), with men and women experiencing a similar acute peak in drug liking, but women exhibiting a steeper decrease over time. Simple effects tests indicated that although men and women reported similar drug liking at the acute post-use assessment (p = .75), men reported marginally greater drug liking 1 -h post-use (p = .09).

3.4. Verbal memory errors

Verbal memory errors exhibited a significant linear effect of time controlling for sex, grams used, condition, and baseline verbal memory errors (B = 0.71, SE = 0.16, p < .001), such that the number of errors made on the delayed verbal recall test increased over time. The time X sex interaction term was not significant (B = −0.07, SE = 0.19, p = .73); across time, men and women made a similar number of errors on the verbal memory task (B = −0.29, SE = 0.38, p = .46).

4. Discussion

Using a novel, naturalistic at-home administration procedure, this is the first study to explore sex differences in plasma cannabinoid concentrations, subjective drug effects, and verbal memory errors after ad libitum use of high potency cannabis concentrates in regular cannabis users. Although 11-OH-THC levels were similar, THC and CBD levels differed significantly between men and women after using concentrates, with men displaying higher levels at the acute post-use assessment time point. Interestingly, despite these differences in plasma cannabinoid levels, men and women reported, on average, similar frequency of use patterns, MDS scores, BMIs, and grams of cannabis concentrate used during the ad libitum administration appointment. Furthermore, there were largely no sex differences in subjective drug effects or verbal memory errors.

These results diverge from previous findings, and suggest that previous findings regarding sex differences in plasma cannabinoid concentrations after acute cannabis use may not generalize to cannabis concentrates or other high potency products as they are commonly used. Wall et al. (1983) found no sex differences in plasma cannabinoid levels and Nadulski et al. (2005) found that women had higher levels of plasma cannabinoids after cannabis administration. Notably, these studies relied on controlled dosing of oral or intravenous administration of THC extracts, rather than smokable or vaporizable forms of cannabis. As such, one possibility is that while both sexes used the same amount of concentrate on average, women were self-titrating by potentially inhaling less of the product. It is also possible that women were unintentionally consuming a lower dose of their product due to a shorter length of inhalation, as studies have suggested that compared to men, women inhale less smoke (LoMauro and Aliverti, 2018) and have a smaller lung capacity (Zang and Wynder, 1996). Future studies should explore sex differences in plasma cannabinoids after using edible cannabis products across a range of potencies in order to determine whether the reported sex differences emerge across different routes of cannabis administration.

Interestingly, while plasma THC levels were higher among men, sex differences in subjective intoxication and verbal memory errors after acute concentrate use were largely nonexistent. This is in line with previous studies which have found that plasma THC levels are not always predictive of subjective intoxication ratings (Spindle et al., 2019). This incongruence between plasma cannabinoid levels, subjective intoxication, and verbal memory error suggests that men may have a greater tolerance to the acute effects of THC than women or have pre-existing differences that impact the way they experience cannabis. Evidence suggests that regular cannabis users can develop a tolerance to the psychoactive effects of cannabis (Bosker et al., 2012; Hirvonen et al., 2012). As men reported an earlier age of onset of cannabis use, it is possible that they were experiencing similar levels of subjective intoxication and verbal memory impairment despite significantly higher plasma THC levels, due to a higher THC tolerance. It is also possible that women metabolize THC into active metabolites (e.g., 11-OH-THC) to a greater degree than men (Cooper and Craft, 2018; Tseng et al., 2004), leading to similar subjective effects despite lower plasma THC levels. Despite similarities in subjective intoxication and verbal memory impairment, it is important to note that women reported a steeper decrease in drug liking over time. As drug liking is an important indicator of abuse potential, this finding is in line with previous studies which suggest that men are at greater risk for cannabis use disorder than women (Cooper and Craft, 2018).

Another possibility is that cannabis users may experience a “ceiling effect” in which cannabinoid receptors become saturated with THC at a certain point after acute use of high potency products, beyond which there is no additional subjective or cognitive effect of THC. It is possible that, after use of high potency formulations, both men and women are reaching this threshold and any differences in plasma THC levels are negligible in terms of influencing their subjective intoxication and cognitive performance. Interestingly, however, the plasma THC levels seen in women were within the range of plasma THC levels seen in studies with lower potency cannabis flower (Bidwell et al., 2020; Spindle et al., 2019) and mean intoxication scores were well below the maximum. Furthermore, it might be the case that verbal memory is more heavily affected by subjective rather than objective intoxication; in other words, how high an individual feels may have a greater bearing on verbal memory than plasma THC levels. This is only speculative, however, and it is plausible that an individual can develop different levels of tolerance to the subjective and cognitive effects of THC.

Strengths of the current study include the naturalistic administration approach, the type of cannabis product used, and a balanced sample of men and women who had similar cannabis use histories. This study makes an important contribution by examining sex differences in acute post-use plasma cannabinoids (THC, 11-OH-THC, CBD), subjective drug effects, and verbal memory errors after use of commercially legally available high potency formulations.

Despite these strengths, several limitations should be noted. While naturalistic data are needed to assess cannabis use patterns across men and women, the inferences that can be drawn from these data are limited by the lack of controlled dosing and a placebo control condition. Furthermore, federal cannabis regulations prohibited us from handling or independently testing the concentrate products assigned to participants. Thus, although all products were labeled in accordance with testing in an International Organization of Standards (ISO) 17025 accredited laboratory, we were unable to verify the accuracy of the labeled cannabinoid content with independent laboratory assays. Given this, we are unable to independently ascertain whether the THC or CBD potency may have differed across participants despite using the same products. Additionally, as batch numbers were not included on product labels, we cannot rule out the possibility that batch effects may have influenced our results.

It is also important to note that all individuals in this study were regular concentrate users recruited from Colorado, one of the first states to legalize cannabis for recreational use and presently a state with liberal policies surrounding such use. Because of this, our results may not generalize to samples of infrequent or naïve users, or users from other state contexts. In addition, research suggests that cannabis use often occurs alongside other substance use and abuse. For example, several studies have found a positive association between the use of cannabis and numerous other substances, including tobacco and alcohol (Degenhardt et al., 2001a,b; Roche et al., 2019; Qato et al., 2020). Due to some of our inclusion criteria (e.g., no daily tobacco use), our results may not generalize to individuals who use cannabis concurrently with tobacco or other drugs. Additionally, although we assessed age of onset of regular cannabis use, we did not assess onset of concentrate use specifically. Future studies should examine whether differences in length of experience with concentrates may impact sex differences in the acute effects of concentrates. Lastly, our measure of cannabis dependence was based on the DSM-IV. Future research should assess cannabis use disorder using diagnostic criteria from the DSM-V in order to more accurately assess cannabis use disorder symptoms among participants.

4.1. Conclusion

This is the first study to examine sex differences in the effects of cannabis concentrates. We found sex differences in THC and CBD levels following ab libitum use of high potency cannabis concentrate products, with men displaying significantly higher plasma THC and CBD levels than women after acute concentrate use. Despite this, the level of acute THC exposure appeared to have little impact on the subjective effects of cannabis, as sex differences in subjective intoxication and verbal memory errors were largely nonexistent. These results contribute to the literature examining the risks of and sex differences associated with use of higher potency forms of cannabis. Our finding that THC exposure after naturalistic use may be lower in female concentrate users, relative to male concentrate users, is relevant to uncovering the mechanisms that underlie sex differences in the responses to cannabis and the risks for and progression to cannabis use disorder.

Supplementary Material

Supplementary Material

Role of funding source

This work was supported by the Colorado Department of Public Health and Environment Marijuana Research Grant (grant number 96947 to LCB). The funding source had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Footnotes

Declaration of Competing Interest

No conflict declared.

Appendix A. Supplementary data

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.drugalcdep.2021.108718.

Data statement

The study protocol and de-identified participant data is available upon request. Data will be available beginning three months and ending five years following article publication. Data will be shared with researchers who provide a methodologically sound proposal. Proposals should be directed to lcb@colorado.edu. To gain access, data requesters will need to sign a data access agreement.

References

  1. Bates D, Sarkar D, Bates MD, Matrix L, 2007. The lme4 Package. ftp://ftp.uni-bayreuth.de/pub/math/statlib/R/CRAN/doc/packages/lme4.pdf. [Google Scholar]
  2. Bidwell LC, YorkWilliams SL, Mueller RL, Bryan AD, Hutchison KE, 2018a. Exploring cannabis concentrates on the legal market: user profiles, product strength, and health-related outcomes. Addict. Behav. Rep 8, 102–106. 10.1016/j.abrep.2018.08.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bidwell LC, Mueller R, YorkWilliams SL, Hagerty S, Bryan AD, Hutchison KE, 2018b. A novel observational method for assessing acute responses to cannabis: preliminary validation using legal market strains. Cannabis Cannabinoid Res. 3, 35–44. 10.1089/can.2017.0038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bidwell LC, et al. , 2020. Association of naturalistic administration of cannabis flower and concentrates with intoxication and impairment. JAMA. 10.1001/jamapsychiatry.2020.0927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bosker WM, et al. , 2012. A placebo-controlled study to assess Standardized Field Sobriety Tests performance during alcohol and cannabis intoxication in heavy cannabis users and accuracy of point of collection testing devices for detecting THC in oral fluid. Psychopharmacology. 223, 439–446. 10.1007/s00213-012-2732-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Calakos KC, Bhatt S, Foster DW, Cosgrove KP, 2017. Mechanisms underlying sex differences in cannabis use. Curr. Addict. Rep 4, 439–453. 10.1007/s40429-017-0174-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cooper ZD, Craft RM, 2018. Sex-dependent effects of cannabis and cannabinoids: a translational perspective. Neuropsychopharmacology 43, 34–51. 10.1038/npp.2017.140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cooper ZD, Haney M, 2009. Comparison of subjective, pharmacokinetic, and physiological effects of marijuana smoked as joints and blunts. Drug Alcohol Depend. 103, 107–113. 10.1016/j.drugalcdep.2009.01.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cooper ZD, Haney M, 2014. Investigation of sex-dependent effects of cannabis in daily cannabis smokers. Drug Alcohol Depend. 136, 85–91. 10.1016/j.drugalcdep.2013.12.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Crane NA, Schuster RM, Gonzalez R, 2013. Preliminary evidence for a sex-specific relationship between amount of cannabis use and neurocognitive performance in young adult cannabis users. J. Int. Neuropsychol. Soc 19, 1009–1015. 10.1017/S135561771300088X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Cuttler C, Mischley LK, Sexton M, 2016. Sex differences in cannabis use and effects: a cross-sectional survey of cannabis users. Cannabis Cannabinoid Res. 1, 166–175. 10.1089/can.2016.0010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Degenhardt L, Hall W, Lynskey M, 2001a. Alcohol, cannabis and tobacco use among Australians: a comparison of their associations with other drug use and use disorders, affective and anxiety disorders, and psychosis. Addiction 96, 1603–1614. 10.1046/j.1360-0443.2001.961116037.x. [DOI] [PubMed] [Google Scholar]
  13. Degenhardt L, Hall W, Lynskey M, 2001b. The relationship between cannabis use and other substance use in the general population. Drug Alcohol Depend. 64, 319–327. 10.1016/s0376-8716(01)00130-2. [DOI] [PubMed] [Google Scholar]
  14. Ehlers CL, et al. , 2010. Cannabis dependence in the San Francisco Family Study: age of onset of use, DSM-IV symptoms, withdrawal, and heritability. Addict. Behav 35, 102–110. 10.1016/j.addbeh.2009.09.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fogel JS, Kelly TH, Westgate PM, Lile JA, 2017. Sex differences in the subjective effects of oral Δ9-THC in cannabis users. Pharmacol. Biochem. Behav 152, 44–51. 10.1016/j.pbb.2016.01.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Haertzen CA, Hickey JE, 1987. Addiction research center inventory (ARCI): measurement of euphoria and other drug effects. In: Bozarth MA (Ed.), Methods of Assessing the Reinforcing Properties of Abused Drugs. Springer, New York, pp. 489–524. [Google Scholar]
  17. Haney M, 2007. Opioid antagonism of cannabinoid effects: differences between marijuana smokers and nonmarijuana smokers. Neuropsychopharmacology 32, 1391–1403. [DOI] [PubMed] [Google Scholar]
  18. Hartman RL, Brown TL, Milavetz G, Spurgin A, Gorelick DA, Gaffney G, Huestis MA, 2015. Controlled cannabis vaporizer administration: blood and plasma cannabinoids with and without alcohol. Clin. Chem 61, 850–869. 10.1373/clinchem.2015.238287. [DOI] [PubMed] [Google Scholar]
  19. Hirvonen J, et al. , 2012. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers. Mol. Psychiatry 17, 642–649. 10.1038/mp.2011.82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ, 1992. Characterization of the absorption phase of marijuana smoking. Clin. Pharmacol. Ther 52, 31–41. 10.1038/clpt.1992.100. [DOI] [PubMed] [Google Scholar]
  21. Khan SS, et al. , 2012. Gender differences in cannabis use disorders: results from the National Epidemiologic Survey of Alcohol and Related Conditions. Drug Alcohol Depend. 130, 101–108. 10.1016/j.drugalcdep.2012.10.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. LoMauro A, Aliverti A, 2018. Sex differences in respiratory function. Breathe 14, 131–140. 10.1183/20734735.000318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Makela P, Wakeley J, Gijsman H, Robson PJ, Bhagwagar Z, Rogers RD, 2006. Low doses of Δ-9 tetrahydrocannabinol (THC) have divergent effects on short-term spatial memory in young, healthy adults. Neuropsychopharmacology 31, 462–470. 10.1038/sj.npp.1300871. [DOI] [PubMed] [Google Scholar]
  24. McCormick M, et al. , 2017. Cannabis-derived products. In: Pool R (Ed.), The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press, Washington D.C, pp. 50–53. [PubMed] [Google Scholar]
  25. Morean ME, de Wit H, King AC, Sofuoglu M, Rueger SY, O’Malley SS, 2013. The drug effects questionnaire: psychometric support across three drug types. Psychopharmacology 227, 177–192. 10.1007/s00213-012-2954-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nadulski T, et al. , 2005. Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract. J. Anal. Toxicol 29, 782–789. 10.1093/jat/29.8.782. [DOI] [PubMed] [Google Scholar]
  27. Orens A, Light M, Lewandowski B, Rowberry J, Saloga C, 2014. Market Size and Demand for Marijuana in Colorado: 2017 Market Update. Marijuana Policy Group, Boulder, CO. [Google Scholar]
  28. Pope HG, Yurgelun-Todd D, 1996. The residual cognitive effects of heavy marijuana use in college students. JAMA 275, 521–527. 10.1001/jama.1996.03530310027028. [DOI] [PubMed] [Google Scholar]
  29. Pope HG, Jacobs A, Mialet JP, Yurgelun-Todd D, Gruber S, 1997. Evidence for a sex-specific residual effect of cannabis on visuospatial memory. Psychother. Psychosom 66, 179–184. 10.1159/000289132. [DOI] [PubMed] [Google Scholar]
  30. Qato DM, Zhang C, Gandhi AB, Simoni-Wastila L, Coleman-Cowger VH, 2020. Co-use of alcohol, tobacco, and licit and illicit controlled substances among pregnant and non-pregnant women in the United States: findings from 2006 to 2014 National Survey on Drug Use and Health (NSDUH) data. Drug Alcohol Depend. 206, 1–7. 10.1016/j.drugalcdep.2019.107729. [DOI] [PubMed] [Google Scholar]
  31. Raber JC, Elzinga S, Kaplan C, 2015. Understanding dabs: contamination concerns of cannabis concentrates and cannabinoid transfer during the act of dabbing. J. Toxicol. Sci 40, 797–803. 10.2131/jts.40.797. [DOI] [PubMed] [Google Scholar]
  32. Ramesh D, Haney M, Cooper ZD, 2013. Marijuana’s dose-dependent effects in daily marijuana smokers. Exp. Clin. Psychopharm 21, 287–293. 10.1037/a0033661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ranganathan M, D’Souza DC, 2006. The acute effects of cannabinoids on memory in humans: A review. Psychopharmacology 188, 425–444. 10.1007/s00213-006-0508-y. [DOI] [PubMed] [Google Scholar]
  34. Roche DJO, Bujarski S, Green R, Hartwell EE, Leventhal AM, Ray LA, 2019. Alcohol, tobacco, and marijuana consumption is associated with increased odds of same-day substance co-and tri-use. Drug Alcohol Depend. 200, 40–49. 10.1016/j.drugalcdep.2019.02.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Saunders JB, Aasland OG, Babor TF, De la Fuente JR, Grant M, 1993. Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption-II. Addiction 88, 791–804. 10.1111/j.1360-0443.1993.tb02093.x. [DOI] [PubMed] [Google Scholar]
  36. Schlienz NJ, Budney AJ, Lee DC, Vandrey R, 2017. Cannabis withdrawal: a review of neurobiological mechanisms and sex differences. Curr Addict Reports. 4, 75–81. 10.1007/s40429-017-0143-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shacham S, 1983. A shortened version of the Profile of Mood States. J. Pers. Assess 47, 305–306. 10.1207/s15327752jpa4703_14. [DOI] [PubMed] [Google Scholar]
  38. Smart R, Caulkins JP, Kilmer B, Davenport S, Midgette G, 2017. Variation in cannabis potency and prices in a newly legal market: evidence from 30 million cannabis sales in Washington State. Addiction 112, 2167–2177. 10.1111/add.13886. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sobell LC, Sobell MB, 1992. In: Litten RZ, Allen J (Eds.), Timeline Follow-Back: A Technique for Assessing Self-Reported Alcohol Consumption. Measuring Alcohol Consumption Humana Press, New Jersey, pp. 41–72. [Google Scholar]
  40. Spindle TR, et al. , 2019. Acute pharmacokinetic profile of smoked and vaporized cannabis in human blood and oral fluid. J. Anal. Toxicol 43, 233–258. 10.1093/jat/bky104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Stephens RS, Roffman RA, Curtin L, 2000. Comparison of extended versus brief treatments for marijuana use. J. Consult. Clin. Psychol 68, 898–908. 10.1037/0022-006X.68.5.898. [DOI] [PubMed] [Google Scholar]
  42. Stogner JM, Miller BL, 2015. The dabbing dilemma: a call for research on butane hash oil and other alternate forms of cannabis use. Subst. Abus 36, 393–395. 10.1080/08897077.2015.1071724. [DOI] [PubMed] [Google Scholar]
  43. Thompson TA, et al. , 2011. Sensitivity and test–retest reliability of the international shopping list test in assessing verbal learning and memory in mild Alzheimer’s disease. Arch. Clin. Neuropsychol 26, 412–424. 10.1093/arclin/acr039. [DOI] [PubMed] [Google Scholar]
  44. Tseng AH, Harding JW, Craft RM, 2004. Pharmacokinetic factors in sex differences in Δ9-tetrahydrocannabinol-induced behavioral effects in rats. Behav. Brain Res 154, 77–83. 10.1016/j.bbr.2004.01.029. [DOI] [PubMed] [Google Scholar]
  45. Vergara D, et al. , 2017. Compromised external validity: federally produced cannabis does not reflect legal markets. Sci. Rep 7, 1–8. 10.1038/srep46528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Volkow ND, Baler RD, Compton WM, Weiss SR, 2014. Adverse health effects of marijuana use. N. Engl. J. Med 370, 2219–2227. 10.1056/NEJMra1402309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Wall ME, Sadler BM, Brine D, Taylor H, Perez-Reyes M, 1983. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin. Pharmacol. Ther 34, 352–363. 10.1038/clpt.1983.179. [DOI] [PubMed] [Google Scholar]
  48. Wardle MC, Marcus BA, de Wit HA, 2015. Preliminary investigation of individual differences in subjective responses to d-Amphetamine, alcohol, and delta-9-tetrahydrocannabinol using a within-subjects randomized trial. PLoS One 10. 10.1371/journal.pone.0140501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Weintraub S, et al. , 2013. Cognition assessment using the NIH toolbox. Neurology 80, S54–S64. 10.1212/WNL.0b013e3182872ded. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Zang EA, Wynder EL, 1996. Differences in lung cancer risk between men and women: examination of the evidence. J. Natl. Cancer Inst 88 (1996), 183–192. 10.1093/jnci/88.3-4.183. [DOI] [PubMed] [Google Scholar]
  51. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG, 1982. Action of cannabidiol on the anxiety and other effects produced by Δ 9-THC in normal subjects. Psychopharmacology 76, 245–250. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material
NIHMS1826066-supplement-Supplementary_Material.pdf (57KB, pdf)

Data Availability Statement

The study protocol and de-identified participant data is available upon request. Data will be available beginning three months and ending five years following article publication. Data will be shared with researchers who provide a methodologically sound proposal. Proposals should be directed to lcb@colorado.edu. To gain access, data requesters will need to sign a data access agreement.

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