Cannabis Use: Neurobiological, Behavioral, and Sex/Gender Considerations

Abstract

Purpose of review:

To summarize the current literature on the effects of cannabinoids in humans and to discuss the existing literature on the sex- and gender-related differences in the effects of cannabinoids.

Recent findings:

Cannabis and its constituent cannabinoids are associated with risk of addiction, cognitive deficits and mood/psychotic disorders. Preclinical and emerging clinical data suggest greater sensitivity to the effects of cannabinoids in women.

Summary:

Cannabis is one of the most commonly used drugs with increasing rates of use. Women in particular may be at a greater risk of adverse outcomes given the previously described “telescoping effect” of substance use in women. Human data examining the sex- and gender-related differences in the effects of cannabinoids and factors underlying these differences are very limited. This represents a critical gap in the literature and needs to be systematically examined in future studies.

Introduction

Cannabis is by far the most commonly used illicit drug in the US, with 37,570 million individuals (13.9% of the general population older than 12) reporting past-year use and 23,981 million (10.6%) reporting past-month use in 2016 [1], These estimates have significantly increased over the past decade from 10.3% of the general population older than 12 reporting past-year use and 6% reporting past-month use in 2006 [1], Acute and chronic exposure to cannabis is associated with a wide range of subjective, cognitive, psychotomimetic effects as reviewed below. These effects vary based on the presence and concentration of constituent cannabinoids (i.e., dose) amount and frequency of use, and route of administration as well as age, prior exposure, and other substance use or psychiatric history in the individual or biological family.

Increasingly, data suggest that there may be sex- or gender-related differences in the acute and chronic effects of cannabinoids. However, while the literature on the acute and chronic effects of cannabis and cannabinoids has burgeoned in the last few decades, a major limitation remains in the lack of adequate studies examining the impacts of sex and gender. For clarity, please note that we refer to sex differences in preclinical studies and sex/gender with reference to human data [2], Historically, rates of use of cannabis as well as cannabis-use disorders have been much higher in men compared to women. More recently, women demonstrate a greater increase in use compared to men [3, 4], While the rate of cannabis use increased by 40% increase for men between 2006 to 2016 (from 8.1 % to 11.3%), women’s cannabis use increased by 63% during this time (from 4.1 % to 6.7%) [1,5], Several factors may have contributed to increased cannabis use, especially among women, including legalization, medical marijuana, and a decreased perceived risk of cannabis use [6], Thus, it is both critical and timely to investigate the effects of cannabis in women.

We present a qualitative review of the current literature on the behavioral effects of cannabis in humans with a particular emphasis on the existing literature on gender-related differences.

Overview on cannabis and its effects in humans

Cannabis and its active compounds

Cannabis contains over 500 unique chemical components [7], Of these, approximately one hundred are classified as cannabinoids, the main biologically active compounds. These are categorized further into ten classes, two of which have dominated research and marketing pursuits—tetrahydrocannabinols, including the potent Δ⁹-tetrahydrocannabiniol (THC), and cannabidiol (CBD). THC is the primary psychoactive cannabinoid and its effects are largely responsible for the “high” reported by people using cannabis, including euphoria, altered/heightened perceptions, and anxiety/paranoia [8] as well as other potentially beneficial effects on appetite and spasticity. For instance, synthetic oral THC (Marinol®and Cesamet®) is approved for nausea and vomiting associated with cancer chemotherapy and anorexia associated with weight loss in patients with AIDS . CBD, while centrally active, does not produce similar rewarding or psychotomimetic effects. Instead, CBD appears to have anxiolytic [9], antiepileptic [10], and antipsychotic [11] properties. In June of 2018, the U.S. Food and Drug Administration (FDA) approved CBD to treat two rare forms of epilepsy (Dravet syndrome and Lennox-Gastaut) [12]. The relative concentrations of THC and CBD are believed to modulate the overall effects of cannabis such that cannabis with higher THC and lower CBD is considered more potent. Terpenes represent another important class of compounds in cannabis [7]. These volatile chemicals are responsible for the aromatic properties of cannabis and vary widely between strains. These compounds may have functions beyond taste and smell and may operate synergistically with cannabinoids to impact the central nervous system (CNS) [13].

The endocannabinoid system

Pharmacological target of cannabis and cannabinoids

Cannabinoids exert their psychoactive effects on the central nervous system primarily via the endogenous cannabinoid system consisting of endocannabinoid receptors (CB1R and CB2R), and endogenous ligands, N-arachidonoyl-ethanolamine (Anandamide or AEA) and 2-arachidonoylglycerol (2-AG). CB1Rs are the best studied cannabinoid receptors and are found throughout the cerebrum, cerebellum, and brainstem [8], but their dense expression in areas implicated in reward processing, including the ventral and dorsal striatum and the amygdala, have made them a target for addiction research and drug development [14]. Cannabinoids also bind to CB2R, expressed primarily in immune cells in the periphery and central nervous system. Endocannabinoid ligands, including AEA and 2-AG, are synthesized and released on demand and are rapidly deactivated soon thereafter [14]. As the role of the endocannabinoid system in addiction has been extensively reviewed [15], we will focus on the effects of cannabis in humans.

Effects of cannabis in humans

Cannabis produces a wide range of subjective, behavioral, neuropsychological, motor, physiological and neuroendocrine effects. This review aims to focus on the subjective and cognitive effects of cannabis, especially as they relate to addictive potential, cognition and mental health.

Several routes of cannabis consumption/administration exist. These include the “traditional” method of smoking herbal cannabis in a joint or pipe, ingesting cannabis in food items, distilling it into tinctures or oils, or concentrating it into a hashish resin, which may be combusted and inhaled (a method called “dabbing”). Electronic vaporizing devices are also sold, which can be filled with THC and/or CBD oils. Laboratory studies have also administered intravenous THC that permits more precise dosing. These differing routes result in differing pharmacokinetics, with the inhaled and intravenous routes producing a more rapid onset and shorter duration of effects and the oral route, a slower more variable onset (as long as two hours post dose), and prolonged duration. The pharmacokinetics of cannabinoids in humans have been reviewed elsewhere [16], Further, cannabis products contain varying concentrations of THC and other cannabinoids such as CBD, and these features may contribute to overall effects and be difficult to assay in population-based/ epidemiological studies. Most psychoactive effects of cannabis are, however, attributed to its primary psychoactive constituent, THC. Indeed, laboratory studies with THC alone replicate many effects of cannabis. Below, we will review subjective and cognitive effects of cannabis and, when specifically studied, THC.

Subjective Effects

Cannabis and THC produce a wide range of subjective effects in humans. The most commonly described acute positive effect is euphoria, or feeling “high” or “stoned,” as well as several others including feeling “calm and relaxed,” “tired” and conversely, especially at higher doses, feeling anxious and experiencing perceptual alterations [17-24], Data remain mixed regarding the dose-dependent nature and development of tolerance to subjective effects [18, 22, 25, 26] induced by cannabis or THC. Dose and route of administration of cannabis/THC, as well as wide inter-individual variability in response, may contribute to the mixed data. Further, even among infrequent users, recent (past month) use of cannabis may influence acute subjective response [18], Several studies have examined the influence of CBD on the subjective effects of cannabis/THC and have found mixed results, as reviewed by Boggs et al [27], Although single doses of CBD did not attenuate THC-induced feelings of being “stoned” [28, 29], higher CBD:THC ratios were associated with reduced attentional bias to both drug and food stimuli, suggesting that CBD may influence reinforcing effects of THC [30], Furthermore, as we discuss later in this paper, sex- or gender-related differences in subjective effects may also contribute to this variance.

Psychotomimetic Effects

Cannabinoids may acutely induce perceptual alterations and psychotomimetic effects including paranoia and thought disorganization [18-20, 31-37], Psychotomimetic effects may be dose-dependent such that cannabis with greater concentrations of THC and lower concentrations of CBD, or the more potent synthetic cannabinoids, may produce greater psychosis-like effects, leading to more frequent visits to emergency departments or hospitalizations [20, 38-40].

Cognitive Effects

The acute cognitive effects of cannabis/THC have been extensively studied [41-43] and may include dose-related deficits in attention, verbal learning and recall, working memory, spatial learning, psychomotor function and response inhibition. Acute cognitive deficits are present in both infrequent as well as frequent users of cannabis, although the latter group may be more tolerant to acute cognitive deficits. Acute cognitive/psychomotor deficits may also have implications for educational achievements and driving [44-48].

Cognitive deficits associated with chronic cannabis use

Cognitive deficits such as impairment in attention, memory, IQ, driving ability and amotivation syndrome [49-52] have been observed with chronic cannabis use. However, data are mixed regarding whether these deficits persist with prolonged abstinence, with some studies [53, 54] but not others [55, 56] reporting persistent deficits despite abstinence. Perhaps more concerning are data on cannabis exposure in adolescents, suggesting that when cannabis use is initiated in adolescence, cognitive deficits persist despite abstinence. Thus, cannabis use in adolescence is associated with a dose-dependent decrease in IQ persisting into adulthood [57], lower educational attainment [58, 59], poorer academic performance [60], higher school drop-out rates [61], increased risk of unemployment [62] and increased risk of psychiatric disorders [51,52].

Cannabis and Mental Health

The negative impact of cannabis use on a variety of mental health disorders has been extensively studied, with much research focusing on psychotic disorders. Epidemiological studies demonstrate an increased risk of psychotic disorders such as schizophrenia [63, 64] and bipolar disorder [51,65]. A meta-analysis reported a four-fold higher risk of psychosis in heavy cannabis users and twice the risk in average cannabis users compared to non-users [66]. Moreover, there is increasing evidence suggesting that cannabis use is associated with an earlier age of psychosis onset [67]. Meta-analyses confirm that the age of psychosis onset is about 3 years earlier in cannabis users compared to non-users [68-70]. Cannabis use is also associated with exacerbation of psychotic or manic symptoms in those with preexisting schizophrenia or bipolar disorder [71]. Several studies report that cannabis users may have greater risk of depressive disorders [72]. Literature on effects of cannabis use and anxiety disorders is mixed. While there exist data supporting cannabis as a possible therapy for post-traumatic stress disorder (PTSD), current evidence is insufficient to form a strong conclusion [73].

Sex as a significant biological variable in the effects of cannabinoids

Emerging data suggest that while the prevalence of recreational cannabis use remains higher in men, the gap in prevalence between men and women continues to decrease, likely related to the greater rate of increase in use among women [3, 74]. The literature on the consequences of cannabinoids in women is sparse, partly because the large majority of clinical studies have included only men or had too few women to examine sex/gender-related differences, compared to the robust preclinical literature demonstrating sex-related cannabinoid differences. Below we review the existing literature on sex/gender-related differences in the acute and chronic effects of cannabinoids from both pre-clinical and clinical studies.

Preclinical studies

Females as compared to male rats are more sensitive to the rewarding and reinforcing effects of CB1R agonists [75], acquire self-administration of CB1R agonists faster and at higher rates, self-administer greater amounts, are slower to extinguish this response [75], and have greater cue/stress induced reinstatement [76]. Female rodents are also more sensitive to the acute sedative, anti-nociceptive, and motoric effects of CB1R agonists, CP 55,940 and THC, while males are more sensitive to the hypothermic and hyperphagic effects [77-80]. Cannabinoids also have sex-specific effects on anxiety-like behaviors in rodents. Harte-Hargrove and Dow-Edwards investigated effects of different doses of THC on male and female rats and reported that female rats are more sensitive to the anxiogenic effects of high doses of THC [81]. Similarly, Wiley investigated effects of high doses of THC on mice and reported that high THC doses increased locomotor activity in female and not male mice [82]. Female rodents also develop greater tolerance to the effects of THC [83, 84] and show more withdrawal symptoms in abstinence. Further, female as compared to male rats demonstrate greater deficits in spatial learning on a water maze task following sub-chronic administration of THC [85].

Clinical studies

Rewarding effects

Data on acute subjective rewarding effects of cannabinoids in humans are mixed. While early studies failed to find any sex-/gender-related differences in acute subjective effects [86, 87], others observed differences with some studies reporting greater THC-induced effects in women [24, 88-90] and some in men [91, 92], Fogel et al. reported that women were more sensitive to the subjective effects of low doses of THC, and men to higher doses of THC [89], Further, women experiencing objective effects such as tachycardia similar to men, endorsed higher effects on measures of “feeling good”, “strong” and “take again,” with findings suggestive of stronger rewarding effects in women [24], In a separate study, nearly 50% of women requested discontinuation of the study, compared to 0% in men, despite no differences from men in subjective ratings of “high” or tachycardia [93].

Among regular cannabis users, women have reported greater tolerance [86] and more frequent and severe withdrawal symptoms compared to men [94-97], and these symptoms are more predictive of relapse. Specifically, women more frequently reported gastrointestinal symptoms such as nausea, abdominal discomfort, and behavioral effects such as anxiety, irritability and agitation [95, 96, 98-100], while men experienced greater goosebumps, craving and sleep disruption [96, 100, 101].

More robust positive reinforcing effects of cannabis use in combination with negative reinforcing effects of severe withdrawal symptoms may explain why women experience faster progression to cannabis-use disorders compared to men. Using data from the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC, n = 43,093), Khan demonstrated that, while cannabis-use disorder is more prevalent in men, women show a faster transition from first use to cannabis-use disorder [102], This phenomenon, termed “telescoping,” has been reported in several studies [103, 104] and has been observed for other addictive behaviors.

Thus, to summarize, the literature on sex-/gender-related differences in rewarding effects of cannabis/cannabinoids remains mixed, possibly related to several confounds including variability in cannabis-use histories, variable doses and routes of drug administration and small sample sizes. However, studies in regular users suggest that, consistent with preclinical data, women may be more sensitive to reinforcing effects of cannabis, experience more severe withdrawal symptoms, develop cannabis-use disorder more rapidly and have persistent negative consequences related to cannabis use.

Cognitive Deficits

Few studies have examined sex-/gender-related differences in cannabinoid-induced cognitive deficits. McDonald et al. reported no sex-/gender-related differences with two doses of oral THC (7.5mg and 15mg) on behavioral measures of impulsivity [105], Similarly, Anderson et al. reported no sex-/gender-related differences in cannabinoid effects on selective and divided attention, cognitive flexibility, and time estimation [93], In contrast, Makela et al. [88] reported that 5mg of sublingual THC acutely improved spatial working memory (SWM) performance compared to placebo in women but not men. Similarly, Roser et al. reported that women were more sensitive to the psychomotor effects of THC [106].

Pope et al. found that heavy/daily cannabis-using women demonstrated greater residual SWM deficits after a brief abstinence [107]. Similarly, Crane et al. reported a stronger association between past-month cannabis use and poorer immediate and delayed recall specifically amongst women, although men performed worse on a decision-making task [108]. In a follow-up study, Crane et al. reported that sex/gender mediated the relationship between age of onset of cannabis use and subsequent neuropsychological differences in chronic cannabis users [109]. In contrast, Skosnik et al. examined sex-/gender-related differences in early visual processing in a small sample of cannabis users and found that female but not male cannabis users had evidence of altered visual steady state visual evoked potentials (SSVPs), suggesting changes in primary visual circuits. [110].

Given the robust literature on cannabinoid induced acute and chronic cognitive deficits, it is surprising that the literature examining sex-/gender-related differences is relatively sparse and indicative of the need to systematically examine the impact of sex/gender in future, well powered studies.

Cannabis and Mental Health

Cannabis use may be associated with earlier ages of psychosis onset in women as compared to men [67]. Typically, the age of psychosis onset is later in women [111] Donoghue et al. demonstrated that this gender gap is diminished in cannabis users. Thus, while the mean age of psychosis onset in non-cannabis users was 27.07 years (SD=7.23) in men and 30.76 years (SD=8.15) in women, among cannabis users this gap in the age of onset disappeared (25.52 years, SD=6.62 in men, vs 26.03 years, SD=5.56 in women) [112]. Similarly, Compton et al. reported that an increase in frequency of cannabis use was associated with an increase in psychotic disorders, especially in women. While they found a larger hazard ratio for the onset of psychosis in men compared to women with no history of cannabis use (2.25 in men vs. 1.00 in women) and infrequent cannabis use (2.33 in men vs. 2.05 in women), among daily cannabis users, the hazard ratio was significantly higher in women (3.36 in men vs. 5.15 in women) [113]. Interestingly, Decoster reported that particularly in women, cannabis use interacted with brain-derived neurotrophic factor (BDNF) genotype, and was associated with an earlier age of psychosis onset only in BDNF Met-carriers [114]. This study showed that among BDNF Met-carriers, while the age of psychosis onset was 1.3 years earlier in men with cannabis use, it was 7 years earlier in women with cannabis use, compared to men and women without cannabis use [114]. Taken together, current evidence strongly suggests that cannabis use may counteract the later onset of psychosis in women, perhaps in concert with other vulnerability factors. Since an earlier onset of psychosis is associated with a worse prognosis, that women may be more sensitive to potential effects of cannabis on hastening the onset of psychosis is concerning, particularly given increasing exposure to cannabis among women.

Moreover, anxiety and mood disorders occur in higher rates in women with cannabis-use disorders compared to men [102]. Of concern, women with cannabis-use disorder in late adolescence and middle adulthood present with higher rates of anxiety and suicide risk, compared to men [115], In a longitudinal study with a large sample size (n=19327), cannabis use was associated with presence of psychological distress after 8 years in women (OR=1.37, 95% CI: 1.1–1.7), but not in men (OR=1.14, 95% CI: 0.9–1.5) [116].

Transgenerational Effects

Emerging clinical evidence suggests trans-generational effects related to cannabis use, consistent with preclinical data [117], Daughters of women with cannabis-use disorders (HR = 3.10, 95% CI = 1.52-6.34) have a greater risk of a cannabis-use disorder compared to daughters of non-users [118], while daughters of fathers with a cannabis-use disorder have an earlier onset of cannabis use (b = −3.71, p<.05) and alcohol use (b = −3.65, p<.05), while there is no such relationship between mothers or fathers and their sons. Further, the age of first cannabis use amongst daughters of male cannabis users was 14.6 years (SD = 2.1), as opposed to 17.2 years (SD = 2.8) in daughters of non-users [119].

Understanding the sex-/gender-related differences in effects of cannabinoids

While the cannabis-related literature has been dominated by effects of cannabinoids in men (in part related to higher prevalence of cannabis use among men), the shifting socio-political landscape with legalization of recreational and medicinal cannabis, rising rates of use amongst women, and recognition of sex/gender as important considerations have resulted in greater examination of sex-/gender-related differences in effects of cannabinoids. Much of the literature, mainly pre-clinical, has shed light on potential pharmacokinetic and pharmacodynamic underlying mechanisms, as discussed below.

Endocannabinoid System differences

Several preclinical and some emerging clinical data demonstrate sex-/gender-related endocannabinoid system differences. Male rodents have a higher density of CB1Rs in most brain regions except in the amygdala where female have more CB1Rs [120, 121]. On the other hand, in spite of having lower CB1R density, females show a higher receptor activity [122], greater desensitization after chronic cannabis exposure [123] and altered CB1R expression [124] compared to males. In addition to central CB1Rs, it seems that CB2Rs also may contribute to sex-related differences in cannabinoid effects. Craft et al. reported that whereas the CB1R antagonist, rimonabant, blocked the anti-hyperalgesic effects of THC in both sexes, the CB2R antagonist, SR144528, decreased the anti-hyperalgesic effects of THC only in females [79].

Interestingly, preclinical studies show that early life stress has sex-specific effects on the endocannabinoid system by increasing CB1R expression in females and decreasing its expression in males [125]. Zamberletti et al. investigated effects of THC on adolescent female and male rats with histories of maternal deprivation early in life, compared to those without. Whereas adolescent THC exposure impaired memory in non-deprived rats, it failed to affect memory in maternally deprived female rats [126]. The endocannabinoid system is intricately implicated in stress modulation and stress-related disorders such as PTSD; thus, a better understanding of inter-relationships between sex, stress and cannabinoids is warranted.

In humans, there have been two in-vivo positron emission transmission (PET) studies with two separate ligands on sex-/gender-related differences in CB1R availability amongst healthy individuals [127, 128], Van Laere et al. reported greater regional CB1R availability in men compared to women and an age-related increase seen only in women [127], In contrast, Normandin et al. reported greater CB1R availability in women [128], Differing PET methodologies may underlie these conflicting reports. Further, although Van Laere et al. reported no significant differences between women on and off hormonal contraceptives, neither examined the influence of sex steroids/menstrual cycle, factors found to influence CB1Rs in rodents.

Pharmacokinetic differences

Preclinical data strongly suggest pharmacokinetic sex-related differences in the metabolism of THC, although similar differences have not been reported in humans. Females produce greater amount of 11-OH-Δ⁹-THC, the principal active metabolite of THC, while males metabolize THC to 11-OH-Δ⁹-THC and several other inactive metabolites such as 8-alpha-OH-Δ⁹-THC, 8-alpha-11-diOH-Δ⁹-THC, and 3'-OH-Δ⁹-THC [129], When 11-OH-Δ9-THC production is blocked by a cytochrome P450 inhibitor, the anti-nociception effects of THC are attenuated in female rodents alone [130], However, in some other studies, adolescent female rats did not show different behavioral effects of THC, in spite of having elevated brain levels of 11 -OH-Δ9-THC compared to males. Authors suggested that sex differences in the effects of cannabinoids cannot fully be explained by THC pharmacokinetics and other factors, such as hormonal effects, should be considered [131].

Sex steroids as modulators of cannabinoid effects

Sex steroids may influence responses to cannabinoids by modulating the endocannabinoid system in a tonic manner and/or by acutely influencing responses to cannabinoids. The literature on the influence of sex steroids is almost completely reliant on preclinical data. Castelli et al. investigated differences in cannabinoid-receptor density and function in ovariectomized female rats compared to normally cycling females and males and reported that cycling females have a lower density of CB1Rs in the prefrontal cortex and amygdala compared to males and ovariectomized females. Interestingly, estradiol was able to decrease the CB1R density in ovariectomized females to equal-cycling females [132]. Similarly, CB1R density, transcription, G-protein coupling, signal transduction, and levels of endogenous cannabinoids are influenced by the ovarian steroid, estradiol [40-44], as reviewed by Lopez [45]. Finally, estradiol has also been shown to modulate responses to exogenous cannabinoids; thus, ovariectomy may abolish and estradiol administration may reinstate sex-/gender-related differences in self-administration of synthetic cannabinoids [15]. Of note, estradiol may enhance rewarding effects and attenuate cognitive deficits induced by THC [2, 45, 46]. Thus, faster acquisition and higher rates of cannabinoid administration and development of more robust tolerance and withdrawal symptoms may all contribute to more rapid and severe cannabinoid dependence in females, as is observed in humans. This is consistent with evidence that female rats have higher rates of cannabinoid reinstatement after abstinence, compared to males or ovariectomized females [133]. Notably, testosterone in gonadectomized male rats decreases withdrawal symptoms, whereas estradiol and progesterone induce opposite effects and increase withdrawal behaviors in gonadectomized females [134].

Conclusion

Cannabis and its constituent cannabinoids may produce robust subjective, cognitive and physiological effects acutely and are associated with addiction, cognitive deficits and risk for mood/psychotic disorders with chronic exposure. Preclinical data demonstrate robust sex-related differences influenced by sex steroids, differences in the endocannabinoid systems and pharmacokinetic differences between males and females. Data in humans similarly demonstrate sex-/gender-related differences in acute effects of cannabinoids, but effects related to chronic use appear more prominent. Given increasing rates of recreational and medicinal use of cannabinoids among women and data suggesting a faster development of cannabis-use disorder with poorer outcomes in women, it is critical to develop a better understanding of the neurobiological underpinnings of sex-/gender-related differences in cannabinoid pharmacology. Importantly, given the wide variability in cannabis products and routes of administration, future studies should carefully examine these factors. Finally, preclinical data suggest that menstrual-cycle phase and sex steroids may contribute to sex/gender-related differences. Indeed, some mixed data in humans may relate to absence of information on menstrual-cycle phase or hormonal contraceptives. Understanding these factors may help identify vulnerability factors and promote the development of targeted prevention and treatment interventions.

Human and Animal Rights.

All cited studies/experiments with human or animal subjects have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).