The relationship between cannabis use and cortisol levels in youth at ultra high-risk for psychosis

Highlights

• Group differences in cortisol levels among cannabis users/non-users were examined.

• Groups included psychosis risk users, non-users, and healthy control non-users.

• Cannabis use was assessed with a urine panel and self-report.

• Psychosis risk cannabis users had the highest salivary cortisol levels.

Abstract

Recent studies have posited a relationship between cannabis use and the biological stress system, but this critical relationship has not been evaluated during the ultra high-risk (UHR) period immediately preceding the onset of psychotic disorders. Salivary cortisol samples were collected on 46 UHR and 29 control adolescents; these individuals were assessed for current cannabis use with a urine panel and self-report. UHR participants where separated into two groups: Current Cannabis Use (UHR-CU) and No Current Cannabis Use (UHR-NC). Healthy Control participants (HC) were free of cannabis use. Consistent with the literature, results indicate UHR individuals showed elevated cortisol levels when compared to HC participants. Further, we also observed that UHR-CU participants exhibited elevated levels when compared to both the non-using UHR and HC groups. Findings suggest that cannabis use may interact with underlying biological vulnerability associated with the hypothalamic-pituitary-adrenal (HPA) axis system.

Introduction

The mean age of onset of psychotic disorders occurs during adolescence; a period that is characterized by significant changes to neurobiological systems (Walker et al., 2008) as well as exposure to substance use (Addington et al., 2014). Cannabis use is common during adolescence and the literature indicates that individuals who are at ultra high risk (UHR) for developing psychosis have higher rates of cannabis use than their peers (Addington et al., 2014). It has been suggested that cannabis use may play an important role in the etiology of psychosis (Moore et al., 2007), yet little is known about the relationship between cannabis use and neurobiological systems such as the hypothalamic-pituitary-adrenal (HPA) axis in psychosis development. In the general population, exposure to cannabis has been shown to affect the HPA axis as indicated by elevated baseline cortisol levels (King et al., 2011). Accumulating evidence suggests that the HPA axis is dysregulated in UHR youth (Aiello et al., 2012, Carol and Mittal, 2015, Walker et al., 2013); however, the relationship between cannabis use and HPA system activity has never been examined in a psychosis risk population. Understanding this relationship stands to inform the etiological conceptualization of psychosis risk and may refine efforts of early detection for adolescents exhibiting sub-threshold psychotic-like symptoms.

The HPA axis is one of the primary biological stress response systems that is activated by psychological and physiological stressors, and its activity is sensitive to a variety of psychoactive substances including cannabis (Ranganathan et al., 2009). The active ingredient in cannabis, delta-9-tetrahydrocannabinol (Δ-9-THC), binds to cannabinoid receptors (CB1) and activates the HPA axis, leading to increased levels of cortisol (Pagotto et al., 2006). Notably, the hippocampus participates in the glucocorticoid negative feedback system for de-escalating stress response of the HPA axis (Sapolsky et al., 1990), and it expresses a high density of cannabinoid receptors (Egertova and Elphick, 2000). HPA axis function is most commonly assessed through measuring cortisol levels and a variety of studies suggest that cannabis use may have different effects on the HPA axis depending on the type of cortisol measure or experimental manipulation that is utilized (Huizink et al., 2006, King et al., 2011; Ranganathan et al., 2009, van Leeuwen et al., 2011). Increased cortisol levels in response to cannabis exposure in humans have been demonstrated in both lab based intravenous administration of Δ-9-THC and in recreational cannabis users (D'Souza et al., 2004; King et al., 2011; Ranganathan et al., 2009). Specifically, intravenous administration of increasing Δ-9-THC levels has been shown to raise plasma cortisol levels in a dose-dependent manner in healthy participants when cortisol was measured before and after the exposure to cannabis (Ranganathan et al., 2009). It has also been reported that chronic active cannabis users have higher basal salivary cortisol levels than non-users (King et al., 2011). Additionally, cannabis use has been associated with a blunted cortisol awakening response (CAR(Huizink et al., 2006, Monteleone et al., 2014), and lower HPA axis stress-reactivity (van Leeuwen et al., 2011). HPA axis dysregulation can have detrimental effects on mental health (Goodyer et al., 2001) and is specifically associated with chronic psychosis and UHR individuals (Carol and Mittal, 2015, Corcoran et al., 2003;Karanikas and Garyfallos, 2015).

As noted above, UHR individuals use cannabis at higher rates and frequency than controls, and this pattern is persistent over time (Addington et al., 2014, Buchy et al., 2015). Additionally, UHR individuals start using cannabis at a younger age and are more likely to use alone during the day when compared with their peers (Buchy et al., 2015). Research indicates that UHR individuals have more perceptual disturbances and worse functioning during periods of increased cannabis use (Corcoran et al., 2008), and positive symptoms are associated with the frequency of cannabis use (Buchy et al., 2015). Therefore, the relationship between cannabis use and psychosis conversion has received increasing attention; however, results focusing on conversion as an outcome measure remain inconclusive. A review of studies examining UHR individuals indicates that two of ten studies have found a significant relationship between cannabis use and the transition to psychosis (Addington et al., 2014). Additionally, a recent meta-analysis suggests a dose-response relationship between cannabis use and transition to psychosis as cannabis abuse and dependence, but not lifetime use, was associated with psychosis conversion (Kraan et al., 2016). This relationship remains complex (Rentzsch et al., 2016), and more research evaluating other domains outside of conversion is needed to better understand if and how cannabis use contributes to the transition to psychosis (Buchy et al., 2015).

Given that cannabis use affects the HPA axis (King et al., 2011, Ranganathan et al., 2009), and the high rates of cannabis use among UHR individuals (Addington et al., 2014), the examination of the relationship between cannabis use and HPA axis functioning could help clarify the role of cannabis as a risk factor for psychosis. Interestingly, in a study of healthy individuals, increasing intravenous doses of Δ-9-THC not only significantly increased cortisol levels, but also produced transient positive and negative symptoms, perceptual alterations, euphoria, anxiety, and cognitive deficits (D'Souza et al., 2004). Although patients with schizophrenia have a flattened cortisol awakening response after cannabis exposure (Monteleone et al., 2014), this relationship has not been examined in UHR individuals. Understanding the relationship between cannabis use and basal cortisol levels during the psychosis risk period has the potential to impact treatment efforts as cannabis use and HPA axis functioning could be targeted with specialized therapy.

In the present study, we evaluated if basal cortisol levels during the first half of the day in a laboratory setting are different across participant groups of UHR youth with Current Cannabis Use (UHR-CU), UHR youth with no current cannabis use (UHR-NC), and healthy control participants with no current cannabis use (HC). In addition, the association between cannabis use frequency and symptomatology was also examined. Based on prior research observing that cannabis use increases cortisol levels (Ranganathan et al., 2009), we predicted that the UHR-CU would exhibit higher cortisol levels compared to UHR-NC. Finally, on the basis of studies reporting a relationship between cannabis use and psychosis risk symptoms (Buchy et al., 2015), we also predicted that greater frequency of cannabis use would be associated with greater symptomatology (i.e. higher positive, negative, and disorganized symptoms).