Biobehavioral Interactions between Endocannabinoid and Hypothalamic-pituitary-adrenal Systems in Psychosis: A Systematic Review

Article type: Review Article

Keywords: Multisystem disorder, central nervous system, mental health, co-morbidity, environment, organ systems, body systems, brain

Authors: Marco Colizzi, Riccardo Bortoletto, Giulia Antolini, Sagnik Bhattacharyya, Matteo Balestrieri, Marco Solmi

Affiliations: Unit of Psychiatry, Department of Medicine (DAME), University of Udine, Udine 33100, Italy;; Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK;; Child and Adolescent Neuropsychiatry Unit, Maternal-Child Integrated Care Department, Integrated University Hospital of Verona, Verona 37126, Italy;; Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada;; Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada;; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany

License: © 2024 The Author(s). Published by Bentham Science Publishers CC BY 4.0 © 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.

Article links: DOI: 10.2174/1570159X21666230801150032  |  PubMed: 37533248  |  PMC: PMC10845076

Relevance: Relevant: mentioned in keywords or abstract

Full text: PDF (4.1 MB)

INTRODUCTION

In recent years, attempts have been made at integrating the different proposed pathophysiological models of schizophrenia into a developmental process whereby a sequence of insults to the central nervous system would make individuals more susceptible to any potential environment-induced neurophysiological perturbation [ref. 1–ref. 3]. Such a conceptual model tries to account for different clinical phenomena occurring in the context of the disorder [ref. 4], such as being sensitive, along with numerous other risk factor exposures, to the psychosis-inducing effects of stress [ref. 5] or cannabis use [ref. 6]. Accumulating evidence regarding stress-related as well as cannabis-associated psychosis has led to the formulation of two different psychosis models that have historically been studied independently of each other [ref. 7, ref. 8].

The 60-year old diathesis-stress model of schizophrenia hypothesizes an interaction between psychosocial stress exposure and genetic susceptibility in the etiopathogenesis of psychosis [ref. 7]. Accordingly, in the presence of a preexisting vulnerability, stress would trigger the onset of an acute psychotic episode [ref. 9]. Subsequent refinements have encompassed the neurobiological underpinnings of the stress response, providing evidence for the role of the hypothalamic-pituitary-adrenal (HPA) axis activation in triggering a cascade of neurochemical events that can elicit a psychotic reaction [ref. 10, ref. 11]. More recent models propose that the HPA axis is widely involved in structural and functional brain networks at the neurodevelopmental, epigenetic, neurotransmitter, and inflammatory levels, with stress leading to dopamine dysregulation, on par with other risk factors for psychosis [ref. 12]. While HPA axis abnormalities are reported across the psychosis spectrum, less clear is whether they are entirely accounted for by psychosocial stressors [ref. 13], calling into question whether the association between stressful life events and psychosis relapse might be mediated by the HPA axis.

Following anecdotical evidence that cannabis use may induce paranoid reactions and acute psychotic symptoms [ref. 14], the last five decades have seen a number of systematic investigations consistently indicating an association between cannabis use and psychosis [ref. 6, ref. 15], thus fueling a cannabinoid-hypothesis of psychosis. However, the causal interpretation of such an association has been questioned [ref. 16], urging the assessment of alternative explanations, such as the confounding effect of other substance use, preexisting higher psychopathology in cannabis users, self-medication (reverse causality), and shared genetic vulnerability. A recent reappraisal of the topic according to Bradford-Hill criteria points in the direction of a robust cause-effect relationship, though of modest strength, with the risk of psychosis increasing as a function of cannabis frequency and potency as well as specific genetic or neurophysiological background [ref. 17–ref. 19]. Independent of such evidence, a more recent systematic review and meta-analysis indicates higher blood and cerebrospinal fluid (CSF) endocannabinoid levels as well as higher cannabinoid receptor type 1 (CB1) expression on peripheral immune cells in psychosis patients as compared to healthy controls [ref. 20]. Also, such parameters were found to be sensitive to symptom severity, stage of illness, and response to treatment [ref. 20]. While it is unclear whether eCB alterations are causally linked to psychosis or a consequence of the disease process, the evidence raises the possibility that such aberrancies in the eCB system might represent a biomarker of psychosis status and outcome.

Accumulating evidence suggests that the two psychosis models are not mutually exclusive, as indicated by evidence of simultaneous and interconnected alterations in the HPA axis and eCB systems in psychosis [ref. 8]. In particular, the role of the eCB system in mediating the HPA axis response to stress has been hypothesized, with implications for the development of psychosis [ref. 21]. Also, such biobehavioral interactions have been suggested to be relevant for both the premorbid phase and the psychosis progression [ref. 12]. Thus, the concomitant assessment of both systems may be a promising strategy to further advance our knowledge of schizophrenia-spectrum disorders. Within this systematic review, we have tried to better clarify the interplay between the HPA axis and eCB system in psychosis, by gathering and discussing all available clinical data, including both physiopathological and outcome studies.

MATERIALS AND METHODS

Inclusion and Exclusion Criteria

All clinical evidence regarding the interplay between the two systems in psychosis risk and outcome was systematically brought together, defining inclusion criteria as outlined: (1) cross-sectional studies, case-control studies, cohort studies, case-reports/series, and randomized controlled trials; (2) studies exploring HPA axis- and eCB system-related biological correlates (e.g., cortisol salivary or plasma levels, eCBs/acylethanolamines (AEs) plasma levels) in relation to psychosis clinical high-risk (CHR) state or psychosis different stages of illness, compared or not to healthy individuals; (3) studies exploring HPA axis- and eCB system-related behavioral correlates (e.g., experimental stress exposure or lifetime stressful events, experimental cannabinoid exposure or lifetime cannabis use) in relation to psychosis CHR state or psychosis different stages of illness, compared or not to healthy individuals, with or without biological correlates. Exclusion criteria were as follows: (1) narrative reviews, systematic reviews, meta-analyses, and animal studies; (2) studies investigating HPA axis and eCB system interplay but independently of psychosis risk, pathophysiology, and outcomes; (3) studies investigating CHR state or psychosis at different stages of illness as per the eCB system modulation but not the HPA axis; (4) studies investigating CHR state or psychosis at different stages of illness as per the HPA axis modulation but not the eCB system.

Search Strategy and Data Extraction

A literature search was conducted using electronic databases (Pubmed, Web of Science, and Scopus) for any published original study written in English, using a combination of broad-meaning search terms describing and/or concerning the HPA axis (‘cortisol’, ‘HPA’, ‘hypothalamus’, ‘pituitary’, ‘adrenal’, ‘axis’, ‘stress’, ‘trauma’, and ‘adversity’), the eCB system (‘cannab*’, ‘CBD’, ‘THC’, ‘delta-9-tetrahydrocanna-binol’, ‘Δ-9-tetrahydrocannabinol’, ‘marij*’, ‘marih*’, ‘sativa’, and ‘indica’), and psychosis (‘FEP’, ‘first-episode’, ‘schizophrenia’, ‘psychosis’, ‘UHR’, and ‘CHR’), on 30 November, 2022. Reference lists of eligible studies were screened to identify additional eligible research. Data screening and extraction were conducted according to a two-step selection process (conventional double-screening), performed by two researchers independently from each other (R.B. and G.A.). In the instances of conflicting opinions regarding papers’ inclusion, a consensus was reached through discussion with a third senior reviewer (M.C.). The entire process was translated into a PRISMA 2020-compliant systematic review flow diagram (Fig. 1) [ref. 22].

Risk of Bias Assessment

Considering the methodological heterogeneity of studies included in this review (Table 1), a risk of bias assessment was conducted, as previously done [ref. 23, ref. 24]. An adapted set of criteria suggested by the Agency for Healthcare Research and Quality (AHRQ) guidance was deemed as appropriate to perform a quality of studies assessment [ref. 25]. Similarities and differences between selected papers were appraised by extracting information about study characteristics, including study design, study population (e.g., healthy subjects, schizophrenia patients, individuals at clinical high-risk for psychosis), gender, age, HPA axis/stress measure (e.g., cortisol salivary or plasma levels, childhood trauma), adequate HPA axis/stress evaluation (e.g., single or multiple assessment), eCB system measure (e.g., cannabinoid dosage and administration route, eCB assessment in tissues, cannabis use), and adequate eCB system evaluation (e.g. daily administration, single or multiple assessment) (Table 3). Besides, the risk of systematic bias across all studies was ruled out by screening all papers for potentially confounding variables (e.g., age, gender, education, tobacco use) (Table 3).

The full study protocol is available at https://doi.org/10.17605/OSF.IO/ERQPG.

RESULTS

Identified Studies for Inclusion in the Systematic Review

In summary, 1184 records were identified through the initial data search. After excluding duplicates as well as articles owing to article type (systematic and non‐systematic reviews), by using a three‐step screening approach, titles, abstracts, or full texts of all records were screened against the inclusion and exclusion criteria (Fig. 1). A final list of 41 studies was used for systematic analysis in this review, investigating different aspects of the interplay between the hypothalamic-pituitary-adrenocortical (HPA) axis and endocannabinoid (eCB) system modulation in psychosis risk, physiopathology, and outcomes (Table 1). These included (i) the effect of exogenous cannabinoid administration on HPA axis functioning in healthy subjects, CHR individuals, and psychosis patients at different stages of illness (4 studies; Table 1); (ii) the effect of cannabis use on HPA axis functioning in healthy subjects, CHR individuals, and psychosis patients at different stages of illness (3 studies; Table 1); (iii) the effect of cannabis use and stress exposure on HPA axis functioning and dopamine system in CHR individuals and psychosis patients at different stages of illness (3 studies; Table 1); (iv) the effect of childhood trauma and exogenous cannabinoid administration over psychosis risk in healthy subjects (1 study; Table 1); (v) the effect of childhood trauma and cannabis use over psychosis risk in the general population and CHR individuals or psychosis exacerbation in patients at different stages of illness (28 studies; Table 1); (vi) the effect of childhood trauma on eCB/acylethanolamine (AE) and its precursor levels in cannabis-using and non-using CHR individuals and psychosis patients (2 studies; Table 1); and (vii) the effect of genetic variation in cannabinoid receptor 1 (CNR1) and cannabis use over perceived stress and neurocognition in patients at their first episode of psychosis (FEP) (1 study; Table 1). A detailed presentation of the results is reported in Table 2. Additional data on the methodological quality of studies included in the review are reported in Table 3. A brief synthesis of the main results is presented below.

Effect of Exogenous Cannabinoid Administration on HPA Axis Functioning in Healthy Subjects, CHR Individuals, and Psychosis Patients at Different Stages of Illness

This review identified four challenge studies addressing the effect of exogenous cannabinoid administration on HPA axis functioning (Tables 1 and 2), using similar but not overlapping methodologies (Table 3) in terms of the study population (schizophrenia/schizoaffective disorder [ref. 26], clinical high-risk (CHR) individuals [ref. 27, ref. 28], and healthy subjects [ref. 26–ref. 29]), sample size (range: 16-58 subjects), cannabinoid exposure (delta-9-tetrahydrocannabinol (THC) [ref. 26, ref. 29], cannabidiol (CBD) [ref. 27, ref. 28]), cannabinoid dosage (2.5/5 mg [ref. 26] and 1.19 mg/2 ml [ref. 29] for THC; 600 mg for CBD [ref. 27, ref. 28]), cannabinoid mode of administration (intravenous for THC [ref. 26, ref. 29], oral for CBD [ref. 27, ref. 28]), cannabinoid period of exposure (single administration [ref. 29], 3 days [ref. 26], 7 days [ref. 27, ref. 28]), and outcome measure (serum cortisol [ref. 26–ref. 29], serum prolactin [ref. 26]). All studies adopted a placebo-controlled design and were sufficiently rigorous in terms of subjects’ comparability and/or excluding/adjusting for confounding factors (Table 3).

Challenge studies have indicated THC administration to disrupt the HPA axis, as indexed by higher cortisol and prolactin levels [ref. 26] as well as flattened diurnal cortisol decrease [ref. 29], when compared to the placebo condition. Independent of the THC challenge, intrinsic differences in the HPA axis between schizophrenia patients and healthy controls were reported. Instead, the THC-induced HPA axis disruption did not seem to change as a function of the diagnosis status, with non-significantly different patterns across the two groups [ref. 26]. However, among healthy subjects, THC was found to result in greater cortisol disruption over time in individuals presenting with THC-induced psychosis-like experiences (PLE) when compared to those who did not develop PLE under the effect of the drug [ref. 29].

Another line of research investigated the potential therapeutic effect of CBD in CHR individuals through the modulation of the HPA axis and stress response. A first study indicated blunted cortisol response as well as greater anxiety and experience of public speaking stress following experimental stress in CHR individuals under placebo when compared to healthy controls, with CBD administration partially reversing such aberrant biobehavioral responses in CHR individuals [ref. 27]. A further study from the same group found that cortisol reactivity following experimental stress negatively correlated with the right parahippocampal activation during fear processing in healthy controls and that such association differentiated the diagnosis status, being statistically different between healthy subjects and CHR individuals. Finally, the absent pattern of coupling between neural response to fear and cortisol response to stress in CHR individuals was not recovered/normalized by CBD administration [ref. 28].

Effect of Cannabis use on HPA Axis Functioning in Healthy Subjects, CHR Individuals, and Psychosis Patients at Different Stages of Illness

In total, three studies evaluated whether cannabis-using and non-using psychosis patients at different stages of illness differ in terms of HPA axis functioning (Tables 1 and 2). The review identified similar but not overlapping methodologies (Table 3) in terms of the study population (schizophrenia [ref. 30], recent-onset psychosis (ROP) patients [ref. 31], CHR individuals [ref. 32], and healthy subjects [ref. 30–ref. 32]), sample size (range: 43-103 subjects), cannabinoid exposure (self-reported cannabis use [ref. 30–ref. 32] and/or cannabis urine screen [ref. 32]), cannabinoid period of exposure (before the onset of psychosis [ref. 30], last week/last month [ref. 32], current [ref. 31]), and outcome measure (salivary cortisol [ref. 30–ref. 32] and cortisol suppression ratio after dexamethasone (DSTR; [ref. 31]). The first of these studies found that, as compared to healthy controls, cannabis-using schizophrenia patients have higher morning cortisol levels and a flattened cortisol awakening response (CAR), while non-using patients would present with a cortisol pattern like that observed among healthy controls [ref. 30]. Another study also found higher cortisol levels among CHR individuals, as compared to healthy controls, with cannabis-using patients presenting with furtherly increased cortisol levels when compared to non-using patients [ref. 32]. Finally, a more recent study confirmed a flattened diurnal cortisol slope as a function of CU, but independent of ROP diagnosis [ref. 31].

Effect of Cannabis use and Stress Exposure on HPA Axis Functioning and Dopamine System in CHR Individuals and Psychosis Patients at Different Stages of Illness

Three studies investigated the effect of CU on the HPA axis functioning in patients with psychosis at different stages of illness experimentally exposed to stress [ref. 33, ref. 34] or with a personal history of stressful life events (SLEs) and childhood trauma (CT) [ref. 31] (Tables 1 – 2). Two of them further explored the interaction between CU, stress, and dopamine signaling [ref. 33, ref. 34]. Using multiple linear regression analysis to study the association between exposure to environmental factors and HPA axis measures in ROP patients, one study found a role for cannabis in disrupting the diurnal cortisol slope, but not SLEs or CT [ref. 31]. Other studies revealed decreased stress-induced cortisol response [ref. 33] and dopamine release in the prefrontal cortex [ref. 33] and striatum [ref. 34] of cannabis-using CHR individuals, as compared to non-using patients. Stress-induced prefrontal dopamine release correlated positively with the stress-induced cortisol response but negatively with the stress-induced change in attenuated psychotic symptoms [ref. 33]. Finally, stress-induced striatal dopamine reactivity was also found to correlate with stress-induced cortisol response, but only in non-using CHR individuals, suggesting a possible decoupling of HPA response from dopaminergic signaling in the context of CU [ref. 34].

Effect of Childhood Trauma and Exogenous Cannabinoid Administration Over Psychosis Risk in Healthy Subjects

This review identified a single study specifically investigating whether childhood trauma (CT) increases the risk of presenting with PLE under the acute effects of THC in otherwise healthy cannabis-using subjects (Tables 1–3). CT was associated with PLE during THC intoxication, with cognitive fusion, i.e., the inability to defuse from internal experience, accounting for increased THC-induced PLE among those with CT. Interestingly, CT was also found to be associated with schizotypy, independent of the acute THC challenge [ref. 35].

Effect of Childhood Trauma and/or SLEs and Cannabis use Over Psychosis Risk in the General Population and CHR Individuals or Psychosis Exacerbation in Patients at Different Stages of Illness

Out of 41 studies, 28 of them investigated the interplay between childhood trauma (CT) and cannabis use (CU) in conferring psychosis risk or exacerbating psychosis symptoms among both healthy individuals and patients (Tables 1 and 2). The review identified similar but not overlapping methodologies (Table 3) in terms of study population (schizophrenia/schizoaffective disorder [ref. 36–ref. 39], bipolar affective disorder [ref. 37, ref. 39, ref. 40], ROP patients [ref. 41, ref. 42], FEP patients [ref. 37, ref. 43], CHR individuals [ref. 44], general population [ref. 45–ref. 59], healthy subjects [ref. 43, ref. 60–ref. 62], cannabis-using subjects [ref. 37, ref. 63]), sample size (range: 112-7403 subjects), type of CT (sexual [ref. 36–ref. 38, ref. 40–ref. 57, ref. 59–ref. 63], physical/violence [ref. 36, ref. 38, ref. 41–ref. 44, ref. 46, ref. 47, ref. 49, ref. 50, ref. 53–ref. 56, ref. 60–ref. 63], emotional [ref. 36, ref. 38, ref. 41, ref. 42, ref. 44, ref. 47, ref. 49, ref. 50, ref. 53, ref. 56, ref. 57, ref. 60–ref. 63], domestic violence [ref. 46], peer victimization/bullyism [ref. 56, ref. 57]), cannabinoid exposure (use [ref. 37–ref. 63], disorder/dependence [ref. 36, ref. 40]), cannabinoid period of exposure (lifetime [ref. 36–ref. 40, ref. 42–ref. 56, ref. 58–ref. 60, ref. 62], past 12 months [ref. 54, ref. 57, ref. 61], past 6 months [ref. 41], past month [ref. 63], current [ref. 44, ref. 56, ref. 61], at follow-up assessment [ref. 55, ref. 58]), and outcome measure (Composite International Diagnostic Interview, CIDI [ref. 45, ref. 47–ref. 50, ref. 53, ref. 56, ref. 58], Structured Clinical Interview for Disorders, SCID [ref. 36, ref. 42, ref. 45, ref. 53, ref. 58], Schedule for Assessment in Neuropsychiatry, SCAN [ref. 38, ref. 51, ref. 52], Schedule for Affective Disorders and Schizophrenia for School-Age Children, K-SADS [ref. 46], Diagnostic Interview for Genetic Study, DIGS [ref. 40], computerized method for diagnoses of functional psychoses, DIAX [ref. 49, ref. 50], Operational Criteria System, OPCRIT checklist [ref. 41, ref. 43], Community Assessment of Psychic Experiences, CAPE [ref. 47, ref. 60, ref. 61, ref. 63], Psychosis Screening Questionnaire, PSQ [ref. 51, ref. 52, ref. 54], The Content of Attenuated Positive Symptoms, CAPS [ref. 44], Prodromal Questionnaire, PQ-16 [ref. 57], Prodromal Questionnaire-Brief Version, PQB [ref. 37], Positive and Negative Symptoms Scale, PANSS [ref. 36, ref. 39, ref. 42], Paranoia Scale, PS [ref. 37], Self-Report Symptom Checklist-90-R, SCL-90-R [ref. 50, ref. 55], Columbia-Suicide Severity Rating Scale, C-SSRS [ref. 36], Global Assessment of Functioning Scale, GAF [ref. 36], Medication Adherence Rating Scale, MARS [ref. 36], Shortened Quality of Life questionnaire, S-QoL-18 [ref. 36], Wechsler Intelligence Scale for Children [ref. 56], The Brief Assessment of Cognition in Schizophrenia, BACS [ref. 39], and white matter integrity [ref. 62]).

Among studies investigating the independent effect of CT on psychosis risk, evidence tips the scale towards a deleterious effect of CT in terms of increasing the risk of getting a psychosis diagnosis and experiencing psychotic symptoms [ref. 38, ref. 42, ref. 44, ref. 46–ref. 48, ref. 53, ref. 54, ref. 57, ref. 61, ref. 63] among different study samples, including schizophrenia/schizoaffective disorder [ref. 38] and ROP patients [ref. 42], CHR individuals [ref. 44], general population [ref. 46–ref. 48, ref. 53, ref. 54, ref. 57], healthy subjects [ref. 61], and cannabis-using subjects [ref. 63]. Also, CT has been found to anticipate psychosis onset [ref. 39] and predict a poorer clinical course [ref. 36] among patient samples. Single studies suggest that such association may be gender-specific, being observed in female individuals only [ref. 59], and only true for those exposed to high levels of CT [ref. 41]. Further, other evidence supports an association between SLEs and higher risk of incident clinical psychosis [ref. 58]. However, a few studies have not suggested any association between CT and psychosis-related measures [ref. 40, ref. 43, ref. 45, ref. 51, ref. 60].

Of those outputs focusing on the main effect of CU, most found that it increases the risk of developing psychosis and presenting with psychotic symptoms [ref. 36, ref. 40, ref. 42, ref. 46, ref. 47, ref. 53, ref. 57, ref. 58, ref. 61, ref. 63], possibly because of recent/current use [ref. 44, ref. 54] as well as regular and more severe use [ref. 38, ref. 41]. Also, another study suggested an earlier psychosis onset as a function of CU [ref. 39]. However, a few studies did not suggest any association between CU and psychosis-related measures [ref. 43, ref. 45, ref. 48, ref. 51, ref. 60].

More importantly, some studies converged in suggesting an interaction effect between CT and CU over the risk of PLE [ref. 46, ref. 48, ref. 61], psychotic symptoms in bipolar disorder [ref. 40], and psychosis diagnosis [ref. 51], possibly because of earlier CT [ref. 47] as well as early [ref. 45], recent [ref. 54], and regular [ref. 38] CU. Mediating and moderating effects of either CT or CU were reported in the association between any of the two variables and both PLE [ref. 53, ref. 63] and psychosis diagnosis [ref. 53], with also relevance for psychosis age of onset [ref. 39]. Further, it is worth mentioning that the history of SLEs itself was found to interact with CU in increasing the risk of incident clinical psychosis [ref. 58]. However, a few studies did not suggest an interaction between CT and CU in either increasing psychosis risk [ref. 42, ref. 44, ref. 49, ref. 59–ref. 61] or affecting functional and clinical outcomes of psychosis, apart from prolonging the duration of hospitalization [ref. 36], possibly because of a confounding effect of stimulants [ref. 52] and CU frequency and potency [ref. 43].

Finally, some studies indicated that the interaction effect between CU and CT on PLE [ref. 37, ref. 50, ref. 55–ref. 57, ref. 60, ref. 61] and ROP [ref. 41] is further complexified by additional factors that would have a role in conferring a greater risk, including catechol-O-methyltransferase (COMT) gene [ref. 60, ref. 61], urbanicity [ref. 50, ref. 55, ref. 56], SLEs [ref. 41], threat-induced cognitive biases [ref. 57], cognitive alteration [ref. 56], and cognitive fusion [ref. 37]. Also, the interaction between CT and CU was found to be relevant for the occurrence of PLE in the context of affective disorders [ref. 55], along with affective and negative symptoms [ref. 56]. Further, white matter integrity, as an intermediate phenotype of psychosis, was reported to be disrupted in otherwise healthy subjects with a history of both CT and CU [ref. 62].

Effect of Childhood Trauma or Stress on eCB/AE and their Precursor Levels in Cannabis-using and Non-using CHR Individuals and Psychosis Patients

This review found two studies to focus on the association between stress and abnormalities in the eCB signaling, including precursors and endogenous lipids belonging to the AE fatty acid (FA) amide family, also as a function of cannabis use (Tables 1–3). The first research on this topic suggested specific alterations, mainly in schizophrenia patients with a former history of cannabis use, with arachidonic acid (AA) and total 16- and 18-carbon monounsaturated and saturated FAs (16, 18 m + sFAs) being downregulated as well as linoleic acid being upregulated in response to stress. Instead, among cannabis-naïve patients, a total of 16,18m + sFAs were increased as a function of stress while AA and LA were not affected [ref. 64]. A later study suggested higher palmitoylethanolamide (PEA) and anandamide (AEA) levels among CHR individuals exposed to CT, as compared to healthy subjects and those with no CT, along with an interaction and a dose-dependent effect of CT and CHR status on PEA levels. Such findings seemed to be independent of cannabis use [ref. 65].

Effect of CNR1 and Cannabis use Over Perceived Stress and Neurocognition in FEP Patients

A single study was found investigating whether FEP patients with different genetic backgrounds regulating the endocannabinoid system and cannabis use are more prone to stress and at risk of poorer cognitive function (Tables 1–3). Cannabinoid receptor type 1 (CNR1) polymorphic loci were found to modulate verbal memory and attention over time as well as perceived stress. Interestingly, a significant interaction of cannabis use and CNR1 genotype was found, such that among cannabis-using patients, the effect of genotype on verbal memory baseline scores and improvement was lost, while it remained in the non-user group. Further, overall highest perceived stress levels were found among cannabis-using patients, if carrying specific CNR1 genetic variants [ref. 66].

DISCUSSION

This is the first systematic review of all studies investigating the interplay between components of the stress response and the cannabinoid system in modulating psychosis risk and outcome in humans. Previous reviews have mainly focused on the two systems independently, summarizing the role of the hypothalamic-pituitary-adrenocortical (HPA) axis [ref. 13] or the stress response system [ref. 67] as well as of exogenous cannabinoids [ref. 6, ref. 15] or the endocannabinoid (eCB) system [ref. 20] in increasing the risk of psychosis onset [ref. 6, ref. 13, ref. 20] or modulating psychosis outcome [ref. 15, ref. 20, ref. 67]. It is noteworthy that the evidence for an alteration and its direction in either the HPA axis/stress response system or in eCB components is not always unequivocal, possibly because of substantial methodological heterogeneity across studies [ref. 8].

Evidence from this review offers some insight into the stress-vulnerability model of psychosis, indicating HPA axis anomalies in the psychosis spectrum, both at baseline [ref. 26, ref. 32] and following experimental [ref. 27] but not lifetime [ref. 31] stress exposure, with the latter being relevant for brain [ref. 28] and dopamine [ref. 33, ref. 34] function as well as symptom manifestation [ref. 33]. Only one study did not find evidence of HPA axis abnormalities in schizophrenia [ref. 30]. In terms of outcome, a higher risk of incident clinical psychosis as a function of SLEs was found [ref. 58]. Also, apart from a few studies not supporting an association between CT and psychosis-related measures [ref. 40, ref. 43, ref. 45, ref. 51, ref. 60], CT, as a proxy of significant stress exposure, was found to be associated with schizotypy [ref. 35] and independently increase the risk of psychosis diagnosis and symptoms [ref. 38, ref. 41, ref. 42, ref. 44, ref. 46–ref. 48, ref. 53, ref. 54, ref. 57, ref. 61, ref. 63] as well as earlier onset [ref. 39] and poorer outcome [ref. 36]. Further, female subjects exposed to CT [ref. 59], and earlier [ref. 47] and more severe [ref. 41] CT were found to carry a greater risk of psychosis-like experiences (PLE) [ref. 47, ref. 59] and recent-onset psychosis (ROP) [ref. 41].

Different lines of research reviewed here also corroborate the cannabinoid-hypothesis of psychosis. Direct evidence points towards a psychosis-inducing effect of THC in otherwise healthy subjects [ref. 29], which is possibly accounted for by cognitive fusion [ref. 35]. Indirect evidence suggests that cannabis use may alter cortical [ref. 33] and striatal [ref. 34] dopamine signaling, with relevance for the onset of attenuated psychotic symptoms [ref. 33], in line with the long-lasting schizophrenia dopamine-hypothesis [ref. 68]. Also, cannabis use was found to increase the risk of PLE [ref. 46, ref. 47, ref. 53, ref. 57, ref. 61, ref. 63], psychosis diagnosis [ref. 53] including ROP [ref. 42], incident clinical psychosis [ref. 58], psychotic symptoms in bipolar disorder [ref. 40], and poorer schizophrenia outcome [ref. 36]. However, a few studies have disconfirmed these findings [ref. 43, ref. 45, ref. 48, ref. 51, ref. 60], possibly because of a higher risk mainly in the context of recent/ current use [ref. 44, ref. 54] as well as regular and more severe use [ref. 38, ref. 41]. Earlier psychosis onset as a function of CU was also suggested [ref. 39]. Finally, cognitive intermediate phenotypes of psychosis were found to differ depending on CNR1 genetic variation and its interaction with cannabis use [ref. 66]. The CNR1 gene encodes for the CB1 receptor, whose localization on different neuronal subpopulations specifically modulates emotional and social behavior [ref. 69–ref. 72], with potential implications for the psychosis phenotype.

However, both preclinical and clinical studies have suggested a crosstalk between the eCB system and HPA axis and stress response, urging a deep reappraisal of the inter-relationship between these two systems, especially in the context of psychosis [ref. 8, ref. 21]. Overall, this review indicates that the HPA axis and the eCB system, both at baseline and following an exogenous perturbation (e.g., stress exposure, cannabis use), interact with each other in health and disease, with relevance for the pathophysiology of psychosis. The most interesting evidence from this review regarding the interplay between the two models of psychosis is discussed in the following section.

First, THC and CBD, two cannabis ingredients with potentially opposite effects in psychosis [ref. 73], may exert specular effects also on the HPA axis. In fact, THC seems to amplify pre-existing HPA abnormalities among psychosis patients [ref. 26] and induce transient psychotic symptoms in otherwise healthy individuals through HPA disruption [ref. 29]. Conversely, CBD is suggested to counterbalance the detrimental effects of experimental stress on the HPA axis and behavior among individuals at risk of developing psychosis [ref. 27], despite not restoring the underlying dysfunctional brain activity [ref. 28]. In line with evidence from THC studies, cannabis use was found to disrupt the HPA axis among patients at different stages of illness, including clinical high-risk (CHR) [ref. 32], ROP [ref. 31], and schizophrenia patients [ref. 30]. Interestingly, such disrupting effect of cannabis on the HPA axis was evident also among control subjects (Fig. 2) [ref. 31].

Second, lifetime stress exposure (e.g., stressful life events, SLEs; childhood trauma, CT) was not found to modulate the HPA axis when the detrimental effects of cannabis use were taken into account [ref. 31]. Also, experimental stress exposure impacted patients’ HPA axis [ref. 33, ref. 34], with relevance for the psychosis-related dopaminergic state [ref. 33, ref. 34] and symptom severity [ref. 33], but such pattern of dopamine-cortisol response to experimental stress was reported to be blunted [ref. 33] or decoupled [ref. 34] in patients who also used cannabis (Fig. 2).

Third, THC was found to induce more severe symptoms of psychosis in those subjects with a history of CT [ref. 35]. In line with such evidence, some [ref. 39, ref. 40, ref. 46, ref. 48, ref. 51, ref. 53, ref. 61, ref. 63] but not all [ref. 36, ref. 42–ref. 44, ref. 49, ref. 52, ref. 59, ref. 60] studies report a greater risk of PLE [ref. 46, ref. 48, ref. 53, ref. 61, ref. 63], psychotic symptoms in bipolar disorder [ref. 40], and psychosis diagnosis [ref. 51, ref. 53] and earlier onset [ref. 39] as a function of being exposed to both cannabis use and childhood trauma (CT), with the highest risk among individuals with earlier CT [ref. 47] as well as early [ref. 45], recent [ref. 54], and regular [ref. 38] CU. Further, additional known risk factors are suggested to play a role in the interaction between CU and CT on the risk of PLE, such as the COMT gene [ref. 60, ref. 61], white matter integrity [ref. 62], urbanicity [ref. 50, ref. 55, ref. 56], threat-induced cognitive biases [ref. 57], cognitive alteration [ref. 56], cognitive fusion [ref. 37], and affective comorbidity [ref. 55, ref. 56], with SLEs being relevant for ROP [ref. 41]. Noteworthy, additional evidence supports a direct role of SLEs in conferring a higher risk of incident clinical psychosis in the context of CU (Fig. 2) [ref. 58].

Fourth, an independent line of research indicates that either stress [ref. 64] and CT [ref. 65] affect endocannabinoid (eCB) signaling in both schizophrenia [ref. 64] and CHR [ref. 65] individuals. Also, a differential effect of cannabis use [ref. 64] as well as a dose-dependent effect of CT and psychosis risk intensification [ref. 65] on disrupting the eCB signaling have been found. Further, single evidence supports the notion that, in the context of specific CNR1 genetic vulnerability, first-episode psychosis (FEP) patients would present with higher stress and poorer memory and attention performance, with the highest perceived stress and the worst longer-term cognitive improvement in those with also a history of cannabis use (Fig. 2) [ref. 66].

The findings of this systematic review must be seen considering some strengths and limitations. While substantially converging, evidence regarding the association between aberrancies in the stress response system and the endocannabinoid system in psychosis is limited and very heterogeneous. It is currently unclear whether the two systems affecting one other are specific to psychosis or would be commonly reported across different clinical conditions. Also, considering evidence that earlier disruption of the two biological systems may result in more severe clinical phenotypes of psychosis, their interplay needs to be further addressed by tracking illness progression in longitudinal studies. Further, potential gender-driven vulnerabilities remain to be investigated. Treatment-wise, while the therapeutic effects of CBD in psychosis seem to be reasonably mediated by its action on both systems, such line of research is still in its infancy and no other treatment strategies to restore the two systems’ function have been identified. In fact, while CBD treatment has been reported to modulate eCB signaling [ref. 74], its direct effect on CB receptors has been disconfirmed in favor of serotoninergic [ref. 75] and dopaminergic [ref. 76, ref. 77] activities, with the modulation of the crosstalk between the dopamine and cannabinoid systems [ref. 78] being particularly relevant for CBD antipsychotic effectuates as an early treatment [ref. 79, ref. 80].

CONCLUSION

In conclusion, concomitant alterations in these two systems, either genetically defined (e.g., CNR1 genetic variation), biologically determined (e.g., dysfunctional HPA axis or eCB signaling), or behaviorally imputed (e.g., cannabis use, stress exposure, and response), are consistently reported in psychosis. Also, a complex biobehavioral perturbation is revealed not only within each system (e.g., cannabis use affecting the eCB tone, stress exposure affecting the HPA axis) but also across the two systems (e.g., THC affecting the HPA axis, CT affecting the eCB signaling) (Fig. 2). Thus, to establish more refined biological relevance, there is a need to complementarily study the two systems’ mechanistic contribution to psychosis, rather than continuing to explore each single psychosis model.

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