A cognitive behavioural model of the bidirectional relationship between disordered eating and diabetes self care in adult men with Type 1 diabetes mellitus.

AIMS: This qualitative study aimed to develop the first cognitive behavioural (CBT) model outlining the development and maintenance of disordered eating in adult men living with Type 1 diabetes to improve on previous theoretical models of Type 1 diabetes and disordered eating and to draw comparisons to women with Type 1 diabetes and disordered eating. METHODS: Twenty-seven men (n = 16 with Type 1 diabetes and disordered eating, n = 11 with Type 1 diabetes without disordered eating) participated in semi-structured interviews. Data were analysed using thematic analysis and individual CBT formulations were developed for each participant to inform the model. RESULTS: Men with Type 1 diabetes and disordered eating experience negative thoughts about food, insulin, weight/shape and diabetes itself, which cause negative emotions such as fear and vulnerability and difficulties with diabetes self care such as problems with hyper and hypoglycaemia and problems accessing structured education and technology result in men feeling more dissatisfied about their body weight/shape. CONCLUSIONS: This CBT model of disordered eating in men with Type 1 diabetes can guide new interventions.

Protocol for the STEADY intervention for type 1 diabetes and disordered eating: Safe management of people with Type 1 diabetes and EAting Disorders studY.

This paper describes the protocol to test the feasibility of the Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY) intervention. STEADY is a novel complex intervention for people with type 1 diabetes and disordered eating (T1DE) of mild to moderate severity. The STEADY intervention integrates cognitive behavioural therapy (CBT) with diabetes education, and was developed using Experience-Based Co-Design. METHODS: The feasibility of STEADY will be tested using a randomised controlled feasibility trial. Forty adults with T1DE will be recruited and randomised into the STEADY intervention or treatment as usual control group. We will collect demographic, biomedical and psychometric data, routine glucose metrics and conduct the Structured Clinical Interview for DSM-5. Participants randomised to the STEADY intervention will receive 12 STEADY therapy sessions with a diabetes specialist nurse trained in CBT, delivered via videoconference and an optional smartphone app. The main outcome at 6 months will be the feasibility of STEADY (recruitment, dropout rates, feasibility of delivery). The secondary outcomes are biomedical (HbA1c and glucose time in range) and psychological (person-reported outcome measures in disordered eating, diabetes distress, depression and anxiety). A process evaluation will evaluate the fidelity, feasibility, acceptability and appropriateness of STEADY, and participant experiences. ETHICS AND DISSEMINATION: The protocol was approved by the East of England-Essex Research Ethics Committee (21/EE/0235). Study findings will be shared with study participants and disseminated through peer-reviewed publications and conference presentations.

Examining the referral of patients with elevated blood pressure to health resources in an under-resourced community in South Africa.

BACKGROUND: Low-and-middle income countries face a disproportionate burden of non-communicable diseases (NCDs) that threaten to overwhelm under-resourced health systems. Community health workers (CHWs) can promote NCD prevention, reach patients, and connect them to local community health resources; however, little has been done to examine how referrals to these resources are utilized by community members. The purpose of this study is to examine the use of referrals to community-based health resources and investigate the factors influencing patient utilization of referrals connecting them to appropriate health resources for elevated blood pressure (BP). METHODS: CHWs conducted home visits, which included BP screening and brief counseling, with community members in Soweto, South Africa. Participants with elevated (systolic BP: 121-139/ diastolic BP: 81-89 mmHg) or high (≥ 140/90 mmHg) BP were referred to either a local, community-based physical activity (PA) program managed by a non-governmental organization or local health clinics. The number of participants that received and utilized their referrals was tracked. Follow-up interviews were conducted with individuals given a referral who: (1) went to the PA program, (2) did not go to the PA program, (3) went to a clinic, and (4) did not go to a clinic. Interviews were transcribed and analyzed to identify common themes and differences between groups regarding their decisions to utilize the referrals. RESULTS: CHWs visited 1056 homes, with 1001 community members consenting to the screening; 29.2% (n = 292) of adults were classified as having optimal BP (≤120/80 mmHg), 35.8% (n = 359) had elevated BP, and 35.0% (n = 350) had high BP. One hundred and seventy-three participants accepted a referral to the PA program with 46 (26.6%) enrolling. Five themes emerged from the interviews: (1) prior knowledge and thoughts on BP, (2) psychosocial factors associated with BP control, (3) perception about receiving the referral, (4) contextual factors influencing referral utilization, and (5) perceived benefits of utilizing the referral. CONCLUSION: CHWs can successfully increase community members' access to health resources by providing appropriate referrals. However, greater attention needs to address community members' barriers and hesitancy to utilize health resources.

Decision-making difficulties mediate the association between poor emotion regulation and eating disorder symptoms in adolescence.

BACKGROUND: The emergence of eating problems during childhood increases the risk for eating disorders (EDs) during young adulthood. Previous studies highlight a relationship between poor self-regulation and onset of eating pathology. In this study, we investigated whether this association is mediated by decision-making difficulties. METHODS: To test this hypothesis, we used data from the Millennium Cohort Study. Decision-making performance was assessed with the Cambridge Gambling Task at age 11. Principal components analysis was used to derive an index of ED symptoms at age 14. The trajectories of scores of two subscales of the Child Social Behaviour Questionnaire, Independence and Self-Regulation (ISR) and Emotional Dysregulation (EmotDy), were modelled from ages 3 to 7 years in a latent growth curve analysis. The individual predicted values of the intercept (set at baseline, 3 years) and the slope (rate of annual change) were then used in the mediation analysis. RESULTS: In our sample of 11 303 individuals, there was evidence for mediation by three measures of decision-making at age 11 (poor quality of decision-making, delay aversion and low risk-adjustment) in the association between EmotDy across ages 3-7 and ED symptoms at age 14 even after the adjustment for relevant covariates. We found no evidence of association between ISR and ED symptoms. CONCLUSION: Our findings suggest that emotion regulation processes during childhood may be relevant for the future onset of ED symptoms via their association with decision-making skills. These findings, obtained from a large, representative, sample, shed light on the relationship between self-regulation, decision-making and symptoms of EDs.

Developing a novel intervention for type 1 diabetes and disordered eating using a participatory action design process: Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY).

AIMS: To develop a cognitive behavioural therapy-based intervention for people with type 1 diabetes and disordered eating using Experience-Based Co-Design as part of the Safe management of people with Type 1 diabetes and EAting Disorders studY (STEADY). METHODS: Fifteen people with type 1 diabetes and experience of disordered eating (33 ± 11 years old, 22 ± 12 years diabetes duration) and 25 healthcare professionals working in type 1 diabetes or eating disorders (44 ± 9 years old; 14 ± 10 years of professional experience) attended six Experience-Based Co-Design workshops from July 2019 to March 2020 to collaboratively develop intervention content. RESULTS: We developed a cognitive behaviour therapy intervention 'toolkit' that can be tailored for individual patient needs. Participants designed and revised toolkit materials to ensure acceptability and relevance for people with diabetes and disordered eating by engaging in guided discussion, brainstorming, and rapid testing to review toolkit prototypes in an iterative process. Workshop themes were 'Insulin titration'; 'Hypoglycaemia'; 'Coming to terms with diabetes'; 'Fear of weight gain'; 'Toolkit revision'; and 'Practical elements of STEADY therapy'. The intervention is focussed on improving diabetes self-care and embedded in a multidisciplinary healthcare approach. The intervention will be delivered in 12 sessions by a diabetes specialist nurse trained in cognitive behavioural therapy. CONCLUSIONS: Through an iterative co-design process, people with type 1 diabetes and healthcare professionals collaboratively developed a novel intervention toolkit that can be used with a wide range of disordered eating presentations. The intervention will be tested in the STEADY feasibility randomised controlled trial.

A description of virtual skills workshops for supporters of loved ones with eating disorders: Indicators of benefit and acceptability, clinical reflections and consideration of neurodiversity.

OBJECTIVE: Providing information and support to those supporting a loved one with an eating disorder is a key part of evidence-based service provision. We report on how we took our workshops for supporters online during the Covid-19 Pandemic when country-side physical distancing restrictions meant we were unable to work face to face. METHODS: We outline the structure of an eight-session 2-h workshop series delivered fortnightly facilitated by a multidisciplinary team of clinicians, researchers and experts by experience. We use a repeated-measures design to understand the possible benefits of the workshops on supporter skills (n = 76). RESULTS: Measured using the Caregiver Skills Scale, we observed small-sized improvements in the overall skills (D = 0.43) of n = 17 supporters who provided data at the end of the intervention. Supporters gave largely positive feedback on the virtual format. They particularly liked the opportunity to interact with other supporters. As facilitators, we overcome our initial anxiety around workshop delivery using a new platform and reflected that having more time to cover key information and for skills practice over a period of 16 weeks offered opportunities to develop and reflect on new skill together as a group. We were also able to work with larger groups of supporters, as several barriers to access were removed. CONCLUSIONS: As the workshops reached a larger number of supporters than through face to face delivery and were of benefit to those who reported on their skills, we plan to continue offering workshops to supporters online in future.

A cognitive behavioural model of the bidirectional relationship between disordered eating and diabetes self care in people with type 1 diabetes mellitus.

AIMS: This qualitative study aimed to develop the first cognitive behavioural therapy model outlining the development and maintenance of disordered eating in type 1 diabetes and report on recovery strategies and resilience factors to improve previous theoretical models of type 1 diabetes and disordered eating. METHODS: Twenty-three women (n = 9 with type 1 diabetes and disordered eating, n = 5 with type 1 diabetes recovering from disordered eating, and n = 9 with type 1 diabetes without disordered eating) participated in semi-structured interviews. Data were analysed using grounded theory and individual cognitive-behavioural formulations were developed for each participant to inform the development/maintenance and resilience models. RESULTS: The development/maintenance model summarises commonly experienced vicious cycles of thoughts, feelings and behaviours in type 1 diabetes and disordered eating. The resilience model summarises strategies and knowledge acquired by those with type 1 diabetes in recovery from disordered eating and individuals with type 1 diabetes who did not develop disordered eating. Early adverse life events, past psychiatric history, perfectionist personality traits, difficult experiences around type 1 diabetes diagnosis and its relentless daily management sensitise individuals to eating, weight and shape cues. Alongside physical symptoms/complications, unhelpful interpersonal reactions and inadequate healthcare, vicious cycles of thoughts, feelings and behaviours develop. 'Good enough' psychological adaptation to type 1 diabetes, integrating type 1 diabetes into one's identity, self care and compassion around eating, weight and shape were key protective/post-traumatic resilience factors. CONCLUSIONS: This first cognitive behavioural therapy model of type 1 diabetes and disordered eating informed by personal experience will inform an intervention for type 1 diabetes and disordered eating.

Disordered eating in women with type 1 diabetes: Continuous glucose monitoring reveals the complex interactions of glycaemia, self-care behaviour and emotion.

OBJECTIVES: Glycaemia in people with type 1 diabetes and disordered eating is not well characterised. We explored the glycaemia, self-care behaviour and emotional state of women with type 1 diabetes and disordered eating. RESEARCH DESIGN AND METHODS: In all, 13 women with and 10 without disordered eating and type 1 diabetes participated in this case-control study. We used a mixed-methods approach with a 7-day blinded continuous glucose monitoring and real-time record of non-prompted capillary glucose (CG), emotion, activity and physical symptoms on a diabetes diary using a smartphone application (mySugr®). We compared groups using Mann-Whitney U test or Fisher's exact test. We conducted thematic analyses of free-text diary entries (NVivo®) and quantitative analysis of emotion/symptom tags. RESULTS: People with type 1 diabetes and disordered eating spent longer time above range in level 2 hyperglycaemia (>13.9 mmol/L, Median [interquartile range]: 21% [16,60] vs 5% [2,17], p = 0.015). They had lower time in range and similar time below range compared to those without disordered eating. The standard deviation of CG was significantly higher in the disordered eating group (4.7 mmol/L [4.5, 6.1] vs 3 [2.8, 3.2], p = 0.018). The median of the percentage of rising sensor glucose trends was three times higher in the disordered eating group. They also had higher negative emotional and physical symptoms associated with high blood glucose (>15 mmol/L). CONCLUSIONS: Disordered eating has a significant impact on the glycaemia and emotion of a person with type 1 diabetes.

Successful Endovascular Therapy in COVID-19 Associated Pediatric Ischemic Stroke.

Cerebrovascular diseases attributed to coronavirus disease 2019 (COVID-19) are uncommon but can result in devastating outcomes. Pediatric acute ischemic strokes are themselves rare and with very few large vessel occlusion related acute ischemic strokes attributed to COVID-19 described in the literature as of date. COVID-19 pandemic has contributed to acute stroke care delays across the world and with pediatric endovascular therapy still in its infancy, it poses a great challenge in facilitating good outcomes in children presenting with acute ischemic strokes in the setting of COVID-19. We present a pediatric patient who underwent endovascular therapy for an internal carotid artery occlusion related acute ischemic stroke in the setting of active COVID-19 and had an excellent outcome thanks to a streamlined stroke pathway involving the vascular neurology, neuro-interventional, neurocritical care, and anesthesiology teams.

The value of including families in the treatment of anorexia nervosa.

The aim of this paper is to consider family and wider carer involvement in the treatment of anorexia nervosa, and how this can be used to add value to services. We discuss widely adopted interventions involving the family that have been manualised and studied in trials that have outcome measures that are of relevance to illness costs. The therapeutic targets of these interventions range from a focus on feeding to the wellbeing of the whole family. The theoretical models that underpin interventions involving the family/wider carers include both intra and interpersonal processes, with the exception of family-based therapy, which in its original form holds an agnostic stance towards aetiology. Although formal evaluation of the cost effectiveness of these interventions is minimal, there is evidence that involving the family can reduce bed use and improve the wellbeing of both patients and family members. Moreover, for the most part, these interventions are acceptable to patients and carers. Finally, we consider how these approaches can be disseminated and scaled up more widely into services.

The social responsiveness scale is an efficient screening tool for autism spectrum disorder traits in adults with anorexia nervosa.

OBJECTIVE: A significant proportion of individuals with anorexia nervosa (AN) show high levels of autism spectrum disorder (ASD) traits, a factor associated with poorer treatment outcomes. An important question for both researchers and clinicians relates to how ASD traits should be assessed in individuals with AN. This study aimed to examine scores on the Social Responsiveness Scale adult self-report version (SRS-2) in individuals in the acute (AN) and recovered stages (REC) of illness compared to healthy controls (HCs). We also aimed to examine associations between the SRS-2 and an observational diagnostic measure, the Autism Diagnostic Observation Schedule - second edition (ADOS-2). METHOD: The SRS-2 and ADOS-2 were administered to 142 adults with AN, REC, and HCs. Eating disorder (ED) psychopathology and functional impairment were also assessed. RESULTS: AN and REC scored significantly higher than HCs on the SRS-2. SRS-2 scores significantly predicted ADOS-2 classification and were positively associated with ED psychopathology and functional impairment. SRS-2 scores were not associated with BMI or illness duration. CONCLUSIONS: The SRS-2 may be a useful tool in screening for ASD traits in individuals with AN. Although cross-sectional, the results also suggest ASD symptoms are independent of BMI and persist in individuals recovered from AN.

Evaluation of a novel transition support intervention in an adult eating disorders service: ECHOMANTRA.

Admissions and re-admissions for inpatient care for anorexia nervosa have been increasing. The aim of this study was to examine whether the transition from inpatient care to the community could be facilitated by supplementing usual treatment with ECHOMANTRA (transition interventions) for both patients and carers. A case series study was employed using a mixed-methods approach to measure the feasibility and efficacy of augmenting intensive hospital treatment with ECHOMANTRA. A consecutive series of consenting patients (n = 31) and carers (n = 21) were assessed on admission, discharge, and at 3 months follow-up. These outcomes were compared with audit data (n = 152) previously collected (2007-2017). The length of stay for the ECHOMANTRA intervention group was 4.5 weeks less than the comparison group, and weight gain was 0.11 kg per week higher. Improvements in patient symptomology were sustained at follow-up. Thematic analysis of the feedback from both patients and carers suggests that the intervention is valued. Carer burden was reduced and their skills improved (both moderate size changes). In conclusion, both the acceptability and efficiency of inpatient care for anorexia nervosa may be improved by augmenting treatment to prepare for transition from inpatient care by giving support to both patients and their carers.

Social anxiety in the eating disorders: a systematic review and meta-analysis.

Social anxiety disorder is one of the most common comorbid conditions in eating disorders (EDs). The aim of the current review and meta-analysis is to provide a qualitative summary of what is known about social anxiety (SA) in EDs, as well as to compare levels of SA in those with EDs and healthy controls. Electronic databases were systematically searched for studies using self-report measures of SA in ED populations. In total, 38 studies were identified, 12 of which were included in the meta-analyses. For both anorexia nervosa (AN) and bulimia nervosa, there were significant differences between ED groups and HCs, with medium to large effect sizes. Findings from the qualitative review indicate that levels of SA are similar across the ED diagnoses, and SA improves with treatment in AN. In addition, high levels of SA are associated with more severe ED psychopathology, but not body mass index. These findings add to the wider literature on socio-emotional functioning in EDs, and may have implications for treatment strategies.

Eye-tracking research in eating disorders: A systematic review.

OBJECTIVE: Those with eating disorders (EDs) show attentional biases to disorder-relevant stimuli, such as food and body shape information. However, attentional bias research in EDs largely relies on reaction time based measures, which are limited in their ability to assess different components and the time course of attention. Eye-tracking paradigms have therefore been utilized to provide greater ecological validity, and directly capture the detailed sequence of processes in perception and attention. While numerous studies have examined eye movements in the mood, anxiety, and psychotic disorders, there has been a lack of studies in EDs. The purpose of this qualitative review is to provide a summary of eye-tracking studies in clinical ED populations. METHOD: The review was conducted using the PRISMA guidelines. Electronic databases were systematically searched to identify studies examining gaze parameters in ED compared to healthy controls (HCs). Thirty-one studies met inclusion criteria. RESULTS: Across ED diagnoses, there was evidence of attentional biases towards food and body stimuli. In addition, differential patterns of attention to social information, and differences in smooth pursuit and saccadic eye movements were found in anorexia nervosa (AN). DISCUSSION: Findings are discussed in relation to research in other psychiatric disorders, and recommendations for future studies using eye-tracking in EDs are given. The findings add to the wider literature on attentional biases in EDs, and provide potential avenues for treatment. IJED-18-0331.R1. Investigación de seguimiento ocular en trastornos de la conducta alimentaria: una revisión sistemática.

An experimental investigation into the use of eye-contact in social interactions in women in the acute and recovered stages of anorexia nervosa.

OBJECTIVE: People with anorexia nervosa (AN) report significant difficulties in social functioning and a growing literature is beginning to explain some of the differences in social skills that might underlie the social challenges experienced by patients. One vital area of social functioning that has been largely neglected to date is how eye-contact is used in the context of social stimuli and in social situations. METHODS: This cross-sectional, experimental study used eye-tracking to measure the frequency and duration of eye-contact made with the eye region of interest (ROI) of (1) static social stimuli (man and woman Ekman faces displaying basic emotions); (2) moving social stimuli (a video of two actors conversing); and (3) during a real-life social interaction in 75 women (25 with AN, 25 recovered from AN, and 25 non-AN controls; mean age = 27.18, SD = 6.19). RESULTS: Participants showed greater eye-contact during a real-life social interaction than when viewing static social stimuli. Those with AN made contact with the eye ROI of the static and moving social stimuli and during a real-life social interaction significantly less often and for significantly less time than non-AN controls. Those recovered from AN showed greater eye-contact than the acute group but significantly less eye-contact with the eye ROI across the static and moving social stimuli and during the real-life social interaction than non-AN controls. DISCUSSION: These findings contribute new knowledge regarding the types of social skills that people with AN may need additional support with to allow them to make greater use of social support in their recovery.

Cognitive remediation therapy for adolescent inpatients with severe and complex anorexia nervosa: A treatment trial.

Cognitive remediation therapy (CRT) is a low-intensity treatment adjunct for individuals with severe and complex anorexia nervosa (AN) with difficulties in globally oriented, flexible thinking. Previously trialled in adults, this study investigated whether individual and group CRT was a feasible, acceptable, and beneficial treatment for 125 adolescent inpatients with severe and complex AN. Seventy patients (mean age = 15.22, SD = 1.44) received 10 sessions of individual CRT, and 55 patients (mean age = 14.89, SD = 1.74) received 10 sessions of group CRT. In individual CRT, 1 patient (1.43%) dropped out, and there were medium-sized improvements in bigger picture thinking and set-shifting, small to large-sized improvements in switching-related initiation and inhibition skills, and large-sized improvements in motivation to recover. Group CRT had higher dropout (9.09%; n = 5) and produced small-sized improvements in global information processing and medium-sized improvements in self-reported cognitive flexibility and high acceptability ratings. Data suggest that a randomised controlled trial for adolescents with AN is warranted.

Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience.

BACKGROUND: Cytomegalovirus (CMV) establishes a lifelong infection that is efficiently controlled by the immune system; this infection can be reactivated in case of immunosuppression such as following solid organ transplantation. CMV viraemia has been associated with CMV disease, as well as increased mortality and allograft failure. Prophylactic antiviral medication is routinely given to renal transplant recipients, but reactivation during and following cessation of antiviral prophylaxis is known to occur. The aims of this study were to assess the incidence, timing and impact of CMV viraemia in renal transplant recipients and to determine the level of viraemia associated with adverse clinical outcomes. METHODS: Data from all adult (18 years and over) Western Australian renal transplant recipients transplanted between 1 January 2007 and 31 December 2012 were obtained from the Australia and New Zealand Dialysis and Transplant registry and were supplemented with data obtained from clinical records. Potential risk factors for detectable CMV viraemia (≥600 copies/ml) and all-cause mortality were assessed using univariable analysis and Cox Proportional Hazards Regression. RESULTS: There were 438 transplants performed on 435 recipients. The following factors increased the risk of CMV viraemia with viral loads ≥600 copies/ml: Donor positive/Recipient negative status; receiving a graft from a deceased donor; and receiving a graft from a donor aged 60 years and over. CMV viraemia with viral loads ≥656 copies/ml was a risk factor for death following renal transplantation, as was being aged 65 years and above at transplant, being Aboriginal and having vascular disease. Importantly 37% of the episodes of CMV viraemia with viral loads ≥656 copies/ml occurred while the patients were expected to be on CMV prophylaxis. CONCLUSIONS: CMV viraemia (≥656 copies/ml) was associated with all-cause mortality in multivariable analysis, and CMV viraemia at ≥656 copies/ml commonly occurred during the period when renal transplant recipients were expected to be on antiviral prophylaxis. A greater vigilance in monitoring CMV levels if antiviral prophylaxis is stopped prematurely or poor patient compliance is suspected could protect some renal transplant recipients from adverse outcomes such as premature mortality.

Why study positive emotions in the context of eating disorders?

Experimental research, supported by systematic reviews, establishes that people with eating disorders have emotional difficulties in terms of recognising, regulating and expressing their emotions. These emotional difficulties contribute to poor social functioning and problems with relationships. The existing literature includes a broad range of studies, many of which have utilised self-report measures, but experimental studies of emotions in eating disorders are still limited. The primary aim of this paper is to highlight gaps in the clinical research on emotions in eating disorders, focusing on experimental investigations from our lab and highlighting potentially useful future directions for further basic research and its translation into new developments in treatment and prevention. Recent findings using experimental paradigms to study the expression of emotions along with neuroimaging research exploring differences in facial emotion processing are discussed, and clinical implications are presented.

Emotion Controllability Beliefs and Young People's Anxiety and Depression Symptoms: A Systematic Review.

Emotion regulation is a powerful predictor of youth mental health and a crucial ingredient of interventions. A growing body of evidence indicates that the beliefs individuals hold about the extent to which emotions are controllable (emotion controllability beliefs) influence both the degree and the ways in which they regulate emotions. A systematic review was conducted that investigated the associations between emotion controllability beliefs and youth anxiety and depression symptoms. The search identified 21 peer-reviewed publications that met the inclusion criteria. Believing that emotions are relatively controllable was associated with fewer anxiety and depression symptoms, in part because these beliefs were associated with more frequent use of adaptive emotion regulation strategies. These findings support theoretical models linking emotion controllability beliefs with anxiety and depression symptoms via emotion regulation strategies that target emotional experience, like reappraisal. Taken together, the review findings demonstrate that emotion controllability beliefs matter for youth mental health. Understanding emotion controllability beliefs is of prime importance for basic science and practice, as it will advance understanding of mental health and provide additional targets for managing symptoms of anxiety and depression in young people.

LC-MS-MS quantification of Δ8-THC, Δ9-THC, THCV isomers and their main metabolites in human plasma.

In recent years, potential therapeutic applications of several different cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC), its isomer Δ8-THC and Δ9-tetrahydrocannabivarin (Δ9-THCV), have been investigated. Nevertheless, to establish dose-effect relationship and to gain knowledge of their pharmacokinetics and metabolism, sensitive and specific analytical assays are needed to measure these compounds in patients. For this reason, we developed and validated an online extraction high-performance liquid/liquid chromatography-tandem mass spectrometry (LC/LC-MS-MS) method for the simultaneous quantification of 13 cannabinoids and metabolites including the Δ8 and Δ9 isomers of THC, THCV and those of their major metabolites in human plasma. Plasma was fortified with cannabinoids at varying concentrations within the working range of the respective compound and 200 µL was extracted using a simple one-step protein precipitation procedure. The extracts were analyzed using online trapping LC/LC-atmospheric pressure chemical ionization-MS-MS running in the positive multiple reaction monitoring mode. The lower limit of quantification ranged from 0.5 to 2.5 ng/mL, and the upper limit of quantification was 400 ng/mL for all analytes. Inter-day analytical accuracy and imprecision ranged from 82.9% to 109% and 4.3% to 20.3% (coefficient of variance), respectively. Of 534 plasma samples following controlled oral administration of Δ8-THCV, 236 were positive for Δ8-THCV (median; interquartile ranges: 3.5 ng/mL; 1.8-11.9 ng/mL), 383 for the major metabolite (-)-11-nor-9-carboxy-Δ8-tetrahydrocannabivarin (Δ8-THCV-COOH) (95.4 ng/mL; 20.7-328 ng/mL), 260 for (-)-11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (Δ9-THCV-COOH) (5.8 ng/mL; 2.5-16.1 ng/mL), 157 for (-)-11-hydroxy-Δ8-tetrahydrocannabivarin (11-OH-Δ8-THCV) (1.7 ng/mL; 1.0-3.7 ng/mL), 49 for Δ8-THC-COOH (1.7 ng/mL; 1.4-2.3 ng/mL) and 42 for Δ9-THCV (1.3 ng/mL; 0.8-1.6 ng/mL). We developed and validated the first LC/LC-MS-MS assay for the specific quantification of Δ8-THC, Δ9-THC and THCV isomers and their respective metabolites in human plasma. Δ8-THCV-COOH, 11-hydroxy-Δ8-THCV and Δ9-THCV-COOH were the major Δ8-THCV metabolites in human plasma after oral administration of 98.6% pure Δ8-THCV.