Cannabis-Responsive Biomarkers: A Pharmacometabolomics-Based Application to Evaluate the Impact of Medical Cannabis Treatment on Children with Autism Spectrum Disorder.

Introduction: Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions that impact behavior, communication, social interaction, and learning abilities. Treatment of ASD with medical cannabis (MC) shows promising results in reducing the severity of certain behavioral aspects. The goals of this observational study are to demonstrate the potential of metabolic biomarkers to (1) objectively determine the impact on metabolites of MC treatment and (2) suggest the metabolic pathways of children with ASD, who respond to MC treatment. Materials and Methods: The impact of effective physician-supervised MC treatment on children with ASD (n=15), compared with an age-matched group of typically developing (TD; n=9) children, was evaluated in an observational study design. Each child followed a unique MC regimen determined by their specific response over at least 1 year of treatment, which included the following: tetrahydrocannabinol-dominant MC (dosing range 0.05-50 mg per dose) in 40% of children and cannabidiol-dominant MC (dosing range 7.5-200 mg per dose) in 60% of children. Samples from the ASD group collected pre-MC treatment and at time of maximal impact, and from the TD group, were subjected to salivary metabolomics analysis. Ten minutes before saliva sampling, parents filled out behavioral rating surveys. Results: Sixty-five potential cannabis-responsive biomarkers exhibiting a shift toward the TD physiological levels were identified in children with ASD after MC treatment. For each biomarker, the physiological levels were determined based on the values detected in the TD group. A similar qualitative improvement trend in children with ASD treated with MC was also observed in the behavioral surveys. Twenty-three potential Cannabis-Responsive biomarkers exhibiting change toward TD mean were categorized as anti-inflammatory, bioenergy associated, neurotransmitters, amino acids, and endocannabinoids. The changes in the levels of the Cannabis-Responsive biomarkers N-acetylaspartic acid, spermine, and dehydroisoandrosterone 3-sulfate have been previously linked to behavioral symptoms commonly observed in individuals with ASD. Conclusions: Our results suggest Cannabis-Responsive biomarkers shift toward the TD mean after MC treatment and can potentially quantify benefit at the metabolic level. These changes appear to be similar to the trend described in behavior surveys. Larger trials are needed to confirm these preliminary findings.

The Potential of Salivary Lipid-Based Cannabis-Responsive Biomarkers to Evaluate Medical Cannabis Treatment in Children with Autism Spectrum Disorder.

Introduction: Autism spectrum disorder (ASD) is a group of heterogeneous neurodevelopmental conditions affecting social communication and social interaction. Medical cannabis (MC) treatment shows promising results as an approach to reduce behavioral difficulties, as determined mainly by subjective observations. We have recently shown the potential of cannabis-responsive biomarkers detected in saliva of children with ASD to objectively quantify the impact of successful MC treatment using a metabolomics approach. Since the pathology of ASD is associated with abnormal lipid metabolism, we used lipidomics on the same samples to (1) expand the repertoire of cannabis-responsive biomarkers and (2) provide preliminary insight into the role of MC on lipid metabolism. Materials and Methods: Saliva samples collected from children with ASD (n=15) treated with MC (both before and at the time of maximal impact of treatment) and an age-matched group of typically developing (TD) children (n=9) were subjected to untargeted lipidomics. The study was observational. Each child from the ASD group was receiving a unique individualized MC treatment regimen using off-the-shelf products as permitted by California law under physician supervision for at least 1 year. Doses of tetrahydrocannabinol (THC) ranged from 0.05 to 50 mg and cannabidiol (CBD) from 7.5 to 200 mg per treatment. The ASD group was evaluated for signs of improvement using parental brief Likert scale surveys. Results: Twenty-two potential lipid-based cannabis-responsive biomarkers exhibiting a shift toward the TD physiological levels in children with ASD after MC treatment were identified. Members from all five lipid subclasses known to be present in saliva were characterized. Preliminary lipid association network analysis suggests involvement of two subnetworks previously linked to (1) inflammation and/or redox regulation and (2) oxidative stress. The significant changes in sphingomyelin in this study and in N-acetyl-aspartate (NAA) previously detected in the metabolomics analysis of the same saliva samples may indicate a role of MC in neuron function. Conclusions: Our findings suggest that lipid metabolites in saliva can potentially serve as cannabis-responsive biomarkers and objectively quantify the impact of MC treatment, and indicate a possible mechanism of action for MC. This preliminary study requires further investigation with a larger population and appropriate clinical trial monitoring.

Patients Receiving Integrative Medicine Effectiveness Registry (PRIMIER) of the BraveNet practice-based research network: Outcomes of the PRIMIER cohort.

OBJECTIVE: To evaluate the real-world effectiveness of integrative medicine treatment on quality of life using the Patients Receiving Integrative Medicine Effectiveness Registry (PRIMIER). DESIGN: A prospective, longitudinal, observational evaluation of patient reported outcomes for quality of life. SETTING: Participants were patients from 17 integrative medicine clinics who received personalized, integrative medicine treatments between August 2013 and October 2017. MAIN OUTCOME MEASURES: Participants completed the Patient Reported Outcomes Measurement Information System (PROMIS)- 29, Perceived Stress Scale-4 (PSS-4), and the Patient Activation Measure (PAM) at index (baseline) visit and at 2, 4, 6, and 12 month follow-up assessments. Electronic health record data included diagnostic and billing codes/descriptions. A linear mixed-effects model was used to test whether outcomes changed from index through 12 months RESULTS: During enrollment, 4883 participants began the assessment, 3658 completed the index measures, and 2374 (65 %) completed at least 1 follow-up assessment, had electronic health record data and at least 1 integrative medicine visit. Most participants (mean age=51.4 years) were white (88.4 %), female (79.7 %), and college-educated (78.5 %). Significant improvements (p < 0.001) were observed at 12-months on all PROMIS-29 measures, PSS-4, and PAM. At 12 months, clinically meaningful improvements were found for 38 % and 28 % on PROMIS-29 Mental and Physical Health Summary scores respectively. CONCLUSIONS: PRIMIER is the largest study to assess the real-world effectiveness of integrative medicine. Results indicate a statistical and clinical improvement across all measures at 12 months. Future research could explore whether dosing, timing or combinations of integrative medicine interventions have differential impacts on quality of life.

Backgrounds and Trainings in Cannabis Therapeutics of Dispensary Personnel.

PURPOSE: A growing body of scientific research indicates that oncology teams tend to offer individuals with cancer little clinical advice regarding medicinal cannabis (MC) and that individuals with cancer instead turn to cannabis dispensaries for MC guidance. Our objective was to investigate dispensary personnel's backgrounds and trainings in MC advising. METHODS: The study design was semistructured interviews across 13 states with cannabis dispensary personnel in managerial or client-facing positions. Of 38 recruited, 26 (68%) completed interview. The primary outcome was training in MC advising. Researchers targeted thematic saturation and adhered to Consolidated Criteria for Reporting Qualitative Research. RESULTS: Of 26 participants, 54% were female, with an average age of 40 (range: 22-64) years. Half worked in client-facing roles; half worked in managerial ones. Study participants endorsed passionate commitment to their profession, often motivated by personal experience with MC therapeutics. Cannabis dispensaries often privileged sales skills over cannabis therapeutics knowledge when hiring, resulting in uneven baseline levels of cannabis therapeutics expertise among staff. Most participants reported workplace cannabis therapeutics training to be unstandardized and weak. They described dispensary personnel as resourceful in pursuing cannabis knowledge, self-financing learning in off-hours, sampling dispensary products, and exchanging knowledge. Nearly half the participants called for quality, standardized cannabis therapeutics training for dispensary personnel. CONCLUSION: The many oncology teams who defer to dispensary personnel regarding MC advising rely on a workforce who views themselves as unevenly trained. Further research should include a national survey of cannabis dispensary personnel to learn whether these findings hold true in a larger sample. If so, the oncology community must determine the best approach to clinically advising individuals with cancer about MC.

Cannabis, Cannabinoids and Cannabis-Based Medicines in Cancer Care.

As medical cannabis becomes legal in more states, cancer patients are increasingly interested in the potential utility of the ancient botanical in their treatment regimen. Although eager to discuss cannabis use with their oncologist, patients often find that their provider reports that they do not have adequate information to be helpful. Oncologists, so dependent on evidence-based data to guide their treatment plans, are dismayed by the lack of published literature on the benefits of medical cannabis. This results largely from the significant barriers that have existed to effectively thwart the ability to conduct trials investigating the potential therapeutic efficacy of the plant. This is a narrative review aimed at clinicians, summarizing cannabis phytochemistry, trials in the areas of nausea and vomiting, appetite, pain and anticancer activity, including assessment of case reports of antitumor use, with reflective assessments of the quality and quantity of evidence. Despite preclinical evidence and social media claims, the utility of cannabis, cannabinoids or cannabis-based medicines in the treatment of cancer remains to be convincingly demonstrated. With an acceptable safety profile, cannabis and its congeners may be useful in managing symptoms related to cancer or its treatment. Further clinical trials should be conducted to evaluate whether the preclinical antitumor effects translate into benefit for cancer patients. Oncologists should familiarize themselves with the available database to be able to better advise their patients on the potential uses of this complementary botanical therapy.

Cancer Treatment: Preclinical & Clinical.

The first evidence that cannabinoids may have in vitro and in vivo antineoplastic activity against tumor cell lines and animal tumor models was published in the Journal of the National Cancer Institute nearly 50 years ago. Cannabinoids appear to induce apoptosis in rodent brain tumors by way of direct interaction with the cannabinoid receptor. They may inhibit angiogenesis and tumor cell invasiveness. Despite preclinical findings, attempts to translate the benefits from bench to bedside have been limited. This session provides a review of the basic science supporting the use of cannabinoids in gliomas, paired with the first randomized clinical trial of a cannabis-based therapy for glioblastoma multiforme. Another preclinical presentation reports the effects of cannabinoids on triple-negative breast cancer cell lines and how cannabidiol may affect tumors. The session's second human trial raises concerns about the use of botanical cannabis in patients with advanced cancer receiving immunotherapy suggesting inferior outcomes.

A cannabis oracle? Delphi method not a substitute for randomized controlled trials of cannabinoids as therapeutics.

BACKGROUND: With millions of people using cannabinoids to treat a host of medical conditions, clinicians want guidance on how to utilize cannabinoids as pharmacotherapy in their practices. The Delphi method is a systematic, interactive forecasting method that aims to develop consensus best practices where guidelines are not available. BODY: A multidisciplinary group of global cannabinoid experts utilized a modified Delphi process to develop three protocols for the dosing and administration of cannabinoids to treat chronic pain. Two protocols recommend cannabidiol (CBD), for which there is limited evidence as an analgesic, starting well below doses required for other indications. Guidance on prescribing CBD for pain may demonstrate consensus recommendations based upon suboptimal evidence. CONCLUSION: Consensus processes like the Delphi method are well-meaning, but they are not a substitute for rigorous RCTs with large sample sizes, adequate duration, and standardized outcome measures.

Considering abuse liability and neurocognitive effects of cannabis and cannabis-derived products when assessing analgesic efficacy: a comprehensive review of randomized-controlled studies.

Background: Pain is the most frequent indication for which medical cannabis treatment is sought.Objectives: The clinical potential of cannabis and cannabis-derived products (CDPs) relies on their efficacy to treat an indication and potential adverse effects that impact outcomes, including abuse liability and neurocognitive effects. To ascertain the extent to which these effects impact therapeutic utility, studies investigating cannabis and CDPs for pain were reviewed for analgesic efficacy and assessments of abuse liability and neurocognitive effects.Methods: A comprehensive review of placebo-controlled studies investigating cannabis and CDP analgesia was performed. Methods and findings related to adverse effects, abuse liability, and neurocognitive effects were extracted.Results: Thirty-eight studies were reviewed; 29 assessed cannabis and CDPs for chronic pain, 1 for acute pain, and 8 used experimental pain tests. Most studies ascertained adverse effects through self-report (N = 27). Fewer studies specifically probed abuse liability (N = 7) and cognitive and psychomotor effects (N = 12). Many studies related to chronic and experimental pain (N = 18 and N = 5, respectively) found cannabis and CDPs to reduce pain. Overall, adverse effects were mild to moderate, and dose-related. Studies investigating the impact of cannabis and CDPs on abuse liability and neurocognitive endpoints were mostly limited to inhaled administration and confirmed dose-related effects.Conclusion: Few studies investigating cannabis and CDP analgesia assess abuse liability and cognitive endpoints, adverse effects that impact the long-term clinical utility of these drugs. Future studies should include these measures to optimize research and clinical care related to cannabis-based therapeutics.

Improving Access to Integrative Oncology Through Group Medical Visits: A Pilot Implementation Project.

Objectives: This article describes the implementation of a group medical visit (GMV) model to increase access to integrative oncology (IO) care. The most challenging and critical time to access high-quality IO care is while patients are receiving conventional cancer therapy. Often demand for individual IO clinic consultations precludes this from occurring. A three-session GMV program was designed to alleviate barriers to receiving integrative care during active cancer treatment. Design: A consolidated framework was used for implementation research and focused ethnography methods to describe the IO GMV implementation process. Data sources included patient evaluations, participant observation, and brief provider and patient interviews. Setting: A pilot program was created to assess the feasibility and acceptability of implementing IO GMVs at a comprehensive cancer center. Intervention: Each three-session GMV consisted of a didactic session, followed by individual visits with the integrative oncologist. Results: The setting, intervention, and implementation process of the IO GMV program were described. Thirty-two patients participated in the first five cohorts of the program. Twenty-two were women; 24 were White. The median age of participants was 52. Patient evaluations demonstrate high levels of satisfaction with the program with all scored aspects rated >4.0 on a five-point Likert scale. For the medical center, group visits are a financially viable alternative to individual IO visits; revenue from group visits exceeded the revenue potential of 6 h of individual visits by an average of 38%. Conclusion: GMVs are a feasible and promising model for increasing access to IO. Patients in active cancer treatment were able to participate in the program. Future research and implementation efforts could examine health outcomes over time after participation in GMVs, as well as the feasibility of using this model with more diverse patient populations.

Should Oncologists Recommend Cannabis?

OPINION STATEMENT: Cannabis is a useful botanical with a wide range of therapeutic potential. Global prohibition over the past century has impeded the ability to study the plant as medicine. However, delta-9-tetrahydrocannabinol (THC) has been developed as a stand-alone pharmaceutical initially approved for the treatment of chemotherapy-related nausea and vomiting in 1986. The indication was expanded in 1992 to include treatment of anorexia in patients with the AIDS wasting syndrome. Hence, if the dominant cannabinoid is available as a schedule III prescription medication, it would seem logical that the parent botanical would likely have similar therapeutic benefits. The system of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) has likely developed to help us modulate our response to noxious stimuli. Phytocannabinoids also complex with these receptors, and the analgesic effects of cannabis are perhaps the best supported by clinical evidence. Cannabis and its constituents have also been reported to be useful in assisting with sleep, mood, and anxiety. Despite significant in vitro and animal model evidence supporting the anti-cancer activity of individual cannabinoids-particularly THC and cannabidiol (CBD)-clinical evidence is absent. A single intervention that can assist with nausea, appetite, pain, mood, and sleep is certainly a valuable addition to the palliative care armamentarium. Although many healthcare providers advise against the inhalation of a botanical as a twenty-first century drug-delivery system, evidence for serious harmful effects of cannabis inhalation is scant and a variety of other methods of ingestion are currently available from dispensaries in locales where patients have access to medicinal cannabis. Oncologists and palliative care providers should recommend this botanical remedy to their patients to gain first-hand evidence of its therapeutic potential despite the paucity of results from randomized placebo-controlled clinical trials to appreciate that it is both safe and effective and really does not require a package insert.

Vitamin D Levels in Patients with Colorectal Cancer Before and After Treatment Initiation.

PURPOSE: We aimed to described 25-hydroxyvitamin D [25(OH)D] levels in newly diagnosed colorectal cancer (CRC) patients and to re-evaluate levels after chemotherapy. METHODS: Permanent residents of the San Francisco Bay Area with a new CRC diagnosis of any stage were recruited prior to any non-surgical therapy. Serum 25(OH)D levels were measured at time of diagnosis and 6-month follow-up. Supplement use was not restricted. The primary endpoint was the frequency of vitamin D deficiency in patients with newly diagnosed CRC of all stages. The Kruskal-Wallis and Spearman correlation tests were used to evaluate associations of patient characteristics with 25(OH)D levels. RESULTS: Median 25(OH)D level at baseline was 27.0 ng/mL (range 7.2, 59.0); 65% of patients had insufficient levels (25(OH)D < 30 ng/mL) (n = 94). Race, disease stage, multivitamin use, vitamin D supplementation, and county of residence were associated with baseline 25(OH)D levels (P < 0.05). The median change in 25(OH)D from baseline to 6 months was - 0.7 ng/mL [- 19.4, 51.7] for patients treated with chemotherapy (n = 58) and 1.6 ng/mL [- 6.4, 33.2] for patients who did not receive chemotherapy (n = 19) (P = 0.26). For patients who received vitamin D supplementation during chemotherapy, the median 25(OH)D change was 8.3 ng/mL [- 7.6, 51.7] versus - 1.6 [- 19.4, 24.3] for chemotherapy patients who did not take vitamin D supplements (P = 0.02). CONCLUSION: Among patients with a new diagnosis of CRC, most patients were found to have 25(OH)D levels consistent with either deficiency or insufficiency. In the subset of patients who received chemotherapy and took a vitamin D supplement, serum 25(OH)D levels increased, suggesting that vitamin D repletion is a feasible intervention during chemotherapy.

An Integrative Approach to Prostate Cancer.

OBJECTIVES: The mostly indolent natural history and long overall survival associated with a diagnosis of prostate cancer provides a unique opportunity for men to explore diet and lifestyle interventions to alter the trajectory of their disease. As many patients may be appropriate for postponing conventional therapy, the effects of various integrative interventions can be investigated. In addition, treatment of prostate cancer with surgery, radiation, or androgen deprivation therapy, all may produce physical or psychological side effects that could be amenable to complementary therapies. This article serves to review salient information in the published literature. DESIGN: A review of published research was conducted. RESULTS: A plant-based antioxidant-rich diet with an emphasis on cruciferous vegetables, tomatoes, soy, pomegranate, and marine omega 3 fatty acids while avoiding saturated fats, including dairy products is the best option. Supplementation with vitamin D3, omega 3, and some nutraceutical-based preparations may be advised. It is likely prudent to avoid vitamin E and selenium supplements. Physical activity has been shown to have multiple benefits in men diagnosed with all stages of prostate cancer from strengthening bones, improving body habitus, and enhancing overall wellbeing. Yoga, combining physical activity with a mind-body component, has been shown to have a salutogenic effect in both prostate cancer patients and their caregivers. Traditional Chinese Medicine may be particularly useful in managing side effects of conventional treatments, especially the hot flashes associated with androgen deprivation therapy. Although the long natural history, availability of a useful blood marker of disease progression and prolonged survival are overall positive features, they also combine to allow men to live for a long time with diagnosed cancer, fear of progression, or recurrence and fixation on changes in their prostate-specific antigen level. The resultant stress can be deleterious to general health as well as possibly the natural history of their disease. Mind-body interventions to reduce stress, including mindfulness-based stress reduction and support groups may be useful adjunctive therapies. CONCLUSION: Men with prostate cancer may benefit from lifestyle and complementary interventions integrated with their conventional care.

The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report.

The National Academies of Sciences, Engineering and Medicine conducted a rapid turn-around comprehensive review of recent medical literature on The Health Effects of Cannabis and Cannabinoids. The 16-member committee adopted the key features of a systematic review process, conducting an extensive search of relevant databases and considered 10,000 recent abstracts to determine their relevance. Primacy was given to recently published systematic reviews and primary research that studied one of the committee's 11 prioritized health endpoints- therapeutic effects; cancer incidence; cardiometabolic risk; respiratory disease; immune function; injury and death; prenatal, perinatal and postnatal outcomes; psychosocial outcomes; mental health; problem Cannabis use; and Cannabis use and abuse of other substances. The committee developed standard language to categorize the weight of evidence regarding whether Cannabis or cannabinoids use for therapeutic purposes are an effective or ineffective treatment for the prioritized health endpoints of interest. In the Therapeutics chapter reviewed here, the report concluded that there was conclusive or substantial evidence that Cannabis or cannabinoids are effective for the treatment of pain in adults; chemotherapy-induced nausea and vomiting and spasticity associated with multiple sclerosis. Moderate evidence was found for secondary sleep disturbances. The evidence supporting improvement in appetite, Tourette syndrome, anxiety, posttraumatic stress disorder, cancer, irritable bowel syndrome, epilepsy and a variety of neurodegenerative disorders was described as limited, insufficient or absent. A chapter of the NASEM report enumerated multiple barriers to conducting research on Cannabis in the US that may explain the paucity of positive therapeutic benefits in the published literature to date.

A Survey of Licensed Acupuncturists in the San Francisco Bay Area: Prevalence of Treating Oncology Patients.

BACKGROUND: Many cancer patients seek traditional Chinese medicine (TCM), the prevalence varying with diagnosis, comorbidities, and demographics. Interventions sought include acupuncture, massage, herbs, diet, and exercise, usually combined with conventional therapies. It is not known what proportion of TCM practitioners care for cancer patients, their cancer specific training or caseload, what interventions they employ, their outcomes, and their communication patterns with conventional oncologists. METHODS: A survey was mailed to all 2213 licensed acupuncturists in the 9-county San Francisco Bay Area gathering descriptive statistics. RESULTS: A total of 472 (21%) responded by mail or web-based Research Electronic Data Capture (REDCap) tool. Most respondents (77%) reported caring for patients with cancer, with 29% reporting having 6 to 10 years of practice experience, and 44.2% having 0 to 20 hours of training specific to the needs of patients with cancer. Improving quality of life was reported by 94% as what their treatment offered cancer patients as well as the area where treatment was felt to have the greatest impact. The most useful TCM modalities were acupuncture (98%), herbs (79%), diet (72%), moxibustion (46%), and meditation instruction (44%). Absence of adverse reactions was noted by 95%. Ninety-one percent reported "never" or "hardly ever" having been contacted by patients' oncologists to discuss treatment. CONCLUSIONS: Many acupuncturists seeing cancer patients have significant clinical experience and have sought specialized training. Improved communication is needed between TCM practitioners and oncologists sharing care of cancer patients.

Perceived Stress in Patients with Common Gastrointestinal Disorders: Associations with Quality of Life, Symptoms and Disease Management.

OBJECTIVE AND METHODS: Research supports relationships between stress and gastrointestinal (GI) symptoms and disorders. This pilot study assesses relationships between perceived stress, quality of life (QOL), and self-reported pain ratings as an indicator of symptom management in patients who self-reported gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and inflammatory bowel disease (IBD). RESULTS: In the full sample (n = 402) perceived stress positively correlated with depression (r = 0.76, P < .0001), fatigue (r = 0.38, P < .0001), sleep disturbance (r = 0.40, P < .0001), average pain (r = 0.26, P < .0001), and worst pain (r = 0.25, P < .0001). Higher perceived stress also correlated with lower mental health-related QOL. Similar correlations were found for the participants with GERD (n = 188), IBS (n = 132), and IBD (n = 82). Finally, there were significant correlations in the GERD cohort between perceived stress, and average pain (r = 0.34, P < .0001) and worst pain (r = 0.29, P < .0001), and in the IBD cohort between perceived stress, and average pain (r = 0.32, P < .0001), and worst pain (r = 0.35, P < .01). CONCLUSIONS: Perceived stress broadly correlated with QOL characteristics in patients with GERD, IBS, and IBD, and their overall QOL was significantly lower than the general population. Perceived stress also appeared to be an indicator of symptom management (self-reported pain ratings) in GERD and IBD, but not IBS. While future research using objective measures of stress and symptom/disease management is needed to confirm these associations, as well as to evaluate the ability of stress reduction interventions to improve perceived stress, QOL and disease management in these GI disorders, integrative medicine treatment programs would be most beneficial to study.

Patients Receiving Integrative Medicine Effectiveness Registry (PRIMIER) of the BraveNet practice-based research network: study protocol.

BACKGROUND: Integrative medicine (IM) provides patient-centered care and addresses the full range of physical, emotional, mental, social, spiritual, and environmental influences that affect a person's health. IM is a "whole systems" approach that employs multiple modalities as opposed to an isolated complementary therapy. Thus, studying outcomes of IM is more challenging than evaluating an isolated intervention. Practice-based research networks (PBRNs) allow for clinicians/investigators at multiple diverse sites using common methodology to pool their data, increase participant sample size and increase generalizability of results. To conduct real-world, practice-based research, the Bravewell Collaborative founded BraveNet in 2007 as the first national integrative medicine PBRN. METHODS AND DESIGN: Patients Receiving Integrative Medicine Effectiveness Registry (PRIMIER) is a prospective, non-randomized, observational evaluation conducted at fourteen clinical sites. Participants receive a non-standardized, personalized, multimodal IM approach for various medical conditions. Using the REDCap electronic platform, an anticipated 10,000 study participants will complete patient-reported outcome measures including Patient Reported Outcomes Measurement Information System (PROMIS)-29, Perceived Stress Scale-4, and the Patient Activation Measure at baseline, 2, 4, 6, 12, 18 and 24 months. Extractions from participants' electronic health records include IM services received, as well as ICD diagnostic codes, and CPT billing codes associated with each IM visit. Repeated-measures analyses will be performed on data to assess change from baseline through 24 months with planned subgroup analyses to include specific clinical population and specific IM intervention or combinations. DISCUSSION: As the PRIMIER registry grows, we anticipate that our results would provide an indication of the promise of PBRN research efforts in IM. Analyses will incorporate a large sample of participants and an expected 10-year observation period and will provide the ability to evaluate the effect of IM on outcomes for specific clinical populations and specific IM interventions or combinations. As such, PRIMIER will serve as a national platform for future evaluations of IM best practices. TRIAL REGISTRATION: Clinical Trials.gov NCT01754038.