Trends in U.S. Medical Cannabis Registrations, Authorizing Clinicians, and Reasons for Use From 2020 to 2022.

BACKGROUND: As medical cannabis availability increases, up-to-date trends in medical cannabis licensure can inform clinical policy and care. OBJECTIVE: To describe current trends in medical cannabis licensure in the United States. DESIGN: Ecological study with repeated measures. SETTING: Publicly available state registry data from 2020 to 2022. PARTICIPANTS: People with medical cannabis licenses and clinicians authorizing cannabis licenses in the United States. MEASUREMENTS: Total patient volume and prevalence per 10 000 persons in the total population, symptoms or conditions qualifying patients for licensure (that is, patient-reported qualifying conditions), and number of authorizing clinicians. RESULTS: In 2022, of 39 jurisdictions allowing medical cannabis use, 34 reported patient numbers, 19 reported patient-reported qualifying conditions, and 29 reported authorizing clinician numbers. Enrolled patients increased 33.3% from 2020 (3 099 096) to 2022 (4 132 098), with a corresponding 23.0% increase in the population prevalence of patients (175.0 per 10 000 in 2020 to 215.2 per 10 000 in 2022). However, 13 of 15 jurisdictions with nonmedical adult-use laws had decreased enrollment from 2020 to 2022. The proportion of patient-reported qualifying conditions with substantial or conclusive evidence of therapeutic value decreased from 70.4% (2020) to 53.8% (2022). Chronic pain was the most common patient-reported qualifying condition in 2022 (48.4%), followed by anxiety (14.2%) and posttraumatic stress disorder (13.0%). In 2022, the United States had 29 500 authorizing clinicians (7.7 per 1000 patients), 53.5% of whom were physicians. The most common specialties reported were internal or family medicine (63.4%), physical medicine and rehabilitation (9.1%), and anesthesia or pain (7.9%). LIMITATION: Missing data (for example, from California), descriptive analysis, lack of information on individual use patterns, and changing evidence base. CONCLUSION: Enrollment in medical cannabis programs increased overall but generally decreased in jurisdictions with nonmedical adult-use laws. Use for conditions or symptoms without a strong evidence basis continues to increase. Given these trends, more research is needed to better understand the risks and benefits of medical cannabis. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse of the National Institutes of Health.

The Association of Cannabis Use After Discharge From Surgery With Opioid Consumption and Patient-reported Outcomes.

OBJECTIVE: To compare outcomes of patients using versus not using cannabis as a treatment for pain after discharge from surgery. BACKGROUND: Cannabis is increasingly available and is often taken by patients to relieve pain. However, it is unclear whether cannabis use for pain after surgery impacts opioid consumption and postoperative outcomes. METHODS: Using Michigan Surgical Quality Collaborative registry data at 69 hospitals, we analyzed a cohort of patients undergoing 16 procedure types between January 1, 2021, and October 31, 2021. The key exposure was cannabis use for pain after surgery. Outcomes included postdischarge opioid consumption (primary) and patient-reported outcomes of pain, satisfaction, quality of life, and regret to undergo surgery (secondary). RESULTS: Of 11,314 included patients (58% females, mean age: 55.1 years), 581 (5.1%) reported using cannabis to treat pain after surgery. In adjusted models, patients who used cannabis consumed an additional 1.0 (95% CI: 0.4-1.5) opioid pills after surgery. Patients who used cannabis were more likely to report moderate-to-severe surgical site pain at 1 week (adjusted odds ratio: 1.7, 95% CIL 1.4-2.1) and 1 month (adjusted odds ratio: 2.1, 95% CI: 1.7-2.7) after surgery. Patients who used cannabis were less likely to endorse high satisfaction (72.1% vs 82.6%), best quality of life (46.7% vs 63.0%), and no regret (87.6% vs 92.7%) (all P < 0.001). CONCLUSIONS: Patient-reported cannabis use, to treat postoperative pain, was associated with increased opioid consumption after discharge from surgery that was of clinically insignificant amounts, but worse pain and other postoperative patient-reported outcomes.

Thoughtfully Integrating Cannabis Products Into Chronic Pain Treatment.

Cannabis products (CPs) and cannabis-based medicines (CBMs) are becoming increasingly available and are commonly used for pain management. The growing societal acceptance of cannabis and liberalization of cannabis laws allows patients to access CPs with minimal clinical oversight. While there is mechanistic plausibility that CPs and CBMs may be useful for pain management, the clinical trial literature is limited and does not refute or support the use of CBMs for pain management. Complicating matters, a large and growing body of observational literature shows that many people use CPs for pain management and in place of other medications. However, products and dosing regimens in existing trials are not generalizable to the current cannabis market, making it difficult to compare and reconcile these 2 bodies of literature. Given this complexity, clinicians need clear, pragmatic guidance on how to appropriately educate and work with patients who are using CBMs for pain management. In this review, we narratively synthesize the evidence to enable a clear view of current landscape and provide pragmatic advice for clinicians to use when working with patients. This advice revolves around 3 principles: (1) maintaining the therapeutic alliance; (2) harm reduction and benefit maximization; and (3) pragmatism, principles of patient-centered care, and use of best clinical judgment in the face of uncertainty. Despite the lack of certainty CPs and chronic pain management use, we believe that following these principles can make most of the clinical opportunity presented by discussions around CPs and also enhance the likelihood of clinical benefit from CPs.

U.S. Trends in Registration for Medical Cannabis and Reasons for Use From 2016 to 2020 : An Observational Study.

BACKGROUND: Cannabis policy liberalization has increased cannabis availability for medical or recreational purposes. Up-to-date trends in medical cannabis licensure can inform clinical policy and care. OBJECTIVE: To describe recent trends in medical cannabis licensure in the United States. DESIGN: Ecological study with repeated measures. SETTING: State registry data via state reports and data requests on medical cannabis licensure from 2016 to 2020. PARTICIPANTS: Medical cannabis patients (persons with medical cannabis licenses) in the United States. MEASUREMENTS: Total patient volume, patients per 10 000 of total population, and patient-reported qualifying conditions (that is, symptoms or conditions qualifying patients for licensure)-including whether these symptoms align with current therapeutic evidence of cannabis-cannabinoid efficacy. RESULTS: In 2020, 26 states and Washington, DC reported patient numbers, and 19 states reported patient-reported qualifying conditions. Total enrolled patients increased approximately 4.5-fold from 678 408 in 2016 to 2 974 433 in 2020. Patients per 10 000 total population generally increased from 2016 to 2020, most dramatically in Oklahoma (927.1 patients per 10 000 population). However, enrollment increased in states without recreational legalization (that is, medical-only states), whereas enrollment decreased in 5 of 7 with recreational legalization (that is, recreational states). In 2020, 68.2% of patient-reported qualifying conditions had substantial or conclusive evidence of therapeutic value versus 84.6% in 2016. Chronic pain was the most common patient-reported qualifying condition in 2020 (60.6%), followed by posttraumatic stress disorder (10.6%). LIMITATION: Missing state data; lack of rationale for discontinuing medical cannabis licensure. CONCLUSION: Enrollment in medical cannabis programs approximately increased 4.5-fold from 2016 to 2020, although enrollment decreased in recreational states. Use for conditions or symptoms without a strong evidence basis increased from 15.4% (2016) to 31.8% (2020). Thoughtful regulatory and clinical strategies are needed to effectively manage this rapidly changing landscape. PRIMARY FUNDING SOURCE: National Institute on Drug Abuse of the National Institutes of Health.

Cannabidiol (CBD) in Rheumatic Diseases (Musculoskeletal Pain).

PURPOSE OF REVIEW: This review will address the many uncertainties surrounding the medical use of cannabidiol (CBD). We will begin with an overview of the legal and commercial environment, examine recent preclinical and clinical evidence on CBD, explore questions concerning CBD raised by healthcare professionals and patients, investigate dosing regimens and methods of administration, and address current challenges in the accumulation of sound evidence. RECENT FINDINGS: CBD has potential for relief of symptoms of pain, sleep, and mood disturbance in rheumatology patients, but sound clinical evidence is lacking. CBD is safe when accessed from a regulated source, whereas wellness products are less reliable regarding content and contaminants. Dosing for symptom relief has not yet been established. As many rheumatology patients are trying CBD as a self-management strategy, the healthcare community must urgently accrue sound evidence for effect.

An assessment of drinking water contamination with Helicobacter pylori in Lima, Peru.

BACKGROUND: Helicobacter pylori is a gut bacterium that is the primary cause of gastric cancer. H. pylori infection has been consistently associated with lack of access to sanitation and clean drinking water. In this study, we conducted time-series sampling of drinking water in Lima, Peru, to examine trends of H. pylori contamination and other water characteristics. MATERIALS AND METHODS: Drinking water samples were collected from a single faucet in Lima's Lince district 5 days per week from June 2015 to May 2016, and pH, temperature, free available chlorine, and conductivity were measured. Quantities of H. pylori in all water samples were measured using quantitative polymerase chain reaction. Relationships between the presence/absence and quantity of H. pylori and water characteristics in the 2015-2016 period were examined using regression methods accounting for the time-series design. RESULTS: Forty-nine of 241 (20.3%) of drinking water samples were contaminated with H. pylori. Statistical analyses identified no associations between sampling date and the likelihood of contamination with H. pylori. Statistically significant relationships were found between lower temperatures and a lower likelihood of the presence of H. pylori (P < .05), as well as between higher pH and higher quantities of H. pylori (P < .05). CONCLUSIONS: This study has provided evidence of the presence of H. pylori DNA in the drinking water of a single drinking water faucet in the Lince district of Lima. However, no seasonal trends were observed. Further studies are needed to determine the presence of H. pylori in other drinking water sources in other districts in Lima, as well as to determine the viability of H. pylori in these water sources. Such studies would potentially allow for better understanding and estimates of the risk of infection due to exposure to H. pylori in drinking water.

Reduced infectivity of waterborne viable but nonculturable Helicobacter pylori strain SS1 in mice.

BACKGROUND: Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of viable but nonculturable (VBNC) H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne VBNCH. pylori could cause gastric infection. MATERIALS AND METHODS: We performed five mouse experiments to assess the infectivity of VBNCH. pylori in various exposure scenarios. VBNC viability was examined using Live/Dead staining and Biolog phenotype metabolism arrays. High doses of VBNCH. pylori in water were chosen to test the "worst-case" scenario for different periods of time. One experiment also investigated the infectious capabilities of VBNC SS1 using gavage. Further, immunocompromised mice were exposed to examine infectivity among potentially vulnerable groups. After exposure, mice were euthanized and their stomachs were examined for H. pylori infection using culture and PCR methodology. RESULTS: VBNC cells were membrane intact and retained metabolic activity. Mice exposed to VBNCH. pylori via drinking water and gavage were not infected, despite the various exposure scenarios (immunocompromised, high doses) that might have permitted infection with VBNCH. pylori. The positive controls exposed to viable, culturable H. pylori did become infected. CONCLUSIONS: While other studies that have used viable, culturable SS1 via gavage or drinking water exposures to successfully infect mice, in our study, waterborne VBNC SS1 failed to colonize mice under all test conditions. Future studies could examine different H. pylori strains in similar exposure scenarios to compare the relative infectivity of the VBNC vs the viable, culturable state, which would help inform future risk assessments of H. pylori in water.

Animal Model Reveals Potential Waterborne Transmission of Helicobacter pylori Infection.

BACKGROUND: Helicobacter pylori infection has been consistently associated with lack of access to clean water and proper sanitation, but no studies have demonstrated that the transmission of H. pylori can occur from drinking contaminated water. In this study, we used a laboratory mouse model to test whether waterborne H. pylori could cause gastric infection. MATERIALS AND METHODS: Groups of immunocompetent C57/BL6 Helicobacter-free mice were exposed to static concentrations (1.29 × 10(5), 10(6), 10(7), 10(8), and 10(9) CFU/L) of H. pylori in their drinking water for 4 weeks. One group of Helicobacter-free mice was exposed to uncontaminated water as a negative control. H. pylori morphology changes in water were examined using microscopy Live/Dead staining. Following exposure, H. pylori infection and inflammation status in the stomach were evaluated using quantitative culture, PCR, the rapid urease test, and histology. RESULTS: None of the mice in the negative control or 10(5) groups were infected. One of 20 cages (one of 40 mice) of the 10(6) group, three of 19 cages (four of 38 mice) of the 10(7) CFU/L group, 19 of 20 cages (33 of 40 mice) of the 10(8) group, and 20 of 20 cages (39 of 40 mice) of the 10(9) CFU/L group were infected. Infected mice had significantly higher gastric inflammation than uninfected mice (27.86% higher inflammation, p < .0001). CONCLUSIONS: We offer proof that H. pylori in water is infectious in mice, suggesting that humans drinking contaminated water may be at risk of contracting H. pylori infection. Much work needs to be performed to better understand the risk of infection from drinking H. pylori-contaminated water.

Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey.

Introduction: Recent research suggests that psychedelics may have potential for the treatment of various substance use disorders. However, most studies to date have been limited by small sample sizes and neglecting to include non-North American and European populations. Methods: We conducted a global, cross-sectional online survey of adults (n = 5,268, 47.2% women) self-reporting past or current psychedelic use and investigated whether psychedelic use was associated with changes in use of other substances. Results: Nearly three-quarters (70.9%; n = 3,737/5,268) reported ceasing or decreasing use of one or more non-psychedelic substances after naturalistic psychedelic use. Among those with previous use, 60.6% (n = 2,634/4,344) decreased alcohol use, 55.7% (n = 1,223/2,197) decreased antidepressant use, and 54.2% (n = 767/1,415) decreased use of cocaine/crack. Over a quarter of the sample indicated that their decrease in substance use persisted for 26 weeks or more following use of a psychedelic. Factors associated with decreased use included a motivation to either decrease one's substance use or self-treat a medical condition. Importantly, 19.8% of respondents also reported increased or initiated use of one or more other substances after psychedelic use, with illicit opioids (14.7%; n = 86/584) and cannabis (13.3%; n = 540/4,064) having the highest proportions. Factors associated with increased substance use included having a higher income and residing in Canada or the US. Discussion: Although limited by cross-sectional study design, this large observational study will help inform future studies aiming to investigate the relationship between substance use patterns and psychedelic use.

Relationship Between Nociplastic Pain Involvement and Medication Use, Symptom Relief, and Adverse Effects Among People Using Medical Cannabis for Chronic Pain.

OBJECTIVES: Cannabis is increasingly being used for chronic pain management, but cannabis' effects remain poorly characterized in chronic nociplastic pain (NPP), which is posited to be caused by disturbances in nervous system pain processing. In this cross-sectional study (n=1213), we used the 2011 Fibromyalgia (FM) Survey Criteria as a surrogate measure for degree of NPP among individuals using medical cannabis for chronic pain. METHODS: Using a quartile-split, we investigated associations between the degree of NPP and medication use, cannabis use characteristics, and symptom relief. Continuous variables were assessed using one-way analysis of variance and categorical variables with Pearson χ 2 test and binomial logistic regression for calculation of odds ratios. RESULTS: Participants were predominately female (59%), with a mean ± SD age of 49.4±13.6 years. Higher FM scores were associated with less self-reported improvement in pain and health since initiating medical cannabis use, as well as more cannabis-related side effects. Paradoxically, higher FM scores were also associated with higher usage of concomitant medication use (including opioids and benzodiazepines) but also with substituting cannabis for significantly more medication classes, including opioids and benzodiazepines. DISCUSSION: This article presents evidence that individuals in higher NPP quartiles have higher analgesic intake, higher odds of substituting cannabis for medications, higher side effect burden, and lower therapeutic effect from cannabis. These seemingly contradictory findings may reflect higher symptom burden, polypharmacy at baseline, or that NPP may be challenging to treat with cannabis. Further research is necessary to further explain cannabinoid effects in NPP.

Protocol for a pragmatic trial of Cannabidiol (CBD) to improve chronic pain symptoms among United States Veterans.

BACKGROUND: Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD's analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD's effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). METHODS: We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). DISCUSSION: Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD's analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. TRIAL REGISTRATION: This protocol is registered at clinicaltrials.gov under study number NCT06213233.

Preferences and Support for Psychedelic Policies and Practices Among Those Using Psychedelics.

Legal, scientific, and social landscapes for psychedelics are changing rapidly. Differences of opinion exist among key stakeholders regarding regulatory control, models of provisioning psychedelic therapy, and medicalization, decriminalization, and/or legalization policies. We assessed the policy preferences of people using psychedelics naturalistically (N = 1221) to understand how they aligned and differed with institutional entities and existing psychedelic policies. Three quarters of participants would support decriminalization and legalization. On average, participants strongly supported individuals being legally able to grow and possess psychedelic plants and/or fungi for personal consumption. Trends included more support for natural over synthetic substances, self-production and consumption over gifting, gifting over sales, and administration of psychedelics with therapeutic support than without therapeutic support. Participants were concerned about pharmaceutical-like policy models, including patents of natural and synthetic psychedelic compounds. Participants were mostly from the State of Michigan, though geographical differences were minor. Those who identified as a psychedelic guide, educator, or therapist had small yet extensive differences from those who did not. As psychedelic liberalization continues to advance, it is critical for policymakers to consider these preferences to ensure laws provide safe and equitable access to these substances and appropriate medical support for their use.

"How Do I Learn More About this?": Utilization and Trust of Psychedelic Information Sources Among People Naturalistically Using Psychedelics.

There is a surge of interest in psychedelics, including new stakeholders and greater media attention. There is a need to examine the information-seeking behavior of people using psychedelics naturalistically, given the importance of preparation and harm-reduction. We examined sources of information for people using psychedelics naturalistically, and the degree to which they are trusted in a large, anonymous, online survey (N = 1221). The most common source of participants' information on psychedelics was their own experimentation and experiences (79.52%). Most also sought information from Internet websites (61.67%), friends (61.02%), Internet discussion forums (57.08%), books (57%), and articles in peer-reviewed scientific journals (54.55%). Few sought information from their primary health care provider (4.83%). Articles published in scientific journals, psychedelic nonprofits, and researchers based in colleges or universities were the most trusted sources of psychedelic information. Government agencies and pharmaceutical companies were the least trusted. Few participants thought that the popular media accurately stated the benefits and risks of psychedelics and most thought that the popular media failed to distinguish between different types of psychedelics. Our results indicate a high level of information seeking among psychedelic users, with a diverse array of information sources typically outside of mainstream health and medical care systems.

Knowledge, Perceptions, and Use of Psychedelics among Individuals with Fibromyalgia.

Fibromyalgia (FM) is a difficult to treat chronic pain condition for which there is strong interest in alternative treatments. There is growing interest in the potential of psychedelic substances (e.g., psilocybin) in conjunction with psychotherapy to treat chronic pain. Via a cross-sectional, anonymous, online survey, we aimed to characterize knowledge, perceptions, and past use of serotonergic ("classic") and non-serotonergic psychedelics among a population of individuals with FM, and to investigate interest in psychedelic-based FM treatments. Among a North American population of 354 participants with FM, 29.9% reported past use of a psychedelic, with lysergic acid diethylamide (LSD) and psilocybin mushrooms being most commonly used. Perceptions of benefit from psychedelic use were generally neutral (59.4%) or positive (36.8%), with <3% reporting negative impacts on overall health or pain symptoms. Among 12 participants who used psychedelics with intentions of treating chronic pain, 11 reported improved symptoms. Regardless of past use, the majority of participants believed that psychedelics have potential for chronic pain treatments and would be willing to participate in a psychedelic-based clinical trial for their pain. These findings support the need for additional studies to understand the potential and effectiveness of psychedelic substances in managing FM symptoms.

Naturalistic Psychedelic Use: A World Apart from Clinical Care.

Interest in and availability of psychedelics for therapeutic purposes has increased in recent decades. In a large, anonymous, online survey, we investigated patterns of communication with healthcare providers and awareness and utilization of substance testing kits or services among people using psychedelics naturalistically. The sample population included attendees of a psychedelic activism event and users of psychedelic social media forums. Among 1,435 participants, 72.5% never discussed psychedelic use with their primary care provider (PCP). Only 4.4% reported using psychedelics with a therapist and 3% in clinical settings, although 77.8% were very or extremely likely to take psychedelics with a therapist if one were legally available. While 62.6% of participants were aware of substance testing services, 42.6% of these indicated never using them. Regression analyses identified several variables associated with disclosure to PCP and utilization of substance testing services including age, gender, frequency and number of psychedelics used, and likelihood of consuming psychedelics under the guidance of a therapist if one were legally available. Further research is necessary to investigate these findings among other groups. Our findings suggest that relevant training and education for healthcare providers is needed, along with more visible options for substance identity testing.

An Assessment of Psychedelic Knowledge Among People Using Psychedelics Naturalistically.

Identifying gaps and strengths in psychedelic-related knowledge is key to developing effective, evidence-based education to inform appropriate use of and harm reduction practices for psychedelics in the naturalistic use landscape. The current study piloted an assessment instrument with questions on legal status, therapeutic potential, and side effects of psychedelics among people reporting current psychedelic use. We recruited participants (N = 1435) at a psychedelic advocacy event and through psychedelic interest groups on social media. Respondents completed a brief survey of psychedelic use and psychedelic knowledge. Items assessed basic knowledge of various topics surrounding psychedelics, such as legal status, active compounds, and known therapeutic efficacy based on the clinical trial literature. Respondents who had used greater numbers of different psychedelics, with higher levels of education, lower age, greater frequency of psychedelic use, identifying as male, used high doses (vs. microdosing only), identifying as Caucasian/White, and with greater annual household income answered more questions correctly. Most respondents exhibited high knowledge of psychedelics, though there is also a demonstrated need for education and outreach, especially in under-represented communities.

Slouching towards engagement: interactions between people using psychedelics naturalistically and their healthcare providers.

Introduction: There is substantial public interest in psychedelics as potential treatments for psychiatric conditions. However, most psychedelics are criminalized under federal law in the USA, so it is unclear whether use occurs with clinical support. Our objective was to assess whether naturalistic psychedelic use occurs with clinical support, interactions between those using psychedelics and healthcare providers (psychiatrist, therapist, or primary physicians), and use characteristics. Methods: We conducted an online, anonymous, confidential, cross-sectional survey of adults reporting psychedelic use (N = 1221) through a psychedelics advocacy event and social media between 9/18/2022 and 11/5/2022. We assessed participant disclosure of psychedelic use with their psychiatric care provider (PsyCP) and/or primary care provider (PCP), desire for provider support, access to support, and rate of taking prescribed psychoactive medications alongside psychedelics. Results: Among participants with such care providers, 22% disclosed psychedelic use to their PCP vs. 58% to their PsyCP. Participants were less confident in PCP vs. PsyCP ability to integrate psychedelics into treatment. Common reasons for nondisclosure included stigma, inadequate provider knowledge, and legal concerns. 23% reported taking psychedelics on the same day as potentially interacting psychiatric medications (e.g., anxiolytics, antidepressants). Despite 81% of participants desiring therapist support during psychedelic experiences, only 15% had received such support. Discussion: Our results show that psychedelic use is generally disconnected from primary and psychiatric clinical care. This disconnection may result in safety issues, including inadequate screening for contraindicated conditions, lack of support during emergent adverse events, and drug interactions. Enhanced clinical education and orienting drug policy towards known harms and benefits of psychedelics is needed.