Cannabis Grow

Low CD4 T cell count  was the dominant predictor of infectious pulmonary diagnoses in multi-variable analyses, yet the association between marijuana smoking and infectious pulmonary diagnoses remained significant in adjusted analyses restricted to visits with CD4 ≥ 200 cells/μl, and sensitivity analyses with no CD4 restriction. Tobacco smoking, reported during follow-up for 44% of HIV+ participants, was a stronger risk factor for chronic bronchitis in HIV+ participants compared to marijuana smoking, while for infectious pulmonary diagnoses in HIV+ participants, the risk associated with ≥1/2 pack/day tobacco smoking was comparable to that of daily or weekly marijuana smoking.Strengths of this study included the large sample size, large number of diagnoses reported, and substantial length of follow-up.Men at risk for HIV are recruited by the MACS from four U.S. urban sites, and thus HIV-infected participants share similar demographic and lifestyle characteristics with uninfected participants. HIV+ and HIV− participants reported substantial daily or weekly marijuana smoking,which allowed assessments of both current and average exposures during follow-up. The sample size allowed for stricter control of tobacco smoking with large numbers of participants in stratified analyses,which may in part explain the lack of association between marijuana smoking and pulmonary disease among HIV− individuals found here compared to previous studies. Injection drug use is a possible risk factor for lung disease among HIV-infected persons, and poly drug use is common in HIV-infected individuals, and we therefore excluded heavy cocaine and heroin users from our analysis to reduce the potential for competing risks from multiple inhaled or injected substances. Limitations of this study include those inherent to longitudinal prospective cohort studies, including the potential for findings to be specific to MSM populations recruited by the MACS, and for nonrandom dropout and ascertainment biases.

Measures of cannabis grow tent intake were limited to self-report during follow-up, with limited detail regarding exposure prior to MACS enrollment or marijuana potency, source, or quantity. These concerns are mitigated in part by the use of three separate measures of marijuana smoking,all of which were associated with infectious pulmonary diagnoses and chronic bronchitis in models of HIV-infected participants. Furthermore, the proportion of daily or weekly HIV+ marijuana smokers here  is comparable to reports from other U.S. cohorts of HIV-infected individuals.The use of self-reported pulmonary symptoms and diagnoses is an additional potential source of bias, and possible under-representation of specific non-infectious diagnoses in the MACS, particularly COPD and pulmonary hypertension, has been reported. Most diagnoses were not assessed from both self-report and ICD-coded sources. This limitation was mitigated in part because most diagnoses were obtained from ICD code data, which consists of more specific diagnosis classifications.Potential ambiguities regarding terminology for diagnoses, and discordance between highly prevalent pulmonary symptoms and low rate of pulmonary diagnostic testing among HIV-infected persons has been noted in other clinical settings, and is mitigated here in part by use of composite diagnoses. The number of diagnoses reported for several categories, including tuberculosis, lung cancers, and Pneumocystis pneumonia, was small and lacked statistical power to assess an adjusted association with marijuana or tobacco smoking. In summary, we found a significant association between long-term marijuana smoking and risk of infectious lung disease and chronic bronchitis in HIV-infected men on ART, independent of tobacco smoking and other risk factors.In contrast, we detected no association between marijuana smoking and lung disease among HIV-uninfected men while controlling for tobacco smoking and other demographic characteristics. These findings suggest that marijuana smoking is a modifiable risk factor that healthcare providers should consider when seeking to prevent or treat lung disease in people infected with HIV, particularly those with other known risk factors including heavy tobacco smoking, and low CD4 T cell count or advanced HIV disease.

Given increasing trends of regular marijuana smoking among HIV-infected people and other high-risk populations in the U.S. and other developed and developing countries, more studies are needed to evaluate potential merits of non-smoked rather than smoked forms of marijuana for medicinal and other purposes.Ms. A, a 48-year-old woman with a history of cholecystectomy complicated by bile duct stricture and multiple hepatic abscesses and liver failure was evaluated for an orthotopic liver transplant. She had a psychiatric history of depression and anxiety, with a brief inpatient hospitalization after cutting her wrists 6 months before her transplant. She then had 1 month of outpatient therapy. During a pretransplant psychiatric evaluation, she reported no illicit drug use. Outpatient medications included opioid analgesics and cyclobenzaprine for pain, as well as zolpidem for insomnia secondary to abdominal pain. Ms. A was admitted to the hospital and received a trisegmental orthotopic liver transplant. She was monitored postoperatively in the surgical intensive care unit and started on 2 agents for immunosuppression  as well as broad spectrum antibiotics and anti-fungal agents. The pain management service was consulted for postoperative pain control given her dependence on opioid analgesia as an outpatient. Per their recommendations, she was started on a hydromorphone PCA.Her transaminases and coagulation studies were reassuring and she was stable enough to be transferred out of the intensive care unit on post-transplant day 3. That same day, she was started on tacrolimus at 2 mg q12 hours. A serum tacrolimus level taken the next morning was 7.7 ng/mL which was at goal. On post-transplant day 5, the transplant psychiatry service was consulted for agitation and deliriumspecifically, she was oriented only to herself, had disorganized speech, was observed to be responding to internal stimuli  and was exhibiting psychomotor agitation in the form of purposeless shifting and fidgeting.

Her vital signs were significant for tachycardia and absence of fever. Laboratory testing revealed a significant increase in her tacrolimus level to 17.2 ng/mL despite no changes in dosing. Labs were otherwise stable.Ms. A’s encephalopathy was felt to be secondary to tacrolimus toxicity, though the reason for the change in the tacrolimus level was initially unclear. Her tacrolimus was held and the psychiatry team recommended low-dose quetiapine as needed for agitation to avoid use of restraints and to mitigate the risk of decannulation or removal of other lines. Later that night, Ms. A’s tachycardia, disorientation, and confusion worsened, and she required 2 doses of IV haloperidol. By post-transplant day 7, her encephalopathy began to resolve, with improving orientation and less psychomotor agitation. Her serum tacrolimus level was downtrending to 7.3 ng/mL and she was restarted at a dose of 1 mg q12 hours. At this time, Ms. A’s family mentioned that as her preoperative pain was poorly controlled by various opioids, she had sought pain management from a medical marijuana clinic in a neighboring state where medical marijuana was legalized. A urine drug screen confirmed her use of cannabinoids. Ms. A produced a bottle of medical marijuana lozenges from her purse at the bedside. The bottle indicated that each lozenge contained 10 mg of tetrahydrocannabinol and 1 mg cannabidiol. She had filled the bottle 10 days before admission, and reported taking 24 lozenges per day up until her transplant, though she denied taking any during admission. She denied any other previous marijuana use. On post-transplant day 9, her level was stable at 3.4 ng/mL and her dose was titrated to 2 mg q12 hours. Ms. A was advised to discontinue cannabis usage due to concern for drug-drug interactions. Her postoperative care was uncomplicated by subsequent mental status issues. Her tacrolimus dosage remained stable at 3 mg po q12 and her level remained at goal, most recently 7.4 mg/mL.Marijuana is the most commonly used illicit substance in the US. In the past decade alternative formulations of its active ingredients have been adopted in many states for the treatment of various medical conditions, including chronic pain.In this case, our patient was seen in a medical marijuana clinic by a pain specialist who was registered with the New Jersey Medical Marijuana Treatment Program.

Under this program, patients must be found to have an “approved debilitating medical condition” that has either been demonstrated to be treatable by cannabis or has not responded to conventional treatment. Our patient met criteria for “chronic pain of visceral origin.” She was able to obtain the lozenges at a licensed dispensary affiliated with her doctor’s office. Anecdotal reports of marijuana use leading to decreased reliance on opioid pain medications have led to new investigations into its analgesic effects. One case study from 2016 described the use of marijuana to wean opioid use in a patient who had received an orthotopic liver transplant.Additionally, while many proponents of marijuana’s analgesic properties distinguish between the potential therapeutic effects of its 2 major ingredients, tetrahydrocannabinol and cannabidiol, it is unclear whether their pharmacokinetics differ meaningfully.In vitro studies have demonstrated tetrahydrocannabinol and cannabidiol to be CYP 3A4 substrates and there is some evidence that they act as inhibitors as well.A case report from 2006 described myocardial infarction in an otherwise healthy 41-year-old man after concomitant use of sildenafil and grow lights for marijuana, thought to be due to 3A4 inhibition.Additionally, constituents in marijuana have been shown both to inhibit or induce P-glycoprotein, which could then interfere with the absorption and distribution of medications like tacrolimus.As mentioned above, the resultant variability in tacrolimus levels not only leaves the potential for neurotoxicity, but it is also associated with worse graft survival.The evaluation and treatment of encephalopathy in post-transplant patients are similar those for delirium in the general postoperative patient, with the additional consideration of immunosuppression as a unique factor. While haloperidol and quetiapine are 3A4 substrates, they are not known to interfere with the metabolism of tacrolimus, and their metabolism is not impaired in patients with poor liver function when used conservatively. There is a case report of QT interval prolongation leading to arrhythmia in a patient receiving both tacrolimus and haloperidol, though tacrolimus is less likely to prolong QT independently when compared to other immuno suppressants.

The increased prevalence of both recreational and medical marijuana use represent challenges to safe immunosuppression in post-transplant patients. Since medical marijuana is not consistently monitored between states and is not thought of universally as a legal medication, it can easily be overlooked as part of medication reconciliation. Additionally, as medical marijuana therapy remains a controversial topic among providers, there is significant stigma attached to its use.In one study, 10.4% of transplant candidates used cannabis, and were found to be less likely to receive a transplant despite similar survival rates to those who did not.The perception that disclosing marijuana use  could hurt her chances at receiving a transplant was likely a factor in our patient not disclosing it to her transplant team. Emerging research on cannabinoids suggest that they offer immunosuppressive effects independently which further complicates their use in patients where tightly controlled immunosuppression is necessary for healthy recovery.Marijuana use is widespread and increasing. In the 2015 National Survey on Drug Use and Health, 8.3% of respondents said that they had used marijuana in the past month. As of April 2018, 30 states, the District of Columbia, Guam and Puerto Rico had passed medical marijuana laws permitting programs public medical marijuana. The total number of medical marijuana patients is unknown but estimates place the number at greater than 2 million patients in the United States. Marijuana refers to the dried leaves and flowers of the Cannabis sativa plant, which are rich in phytocannabinoids. The plant is grown either indoors or outdoors before it is harvested, cured, and dried. Molds may be present and can multiply under conditions of high moisture as with inappropriate watering, humidity or ventilation or inadequate drying and curing. Mold spores may survive the drying and curing process even under ideal conditions.Marijuana obtained from medical dispensaries does not differ significantly with regards to microflora when compared to illicit marijuana. One analysis of twenty marijuana samples obtained from dispensaries in northern California showed the presence of 20 fungal genera including Aspergillus, Cryptococcus, and Mucor as well as several bacterial pathogens such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Previous case reports have documented cases of pulmonary aspergillosis associated with marijuana smoking in immunocompromised patients.

The coding categories used in this study may raise questions about the results in terms of validity and reliability. Thus, future studies should test the same categories that this study used and then develop more correct coding categories. Lastly, the time period for this study was between 1995 and 2014. Although marijuana was initially legalized in 2012, the first recreational sales were in 2014. Thus, news stories during 2014 could be quite different than stories from previous years.Substance use among young adults is a major public health concern and is associated with academic problems. The bulk of research in this area has focused on undergraduate students, as alcohol and marijuana use among this population are fairly common.In addition to academic difficulties, alcohol and marijuana use are associated with other negative consequences during the college years, including risky sexual behaviors, social and interpersonal problems, injury, and impaired driving.Longitudinal research has shown that alcohol and marijuana use during college might have long-term consequences after college graduation. Heavy drinking and marijuana use during college are associated with post-college substance abuse and dependence, unemployment, less prestigious employment, and lower income.Marijuana use during college and the immediate post-college years, particularly heavy use, is associated with several negative health outcomes at ages 24 and 27, including emotional problems, injury, illness, decreased quality of life, and less service utilization for physical and mental health problems.

Degree non-completion as a consequence of substance use has been found in longitudinal studies of high school and college students. Adolescents who use alcohol, tobacco, and cannabis grow tray during ninth grade are less likely to complete high school than nondrug users.One study integrated data from three longitudinal studies and found that daily marijuana use during adolescence was significantly associated with decreased odds of both high school and college completion.In a study of college students, frequent marijuana use during the course of college was associated with increased likelihood of dropping out.Despite evidence of associations between alcohol and marijuana use and high school and undergraduate degree non-completion, the possible impact on graduate degree completion has not been explored. An increasing number of college graduates are enrolling in graduate school, with almost 40% of college graduates pursing a graduate degree within four years of graduation.However, only 50% to about 75% of those who enter graduate school ultimately complete their degree, with differences by degree type and academic discipline.Existing theories of student attrition, centered primarily on the undergraduate student experience, posit that attrition is influenced by individual, institutional, and social factors.Institutional factors include program characteristics, administrative policies, and academic requirements, and social factors include peer culture, faculty/staff interactions, and social integration. Individual pre- and post-matriculation factors include demographic characteristics, skills and abilities, goals and expectations, external commitments, and academic history. Largely missing from theories of student attrition are health status and health behaviors, particularly substance use prior to and after enrollment in an academic degree program. The relationship between alcohol and marijuana use and graduate degree completion is likely influenced by demographic characteristics. Both heavy drinking and marijuana use are more prevalent among college males than females,and substance use disorders are associated with being male, white, and unmarried.Having children is associated with a lower prevalence of substance use among both men and women.

Demographic characteristics are also associated with graduate school completion, with burnout and attrition highest among women.Attrition is also more common among African-American/Black students,domestic students,and students enrolled in master’s degree programs.This study aimed to fill a gap in the literature by assessing the relationships between alcohol and marijuana use before and after graduate school enrollment and graduate degree completion. It is hypothesized that lower levels of alcohol and marijuana use both before and after graduate school enrollment are associated with graduate degree completion after adjustment for potentially confounding variables.Alcohol use was measured annually in Y1-Y12. To assess frequency of alcohol use, participants were asked, “In the past 12 months, on how many days have you drank any drink with alcohol in it?”. To assess quantity of alcohol use, participants were asked the number of drinks they had on a typical drinking day.Data on days used during the past year were used to estimate average alcohol use frequency  for descriptive purposes. Marijuana use frequency was assessed annually in Y1-Y12 with the question “In the past 12 months, on how many days have you used any type of marijuana?”.Data on days used during the past year were used to estimate average marijuana use frequency  for descriptive purposes. Past-month frequency of both alcohol and marijuana use were also assessed, but because of the high degree of correlation with past-year measures,only past-year variables were used in the analyses. For each participant, alcohol use frequency, alcohol use quantity, and marijuana use frequency were averaged separately for each of two time periods: before and after the first year they indicated enrollment in a graduate degree program. The mean for each of the six separate variables  was used to capture variation in substance use during the pre- and post-enrollment periods, particularly because the before enrollment period included the undergraduate college years as well as the interim years after college graduation but before graduate school enrollment.

Descriptive statistics  were used to analyze the distributions of all study variables. Pearson correlation coefficients were used to analyze the relationships between all six alcohol and marijuana use predictor variables. A series of logistic regression models were fit to assess the relationships between alcohol and marijuana use and graduate degree completion. First, in Stage 1, separate logistic regression models were fit to analyze the relationships between each alcohol and marijuana use predictor variable and graduate degree completion while controlling for demographic and program characteristics. Second, in Stage 2, a best fitting model was obtained by entering each of the six alcohol and marijuana use predictor variables into the model one at a time, retaining any predictor variable that was statistically significant and dropping those that were not significant. All demographic and program characteristic variables were retained in the final model regardless of significance. The Nagelkerke R2 value was used to examine the variance in graduate degree completion explained by the Stage 2 variables. A similar method has been used in prior work by the research team.SPSS Version 24.0 was used for all analyses, and the alpha level was set at 0.05.The majority of participants drank alcohol during at least one year before graduate school enrollment  and after graduate school enrollment.Among drinkers, the average alcohol use frequency was about 75 days during the past year before enrollment in graduate school and 88 days during the past year after enrollment.Among drinkers, mean alcohol use quantity decreased from a mean of 3.9 drinks per drinking day before graduate school enrollment to 2.6 drinks per drinking day after enrollment. The typical quantity consumed for male drinkers was greater than female drinkers both before and after graduate school enrollment.Based on past-year data, it was estimated that about 35% of drinkers drank less than weekly and about 24% drank twice a week or more before graduate school enrollment. After graduate school enrollment, 32% of drinkers drank less than weekly and about 31% drank twice a week or more.The prevalence of marijuana use was 72% prior to graduate school enrollment and 49% after graduate school enrollment. As seen in Table 2, marijuana use frequency among users was about the same prior to and after graduate school enrollment with a mean of about 40 days during the past year.

Among those who used marijuana prior to graduate school enrollment, 56% used once a month or less and about a quarter used at least weekly.Among those who used marijuana after graduate school enrollment, 64% used once a month or less and about 18% used at least weekly.The correlations between the six alcohol and marijuana use predictor variables are presented in Table 3. There were moderate to strong correlations between the before enrollment estimates and the after enrollment estimates. Despite this statistical overlap, both before and after enrollment variables were retained due to their importance to the research question of interest. Alcohol use frequency before graduate school enrollment was strongly correlated with alcohol use quantity before graduate school enrollment  and moderately correlated with alcohol use quantity after graduate school enrollment.To avoid the potential for multicollinearity effects on the statistical models, only the alcohol use frequency variables were retained for further analyses. There is prior evidence that frequency of alcohol use increases during the post-college period while quantity of alcohol use decreases,and alcohol use frequency has higher sensitivity and specificity in identifying alcohol-related problems than alcohol use quantity .This study examined whether or not alcohol and marijuana use before and after graduate school enrollment were associated with graduate degree completion. Alcohol and marijuana use were moderate among participants in this sample. Results showed that more frequent marijuana use after graduate school enrollment was associated with decreased odds of graduate degree completion after adjustment for potentially confounding variables. This finding is consistent with prior research that has shown a relationship between frequent marijuana use and degree non-completion among high school and undergraduate college students.Marijuana use was less prevalent after graduate school enrollment as compared with before, vertical grow systems for sale which is consistent with research showing that marijuana use declines as young adults age.However, while past-year marijuana use frequency among marijuana users who completed their graduate degree declined from 40 days before enrollment to 35 days after enrollment, frequency among users who did not complete their graduate degree increased from 45 days before enrollment to 85 days after enrollment.

The first is through decreased academic performance, with underachievement cited as the most well-supported correlate of marijuana use.While little research has been done on the relationship between marijuana use and decreased academic performance among graduate students, existing evidence among high school and college students shows that frequent marijuana use is associated with academic unpreparedness,lower grades,and lower academic achievement.The relationship between marijuana use and degree non-completion might also be explained by the effects of marijuana use on cognition.Verbal learning, memory, executive functioning, IQ, and attention, which are critical for academic success, are impaired by both acute and chronic exposure to marijuana.Arria, Barrall, Allen, Bugbee, and Vincent  suggest that the immediate, rewarding effects of substance use might lead to a re-prioritization of academic pursuits that are associated with longer-term rewards. This study also observed a positive relationship between alcohol use frequency prior to graduate school enrollment and graduate degree completion. There is evidence that alcohol use is associated with dropout from both high school  and college.However, some research has suggested that students who drink more frequently might be more likely to engage in the academic environment and elicit social support.Molnar, Busseri, Perrier, and Sadava  found a prospective relationship between alcohol use and higher levels of subjective well being among college students, and Blank, Connor, Gray, and Tustin  found increased self-efficacy among college students who consumed alcohol. Existing longitudinal studies have found paradoxical effects between alcohol use and education,highlighting the complex relationship between alcohol use and academic success and calling for increased research in this area. The present study findings should not be misinterpreted to mean that excessive drinking is associated with graduate degree completion, as the vast majority of the students in this sample were light to moderate drinkers. A strength of this study was the use of longitudinal cohort data spanning twelve years of young adulthood. However, because the sample was originally enrolled in a single, large publicly-funded university, findings might not be generalizable to young adults starting their college career in different types of educational institutions. The present sample was somewhat homogenous with respect to demographic characteristics. Further research with larger, more diverse samples is needed to explore the associations between demographic variables and developmentally-salient variables, such as having children, on graduate degree completion. Additionally, graduate degree completion among this sample was 82%, which is higher than the national average of around 65%.Completion of a graduate degree was only analyzed through Y12, and students might have completed their graduate degree later on in adulthood. This study also did not account for several factors that might have influenced graduate degree completion, including academic ability, mental health, motivational factors, employment opportunities, personality, academic goals, external commitments, institutional factors, and social and professional support.

Alcohol intoxication is a common comorbidity in traumatic brain injury,with 30%–50% of all TBIs occurring under the influence of alcohol. Preclinical studies have indicated that ethanol pretreatment results in a faster recovery with better outcomes after TBI. However, numerous clinical studies have examined the relationship of alcohol exposure and risk of mortality in patients with TBI with inconsistent results: some studies have found a positive blood alcohol content  had no significant relationship with mortality, while others have found that mortality rate due to TBI with alcohol intoxication is lower compared to those without alcohol intoxication. Additionally, marijuana has been implicated as a major risk factor for all types of trauma. The anti-inflammatory properties of endocannabinoids have been demonstrated to provide neuroprotective effects after TBI. A previous study found a positive tetrahydrocannabinol screen to be independently associated with survival after TBI. While the risk of injury from alcohol,marijuana,and other drugs in combination is increased,the neuroprotective effects of combined marijuana and alcohol have not yet been studied. Few studies have determined the effects of combined drug use on mortality after TBI, and the relationship of combined alcohol and THC on TBI outcomes remains unknown.The aim of this study is to use a data-set of regional data from 26 regional hospitals to evaluate the combined effects of a positive THC and alcohol screen on patient outcomes after sustaining mild, moderate, and severe traumatic brain injury.

Our results demonstrate TBI patients with a positive toxicology for THC and alcohol were found to have significantly lower mortality at discharge when compared to patients with no substances.However,mobile vertical rack in a multiple logistic regression, combined BAC and drug class were not found to be independent predictors of mortality at discharge, while age, GCS, ICU days, ISS, and LOS were found to be independent predictors of mortality. Though somewhat contested, the effect of alcohol intoxication on patients with TBI has been shown in many studies to improve mortality. A meta-analysis of observation studies by Raj et al. included 11 studies with 95,941 patients, and found that positive BAC was significantly associated with lower mortality rates in moderate to severe TBI. Conversely, a meta-analysis examining the impact of day-of-injury alcohol consumption on outcomes after TBI by Mathias et al., found that positive blood alcohol levels were associated with significantly poorer cognitive outcomes and higher levels of disability. Overall, they found that day-of-injury alcohol consumption is not consistently associated with better or worse outcomes, other than subtle cognitive deficits. The effect of marijuana on TBI is far less studied than alcohol, though many preclinical studies have shown THC is associated with neuroprotective effects including alleviation of brain edema, attenuated cell apoptosis, improved neurobehavioral function, and enhanced cerebral blood flow. These effects are partially attributed to the upregulation of NFE-2 factor, which regulates the cellular antioxidant response, following TBI and modulation of the mitochondrial apoptotic pathway. A study by Nguyen et al. found that after adjusting for differences between study cohorts, a positive THC screen was found to be associated with increased survival after TBI. With the individual effects of alcohol and marijuana on TBI still contested, their combined effects on mortality have not been explicitly studied.

DiGiorgio et al. investigated the impact of drug and alcohol intoxication on GCS assessment in patients with TBI, and found that intoxicating substances can confound GCS score with impaired patients having a significantly higher mean change in GCS score compared with patients with a negative screening test. A retrospective review by O’Phelan et al. studied the impact of substance abuse on mortality in patients with TBI by comparing amphetamine, benzodiazepine, narcotic, cannabis, cocaine, alcohol, polydrug, and polydrug, excluding alcohol, and found that methamphetamine use was a significant predictor of mortality. They also demonstrated that patients who tested positive for methamphetamine were also more likely to test positive for cannabis and hypothesized the synergistic effects of methamphetamine and THC may have contributed to overall lower mortality in this cohort. In our study we employed a logistic regression model that controlled for age, gender, GCS, ICU days, LOS days, ventilator days, ISS, and complications and found neither THC nor a positive BAC screen to be independent predictors of mortality, which is consistent with the analysis by O’Phelan et al.Over the last decade, marijuana use and the legalization of marijuana, medically and recreationally, has continued to increase in the United States.1 The internet is rife with claims of the beneficial effects of marijuana on several aspects of sexual function including libido, arousal, and orgasm. However, our scientific research on the effects of marijuana on sexual functioning is limited. Recently Palamar et al2 evaluated self-reported sexual effects of marijuana, ecstasy, and alcohol use in a small cohort of men and women aged 18e25. They found that the majority of marijuana users reported an increase in sexual enjoyment and orgasm intensity, as well as either an increase or no change in desire.2 Endocannabinoids, which are structurally similar to marijuana, are known to help regulate sexual function.3 The cannabinoid receptor, discovered in the 1990s, has been mapped to several areas of the brain that play a role in sexual function.3 Cannabinoids and endocannabinoids interact with the hormones and neurotransmitters that affect sexual behavior. Although these interactions have not been clearly illuminated, some studies in rodents have helped to clarify the relationship between cannabinoids and the hormones and neurotransmitters that affect sexual behavior.Although there is less data on human subjects, some studies have measured patient’s perceptions of the effects of marijuana on sexual function. Studies have reported an increase in desire and improvement in the quality of orgasm.

Most recently, Klein et al6 evaluated the correlation between serum levels of 2 endogenous endocannabinoids and found a significant negative correlation between endocannabinoids and both physiological and subjective arousal in women. Sumnall et al7 reported that drugs such as cannabis and ecstasy were more frequently taken to improve the sexual experience than was alcohol. The primary aim of this study was to determine how women perceive the sexual experience, specifically overall sexual satisfaction, sex drive, orgasm, dyspareunia, and lubrication, when using marijuana before sex. The magnitude of the change was also evaluated. The secondary aim sought to understand the effect of the frequency of marijuana use, regardless of marijuana use before sex, on satisfaction across the different sexual function domains.Women were enrolled prospectively from a single, academic, obstetrics and gynecology practice from March 2016eFebruary 2017, and their data were retrospectively reviewed. The protocol was approved by the Institutional Review Board. Eligibility criteria consisted of being a female, 18 years of age, and presenting for gynecologic care irrespective of the reason. Each participant completed a confidential survey, including demographic data without unique identifiers after their visit, which was placed in a sealed envelope and dropped in a lock box at the clinic. The Sexual Health Survey was developed for the purpose of this study based on the aims of the study. There are several validated tools for evaluation of sexual function. The Female Sexual Function Index 8 assesses several domains of sexual function, but it does not address specifically marijuana or other substance usage. The Golombok Rust Inventory of Sexual Satisfaction 9 specifically relates to vaginal intercourse, but, for purposes of this study, sexual activity was deliberately left open-ended and not restricted to vaginal penetration. In addition, the goal was not to measure whether women had sexual dysfunction, which the FSFI addresses, but to assess basic questions regarding overall sexual activity. To limit bias, the authors embedded the questions about marijuana deeper into the questionnaire.

If these specific questions had been added to the standard FSFI, there was concern that the questionnaire would have been too long and that the patients would get questionnaire fatigue and not finish or answer thoughtfully. Measurement of marijuana use before sex was dichotomized as yes or no. The exact timing of marijuana use in relation to sex was not defined, and the majority of users were smokers of marijuana. For purposes of the study, groups consisted of non-marijuana users, marijuana users before sex, and marijuana users who didn’t use before sex. Patients reported their usage as several times a day or week or year, once a day, week or year and less than once a year. For purpose of analysis, frequency of marijuana use was measured by dichotomizing into frequent  and infrequent .In our study, the majority of women who used marijuana before sex reported positive sexual effects in the domains of overall sexual satisfaction, desire, orgasm, and improvement in sexual pain but not in lubrication. Women who used marijuana before sex and those who used more frequently were more than twice as likely to report satisfactory orgasms as those who did not use marijuana before sex or used infrequently. Our study is consistent with past studies of the effects of marijuana on sexual behavior in women. In the above-mentioned study by Palamar et al,2 38.6% of respondents were women. Participants were asked questions similar to this study’s questions regarding sexual domains, including sexual enjoyment, desire, and orgasm intensity and how these were affected by being under the influence of marijuana. The majority of respondents noted an increase in sexual enjoyment  and orgasm intensity,whereas 31.6% noted an increase in desire, and 51.6% noted no difference.2 Our data showed a higher percentage of participants reporting improvements in each domain across the board. However, vertical grow rack their data included both men’s and women’s responses, and their questions were worded differently. Dawley et al10 evaluated a group of marijuana using students  and found that marijuana smokers reported increased sexual pleasure, increased sensations, and increased intensity of orgasm. Only more-frequent users felt that marijuana was an “aphrodisiac,” a surrogate measure of desire. This study included only 22% women.10 Finally, Koff11 evaluated sexual desire and sexual enjoyment after marijuana use in women via a questionnaire. The majority of the female respondents reported that sexual desire was increased.

Sexual enjoyment increased 42.9% of the time.11 Interestingly, Sun and Eisenberg12 reported a higher frequency of sexual activity in marijuana users, even when controlling for multiple variables.The authors surmise from their data that marijuana use does not seem to impair sexual function. However, it is important to note that marijuana use may be harmful. Our study provides an interesting insight into women’s perceptions of the effect of marijuana on the sexual experience. It differs from other studies in that it is one of the largest series to date and has a wider range of ages. It also differed in that it was a cross-section of healthy women presenting for routine gynecologic care, where most studies target younger patients and include both sexes. For this reason, it is difficult to directly compare the studies, because the sexual activity, frequency, and expectation of these groups may be very different. However, we believe it is important to understand the potential effect in this patient population. The question of how marijuana leads to these positive changes in sexual function is unknown. It has been postulated that it leads to improvement in sexual function simply by lowering stress and anxiety.It may slow the temporal perception of time and prolong the feelings of pleasurable sensations.It may lower sexual inhibitions and increase confidence and a willingness to experiment.7 Marijuana is also known to heighten sensations such as touch, smell, sight, taste, and hearing.Although this was not specifically addressed in this article, according to Halikas et al,the regular female marijuana user reported a heightened sensation of touch and increased physical closeness when using marijuana before sex. It is postulated that marijuana works through a variety of mechanisms. It is recognized that marijuana and the hypothalamic-pituitary-gonadal axis, which controls the sex hormones, interact with each other. There are cannabinoid receptors in the hypothalamus that regulate gonadotrophinreleasing hormone and oxytocin release, both of which play a role in normal sexual functioning.In addition, marijuana has been shown to affect testosterone levels, which play a role in sex drive, but how and in which direction in women is unclear.Female sexual function is not only regulated by hormones, but also by centrally acting neurotransmitters, such as dopamine and serotonin.

In some countries, such as Spain, only cannabinoid-based preparations are approved for select diseases , while other countries, such as Germany or UK, have established a more liberal approach, which allows physicians to prescribe unprocessed herbal cannabis for certain illnesses. Based on a growing body of evidence supporting the therapeutic potential of cannabis, the World Health Organization recommended that cannabis should be rescheduled in order to facilitate medicinal regulations in member states. With some delays, the rescheduling was carried out in December 2020 by the United Nations Commission on Narcotic Drugs. It is now reasonable to expect more European countries to follow this decision and legalise unprocessed herbal cannabis for medical purposes. Moreover, in light of the liberalisation of cannabis policy in North America, the option of recreational legalisation is broadly discussed in many European countries . In fact, Luxembourg announced a decision to legalize the sale of cannabis for recreational use in 2019. In the same year, the Netherlands passed a controlled cannabis supply experiment bill which will evaluate the impact of legalising the supply of cannabis for recreational use in an experimental design. Lastly, legislative changes towards decriminalization have been implemented in 2001 in Portugal and more recently in Czechia. In order to provide a strong empirical framework for assessing the health effects of changes in cannabis policy in Europe,trimming tray weed rigorous public health monitoring of cannabis in Europe is crucial.

Currently, public health monitoring of adult cannabis use is carried out by two international bodies that routinely collect and publish data on several cannabis indicators, including prevalence of use, treatment rates, and potency levels. First, the United Nation Office on Drugs and Crime collects annual data on prevalence of illegal drug use as well as further drug-related indicators from all UN member states . In their annual “World Drug Reports”, these data are summarized at the regional as well as global level. Second, the European Monitoring Centre for Drugs and Drug Addiction the responsible body for monitoring illegal drug use and drug addiction in Europe compiles a number of cannabis related indicators, which also serve as base for the annual European Drug Reports. In addition to these two agencies collecting empirical data on cannabis, the GBD study routinely estimates the prevalence of CUD for all countries. In the current contribution, we extracted and analysed cannabis indicator data from publicly available sources, including prevalence of use, prevalence of cannabis use disorder , treatment rates, and potency of cannabis products in Europe. We aimed to describe the trends of these indicators for the period 2010 to 2019 and the possible public health implications. Further, we aimed to highlight limitations in the available data, in order to identify the steps required to improve current practice in monitoring of cannabis use and harm in Europe.The treatment demand indicator reflects information about the number and the profile of people who enter treatment for drug problems each year. A uniform protocol guides EMCDDA member states to collect the required data in a comparable way across all countries. For the formal TDI definition and further methodological details, see Supplemental Material 1. For interpreting TDI data, variations in coverage of treatment entries between countries and over time need to be taken into consideration. We attempted to consider differences in coverage of TDI data, i.e., the share of all relevant treatment units covered by the indicator, between country and over time.

However, a complete assessment of TDI coverage is not available but the most recent report for the year 2014 marks substantial cross-country differences in the TDI coverage rates from 60% to 100% for out-patient treatment centers and from 30% to 100% for in-patient treatment centers. To further elaborate on TDI coverage variations, we examined how the number of treatment units covered by the TDI differs between countries and developed over time .EMCDDA member states monitor and report cannabis potency according to the total concentration of delta-9-tetrahydrocannabinol in sample weight, to the nearest 0¢1%. For the current analyses, we obtained the median THC levels in herbal cannabis and resin. In contrast to survey and TDI data, the EMCDDA does not disclose any details on the underlying sources of THC data per country and year. While the THC data aim to be representative of the retail level, the agency acknowledges several methodological limitations that might render some data not representative. It can be assumed that the presented data are predominantly obtained from a sample of police seizures of cannabis. For Germany, THC data were corrected and completed by the respective EMCDDA focal point.We reviewed UNODC data but could not identify any cannabis-related indicators relevant for public health monitoring that are not already captured by the EMCDDA data collection. In fact, both agencies collect data on prevalence of use and on treatment rates. However, we chose to refer to EMCDDA data for the following reasons: the UNODC ‘general population’ prevalence database does not include information on the age range of the target population or exact references. Further, it contains several estimates derived from the school survey initiative ESPAD, which should not be reported as general population estimates.

As for TDI, we compared data from UNODC and EMCDDA for 2017 for 16 countries with data available in both data bases. For any drug treatment, data were only consistent in half of the countries. Further, treatment demand for CUD was only reported as percentage of all treatment demand in the UNODC data base, requiring recalculations and additional assumptions to report CUD treatment rates. Based on this assessment, we restricted our analyses to data provided by the EMCDDA.Data on CUD prevalence including uncertainty intervals by 5-year age bands were retrieved from the GBD study for the years 2010 to 2019. In the GBD study, CUD is defined by ICD-10 or DSM-IV criteria for cannabis dependence and prevalence estimates are based on school and adult survey data. In brief, cannabis use prevalence estimates were first converted into regular use estimates and then into CUD estimates. The first conversion ratio was determined using a meta-analytical approach, resulting in a factor of 2¢9 . The second conversion ratio was determined using a Bayesian meta-regression, which accounted for risk differences between youth and adults. For more details on the estimation of CUD, see supplement of .All available data were retrieved from the indicated data sources, however, for prevalence of use, potency and TDI, data were missing for some countries and years. To obtain country- and year-specific CUD estimates for the 15 to 64 year old target population, age-specific data were aggregated using UN population data. Using TDI data, treatment rates, expressed as the number of treatment entries per 100,000 adults were estimated. We calculated the share of daily users among past-month users as an indicator for high-risk consumption patterns for countries with available data. This indicator sheds light on differences in use patterns between countries.

To obtain European averages across all countries with available data, population-weighted means of the indicators were calculated using UN population data. For THC concentrations, weighted averages would have required to account for the respective share of both resin and herbal cannabis in total use per country, however, these data were not available. Thus, we aggregated the country-level estimates by reporting medians and inter-quartile ranges.All data were analysed using R version 4¢0¢5 and are available as Supplementary Material 2, including the corresponding R code. Given the lack of uncertainty intervals for most indicators, meta analytical trend analyses were not feasible. For estimating changes in the indicators at the European level, the oldest and most recent data points were selected and reported. For prevalence of use, at least one of these two points was not available in four countries , which were excluded from estimating changes. The difference in adult and age specific prevalence of use as well as for THC levels did not account for the degree of uncertainty associated with each point estimate, as these data were not available from the EMCDDA data repository.To describe country-level trends in prevalence of use and CUD, statistical models were not applied as too few data points were available for most countries or because the estimates were predicted from statistical models . Thus, for these two indicators, we only compared the first and last available estimate in each country to estimate changes from the oldest to the most recent data point. To describe country-level trends in treatment rates and THC concentrations, linear regression models were conducted, separately for each country with at least 5 observations. In each model, year was entered as a single covariate, describing the annual change score in the outcome.

Results are reported for all models in which the coefficient was significantly different from 0 at alpha = 1%.The most recent estimates of prevalence of use are summarized in the map in Figure 1. Overall, cannabis use appears to be more common in Western than in Eastern countries. Based on data collected between 2013 and 2019, past-month prevalence of use was below 1% in Malta, Hungary, and Turkey. In three countries , between 5 and 6% of adults reported past month cannabis use. Highest use rates were recorded in Spain and France . The country-level cannabis use prevalence rates are further reported in Supplemental Material 1 . Re-examining the available EMCDDA data for all countries since 2010 allowed for a more precise analyses of trends of cannabis use in Europe. At the European level,trimming trays for weed cannabis consumption appeared to have increased in the past decade. Comparing the last and first available estimates, an increasing past-month prevalence was identified for 24 out of 26 countries that had at least two data points available. The country-specific changes in prevalence of use for the adult population are further illustrated in Supplemental Material 1 . Age-specific comparisons of first versus last years suggest that an increase in both past-month and past-year use was observed across all age groups in Europe . Among younger adults, cannabis consumption is overall more prevalent and absolute increases were more pronounced in this age group. Among 35 to 64 year-olds, increases were smaller in absolute terms but greater in relative terms. In this age group, prevalence of use increased by 50% or more between 2010 and 2019. The age-specific trends in prevalence of past-month use at the country level, based on the first and last available estimate, are further displayed in Figure 2. Only in Czechia and Poland, marked decreases in prevalence of use in most if not all age groups were observed.

In France, the Netherlands, and Spain, pronounced increases among middle-aged adults were identified. In contrast, Germany reports increases in total use which were driven mostly by younger adults. Very similar country patterns were present for age specific changes in past-year prevalence . Prevalence estimates for daily cannabis use among 15 to 64 year olds are displayed in Supplemental Figure 4. In 18 countries out of 26 countries with available data, indications for increasing trends in daily cannabis use could be observed.Most pronounced increases were reported in Portugal and Spain . Based on the last available estimates, the share of daily users among past-month users differed largely across all European countries. In countries like Lithuania, Czechia, Bulgaria and Poland, less than one in ten users reported high-risk use patterns. In contrast, 50% and 70% of all past-month users reported daily use in Luxembourg and Portugal, respectively. In half of all countries examined, the share of past-month users engaging in daily use was 20% or higher .In 2019, 115,477 treatment entries were registered by 25 countries and reported to the EMCDDA. At the country level, vast differences in treatment rates are reported. In Bulgaria and Slovenia, less than 2 treatment entries for cannabis problems per 100,000 adults were recorded in 2019. In contrast, more than 100 treatment entries per 100,000 adults were registered in Malta. For an illustration of country-specific trends of treatment rates, see Supplemental Material 1 . Based on the 22 countries with available data in the years 2010 and 2019 , the rate of treatment entries for cannabis as primary problem per 100,000 adults increased from 27¢0 to 35¢1 .

For cannabinoid biosynthesis, there exist three major reactions: biosynthesis of monoterpene precursor via MEP and fatty acid intermediate from polyketide pathway, prenylation of the precursors, and cyclization. The MEP pathway in plastid prenylation is localized in the chloroplast membrane, where the C-prenylated CBGA synthase is membrane-bound. The integration of the enzyme in the membrane seems essential, and the folding pattern is crucial for its functioning. Therefore, simple cloning and functional expression of this enzyme in a heterologous host such as yeast to generate the desired cannabinoids is challenging. Terpenoid cyclization reactions are the most complex reactions found in nature and the biotransformation from CBGA to THCA by the THCA synthase is assumed to occur in the cytosol. This hypothetical model is under ongoing debate and it might be likely that biocatalysis occurs in the extracellular oil container under a non-aqueous environment . In 1992, Mahlberg and Kim postulated that THCA synthase is located in the outer membrane of the head cells or even attached on the outer membrane surface extending into the essential oil . In recent studies, LC-MS/MS was used to detect a functional active THCA and CBGA synthase in the exudates from glandular trichomes of cannabis . Zirpel et al., described the need for an excellent understanding of protein chemistry and folding of these enzymes to produce the cannabinoid using a heterologous host . Detailed knowledge of genetic regulatory mechanisms underlying cannabinoid biosynthesis is a future challenge. identification of regulatory elements such as transcription factors and microRNAs could be utilized to understand the mechanistic insights of trichomes initiation, development, and densities. An in-depth understanding could be applied toward the breeding of genetically improved cannabis varieties with enhanced cannabinoids concentration in trichomes.

Drug- and fiber-type plants differ in biosynthesis, concentration, and composition of metabolites . To determine the genetic variations regulating plant-specific differences, it is essential to compare the genomes. Advanced sequencing technologies combined with continuously improving bioinformatics tools have allowed rapid sequencing and analysis of multiple genomes and transcriptomes. The very first draft genome of C. sativa was released in 2011 by Bakel et al. . They sequenced marijuana cultivar Purple Kush by using Illumina short reads and assembled them in combination with 454 reads. They also sequenced fiber-type hemp cultivar Finola for a genome-level comparison. In addition to whole genome,cheap grow tents the first complete mitochondrial reference genome was also obtained in 2016 from the cannabis hemp variety Carmagnola . Later in July 2016, two complete chloroplast genomes of marijuana African variety Yoruba Nigerian and Korean hemp non-drug variety Cheungsam were sequenced and used to determine the phylogenetic position of C. sativa relative to other members in the order Rosales. Furthermore, in September 2016 released complete chloroplast genomes of two Cannabis hemp varieties, the Carmagnola and Dagestani , to determine their genetic distance compared with the closest cannabaceae chloroplast of Humulus lupulus variety Saazer. Increasingly growing support for open-data policy by multiple industries is improving transparency in cannabis agriculture. In 2016, the industrial lead in cannabis research from Courtagen Life Sciences and Phylos Bioscience independently generated the genomes of hybrid marijuana strain Chemdog91 and marijuana strain Cannatonic , respectively. Phylos Bioscience also released genomic data of 850 Cannabis strains as a part of ‘‘Open Cannabis Project’’ for plant breeding programs.

With an objective to explore Cannabis population genetics, Phylos Bioscience developed three-dimensional interactive map of nearly 1000 cannabis strains . In 2017, the genome of hybrid marijuana cultivar Pineapple Banana Bubba Kush was released as part of Cannabis Genomic Research Initiative. In 2018, Grassa et al. generated the first chromosome-level assembly for the genome of CBDRx, a high CBD cultivar of C. sativa by using advanced long-read Oxford Nanopore Technology and PacBio Single-Molecule Real-Time sequencing . Later in 2019, Laverty et al., improved the initial draft assemblies of drug-type Purple Kush and hemp-type Finola to chromosome-level by using ultra-long PacBio reads . In addition to genomes of high CBD and THC marijuana and hemp cultivars, a medicinal Cannabis strain with a balanced THC/CBD ratio was sequenced by Shivraj et al. . Until 2020, nearly all Cannabis genomes had been obtained from the hemp and marijuana cultivars, selectively bred for generations. However, cultivars lose genetic diversity owing to domestication and successive plant breeding for selected traits. In contrast, the wild-type genomes exhibit relatively high heterozygosity and genetic diversity, which might provide unique evolutionary insights into the cannabis genome. Therefore, in 2020, Gao et al. sequenced the first samples of C. sativa wild-type ‘‘Jamaican Lion’’ variety growing in the geographically isolated Himalayan region in Tibet. Because these wild-type plants retained the ancestral genetic make-up, therefore, the data generated from this study was used as a tool to determine the inheritance patterns and evolutionary inference of cannabis . The published genomes of high THC, high CBD marijuana cultivars, and hemp varieties, exhibited inconsistent chromosomal nomenclature, arrangement, and varying degree of gaps. Therefore, by end of 2020, Shivraj Braich et al. generated a relatively complete draft genome assembly for Cannbio-2, the medicinal cannabis strain with a balanced THC/CBD ratio . To present date, only 13 Cannabis genomes are publicly available at National Center for Biotechnological Information . Of which 3 assemblies are at chromosome-level, 7 at contig-level, and one at scaffold-level. However, by March 2021, the1000 Cannabis Genomes Project comprises of genomic data of nearly 1000 samples from multiple cannabis strains. These datasets were the first genome data released on Google Cloud Big Query database.

Continuously expanding the list of cannabis genomes needs collaborative efforts toward curating the information. Therefore, academic and industry experts in diverse fields formed the International Cannabis Research Consortium during the annual PAG meeting in 2020. Despite several cannabis genome assemblies, the selection of single standard reference genome is still a huge challenge for the scientific community, especially plant breeders. Therefore, ICRC proposed CBDRX Cs10 assembly as the most complete reference for use in cannabis genome research . Additionally, a member genomics company, NRGene, generated an integrated Cannabis, and Hemp Genomic Database optimized and curated for the genomics-based breeding of cannabis varieties. Finally, in 2021, the first-ever open-access and comprehensive database of cannabis genome Cannabis GDB were released with integrated bioinformatic tools for the analysis of datasets. Overall, the genomic data of diverse cannabis genotypes are the untapped reservoirs of genetic information which could be applied toward pan-genomic understanding of cannabis evolution and determining the effect of genetic variations upon the pathways, development, and concentration of cannabis derivatives.The availability of several high-quality cannabis genomes made it easier to apply the transcriptome sequencing to elucidate detailed expression dynamics in time-, tissue-, stage-, and chemotype-dependent manner. Furthermore, the differential expression analysis provides in-depth insight into co-related gene networks. In 2011, Bakel et al. sequenced and compared the transcriptomes of marijuana variety Purple Kush and hemp cultivars Finola and USO-31. Gene expression analysis revealed preferential expression of cannabinoid and precursor pathway-associated genes in marijuana . Expression of THCA synthase in the PK and cannabidiolic acid synthase in FN was found to be consistent with the exclusive production of psychoactive THC in marijuana.

In a recent study, transcriptomics of hemp-type plants was analyzed to determine the expression profile of the fiber-type plant at the various developmental stages . Similarly, the transcriptome of marijuana flowers at different stages was captured and sequenced and found the gene expression pattern consistent with the cannabinoid contents . As glandular trichomes are the central reservoir for cannabinoids , therefore, the trichome transcriptome could yield valuable insight to determine the variation in cannabinoid biosynthesis, composition, and concentration between the drug and fiber-type plants. Importantly, the identification of the differentially expressed genes could unravel the underlying molecular mechanisms of natural genetic and metabolic variation. The gene expression in trichomes of female plant strain Cannobio-2 was compared with genome-wide transcriptomics of female floral tissues at different stages of development as well as other tissues including female and male flowers, leaves, and roots . The extensive-expression atlas was applied toward the identification of genes expressed preferentially in various tissues at different developmental stages. Interestingly, the majority of genes involved in terpenoid and cannabinoids synthesis were significantly over-expressed in trichomes. In 2021, Grassa et al. used genomic, and expression associated expression of THCAS and CBDAS with THC:CBD ratio by Quantitative trait Loci analysis of Cannabis cultivars . Datasets from similar genomics,grow tent indoor transcriptomics, micro-biome, and metagenomics studies of various cannabis strains are currently accessible from the Sequence Read Archive repository at NCBI. In the past 3 years, there has been unprecedented growth in Cannabis genome and transcriptome studies and corresponding SRA entries. To date, there are over 4571 BioSamples from multiple studies related to Cannabis of which 2871 public BioSamples are exclusively for C. sativa with 2546 DNA and 325 RNASeq datasets in SRA. The SRA data for transcriptomics and metagenomics have reportedly procured from various tissues including seeds , flowers , leaves , shoot stem , root , and trichomes , while genomic data lacks tissue-specific information.

In-depth transcriptomic studies will be required in the future to improve the understanding of regulatory genetic networks.One of the fundamental aspects of patents, especially in medical science or biotechnology, is to involve industrial partners in investing in research and development . Cannabis-related patents have been issued by the US-patent office since 1942. More than 1,500 applications have been filed only in the US patent office. Among them, approximately 500 applications got patent protection rights and most of them were from the last decade. The exponential increase in the number of patents shows the future potential for the growing cannabis industry. Here, we analyzed the patents spatiotemporally and categorized them into four main classes: patents related to cannabinoids as constituents, pharmaceutical applications, endocannabinoid pharmacology, and genome and gene related. Among the suggested four categories, the patents related to the pharmaceutical application were the most significant category with 73 patents registered. These are further sub-grouped into the preparation of the drugs, treatment, delivery technology, and detection method each with 14, 33, 13, and 13 patents, respectively. Endocannabinoids-related patents comprised of the CB1/2 receptor , TRPV1 , and GPR119 reviewed in . The category of cannabinoids consists of cannabinoid isolation, extraction, and synthesis or biosynthesis-related patents each with 6, 6, and 12 patents granted, respectively. For the division of the sequences, 15 patents are from enzyme inhibition followed by the gene and the protein each with two patents. Most of the patents are from the US followed by the GB and the other European countries Figure 2 . In addition, 25 patents for fiber/textile, 10 for foodstuff, 5 for the paper industry, 3 for architecture, 1 for biofuel, and 3 for plant breeding have been registered. Also, four patents each in the category of oil, extracts, and cosmetics each with four have been filed. However, we have to keep in mind that a certain cannabinoid invention can be referred into more than one patent category.

For instance, cannabinoids are highly hydrophobic by nature and thus they have low bioavailability in the human body. As a result, a new class of cannabinoid-glycosides has been created, whose representatives are produced through enzymatic glycosylation. This novel strategy led to increased aqueous solubility of the target cannabinoids and resulted in four patents . Recently a new method of producing one or more cannabosides by feeding an insect a cannabinoid was patented . These new classes of cannabinoid glycosides generated vast structural diversity and have greatly improved water solubility, enabling new pharmaceutical formulations, and multiple administration routes . The discovery of the genes encoding glycosyltransferases may belong to different categories of the cannabinoid patent family, that is, genes, enzymes, delivery technology, etc. The exponential enhancement of the patent number during recent years in the diverse areas of cannabinoid applications is indicative of the increased commercial interest in this class of natural compounds. The various pharmaceutical applications will continue to shape primarily the the path of the future invention cannabinoids.C. sativa has been well-known for the anti-inflammatory properties reviewed in .

Oral bacteria can enter into the systemic circulation through inflamed gingiva and thereby affect peripheral organs and the CNS. In mice, oral administration of Campylobacter jejuni activated visceral sensory nuclei in the brainstem that processed gastro-intestinal sensory information; Porphyromonas gingivalis, an oral pathogen contributing to the development of chronic periodontitis, may be a risk factor for developing amyloid-beta plaques, cognitive impairment, and dementia. Further, exposure to viral or bacterial pathogens upregulates neuronal Ab expression in nontransformed cell culture models and wild-type rat brains, which may represent a naive antimicrobial defense response. Cannabis smoking alters the oral environment and produces numerous chemicals that directly interact with oral bacteria. Some of the chemicals are toxicants and may perturb the oral microbial ecology.In this study, we found that saliva Actinomyces, Veillonella, Megasphaera, and Streptococcus bacteria were increased, and Neisseria bacteria were decreased in cannabis smokers compared to non-smokers. Two Actinomyces species bacteria and one control Neisseria species bacterium were inoculated to the B6 mice via oral inoculation. A. meyeri administration resulted in reduced global mouse activity, macrophage infiltration,trim tray pollen and increased Ab 42 protein production in the brain.

Non-smoking controls were recruited from the Medical University of South Carolina and University of Connecticut by advertisement on the campus and chosen by self-report of non-drug use. Cannabis-smoking individuals with cannabis use disorder were recruited from the Addiction Center at MUSC. This study was approved by MUSC institutional review boards. All participants provided written informed consent. The cannabis smoking cohort included 16 cannabis smokers and 27 non-smoking controls. The cannabis smokers were on current non-injection cannabis use but not on prescription drug and other illicit drug uses identified by chart reviews and urine tests. The clinical characteristics of cannabis smokers were shown in Supplementary Table 1. We conducted a Timeline Follow-back method, a web-based self-administered, to assess frequency and quantity of past 90-day cannabis uses prior to the study visit. Whether the participants used cannabis and the number of joints, blunts, pipes, bowls, vaporizers, spliffs, edibles, or other methods used. If participants shared a joint/blunt/etc. or otherwise did not use a full joint/blunt/etc., partial numbers were reported. Daily gram calculations of THC uses were calculated .Non-smoking controls were recruited from the Medical University of South Carolina and University of Connecticut by advertisement on the campus and chosen by self-report of non-drug use. Cannabis-smoking individuals with cannabis use disorder were recruited from the Addiction Center at MUSC. This study was approved by MUSC institutional review boards. All participants provided written informed consent. The cannabis smoking cohort included 16 cannabis smokers and 27 non-smoking controls. The cannabis smokers were on current non-injection cannabis use but not on prescription drug and other illicit drug uses identified by chart reviews and urine tests. The clinical characteristics of cannabis smokers were shown in Supplementary Table 1.

We conducted a Timeline Follow-back method, a web-based self-administered, to assess frequency and quantity of past 90-day cannabis uses prior to the study visit. Whether the participants used cannabis and the number of joints, blunts, pipes, bowls, vaporizers, spliffs, edibles, or other methods used. If participants shared a joint/blunt/etc. or otherwise did not use a full joint/blunt/etc., partial numbers were reported. Daily gram calculations of THC uses were calculated .For individuals with cannabis use disorder, we assessed exclusionary psychiatric diagnoses using appropriate modules of the MiniInternational Neuropsychiatric Interview, as described in our previous study. Briefly, The M.I.N.I., a brief structured interview, was to assess current Diagnostic and Statistical Manual of Mental Disorders, 5th edition diagnoses. Because the M.I.N.I. only assesses current diagnoses and a more thorough history of substance use is needed, the substance use module of the Structured Clinical Interview for DSM-V was used for substance use disorder diagnosis. Drug screens were performed using the onTrak test cup, an in vitro diagnostic test for the qualitative detection of drug or drug metabolite in the urine. Results of urine screenings were used to substantiate self-reports of cannabis use.The saliva micro-biome was analyzed and compared between cannabis smoking individuals and non-smoking control individuals. We found that cannabis smoking was associated with decreased oral microbial diversity compared to those in the non-smoking control group. The oral microbial communities differed in the two study groups reflected by the b-diversity. Next, we examined the relative abundance of individual bacterial taxa. The phylum Proteobacteria were decreased in cannabis smokers compared with those of non-smoking controls . At the genus level, enrichment of Neisseria was lower in cannabis smokers than in non-smokers; in contrast, Actinomyces, Veillonella, Megasphaera, and Streptococcus were found to increase among cannabis smokers .

At the species level, 36 species were significantly different in cannabis smokers compared to non-smoking controls after adjusting for multiple comparisons , including 16 species that were decreased and 20 species that were increased in cannabis smokers compared to non-smoking controls . Among the taxa that were increased in the saliva of cannabis smokers, five belonged to the Streptococcus genus, and four belonged to the Actinomyces genus. Among the taxa that were enriched in the saliva of non-smoking controls, six belonged to the Neisseria genus . No differences were observed based on quantity of cannabis use or presence of neurological disease history between the heavy users and light users , and between smoked cannabis containing THC and cannabis containing no THC . Nonetheless, the enrichment of A. meyeri was inversely correlated with the age of first cannabis use . To study which taxa may represent the cannabis smoking oral micro-biome, we reanalyzed and compared the saliva micro-biome from tobacco smokers and non-smoker controls from our published data. Consistent with the results from previously published studies, we found increased Streptococcus and decreased Neisseria in the oral micro-biome of tobacco smokers compared with those in non-smoking controls , which was similar to cannabis smokers. However, Actinomyces genus was only increased in cannabis smokers but not in tobacco smokers . To further analyze Actinomyces genus bacteria, we have shown four Actinomyces species bacteria that were significantly increased in cannabis smokers . Only Actinomyces turicensis was increased in tobacco smokers when compared with non-smoker controls . We further analyzed the difference after adjusting for age, sex, and/or alcohol use. All differences between cannabis users and controls identified in the univariate analysis shown in Fig. S1 remained significant after adjusting for sex, age, and alcohol consumption, although P values were attenuated slightly . When comparing tobacco users to controls, only Streptococcus and A. turicensis , but not Neisseria, remained significant after adjusting for sex and age.

Cannabis smokers have shown premalignant lesions in the oral mucosa with surface decay relative to a control group. The smoking and altered micro-biome composition may lead to a compromised mucosal epithelial barrier, which results in the translocation of bacteria or microbial products into circulation. Thus, bacterial fragments or whole bacteria can appear in the blood from translocation and thereby influence the immune system. To study oral microbial translocation in cannabis users, we evaluated the plasma levels of IgG antibody against antigens derived from A. meyeri, A. odontolyticus, and N. elongata. Plasma levels of IgGs against A. meyeri antigens tended to increase in the cannabis smokers compared to controls , while similar levels of IgGs against antigens from the other two bacteria were observed . These results imply that A. meyeri or its antigens may preferentially translocate from the oral mucosa to the circulation in the setting of an altered oral or periodontal environment in cannabis smokers.In a previous study, oral administration of Campylobacter jejuni activated state of neurons in nucleus tractus solitarius and increased c-Fos expression in the hypothalamic paraventricular nucleusas in mice. To determine if cannabis use-associated oral micro-biome affects CNS, we inoculated live A. meyeri, A. odontolyticus, and N. elongata into the oral cavity of C57BL/6 mice. A. meyeri and A. odontolyticus are oral commensal bacteria and were enriched in the oral micro-biome of cannabis smokers found in this study. N. elongata, which was enriched in non-smoking controls , was used as a control. We examined mouse activity through a uniformly cylindrical arena. The behaviors of mice were quantified and shown by global activity, total distance traveled , average speed , and resting time. The behavior of N. elongata-treated mice in the arena was comparable with the PBS-treated mice. However, compared with N. elongata-treated mice, A. meyeri-treated mice exhibited decreases in global activity,trim bin tray distance traveled, and mean speed, as well as increases in resting time . Next, we have evaluated amyloid production in mouse brain tissues as it is a marker of neurodegenerative diseases. Although Ab 40 tended to be increased in A. meyeri-treated mice, there was no statistical difference between any two groups .

Notably, the Ab 42 peptide in the brain from A. meyeri-treated mice was increased significantly compared to the control groups . To validate alterations in oral and gut micro-biome, we collected the samples from oral swab and stool one week after the final oral administration of live bacteria. specific bacteria were quantified using qPCR, and the abundance of each bacterium was normalized by total 16S rDNA. We con- firmed oral inoculated bacteria by qPCR . Notably, both A. odontolyticus and N. elongata, but not A. meyeri, presented in the oral swab of some mice from the PBS group, suggesting A. odontolyticus and N. elongata may be oral commensal micro-biome in mice . A. meyeri did not present in any group except the orally inoculated A. meyeri group. Furthermore, N. elongata presented in the stool samples from some mice after oral inoculation, but was not signififi- cantly elevated compared to the controls; elevation of A. meyeri in stool after oral inoculation was extremely limited . These results indicate that A. meyeri may not be an oral commensal bacterium in B6 mice, but it can colonize well on the surface of the oral cavity during oral inoculation.Long-term heightened systemic inflammation affects neuroin- flammation, and neuroinflammation may result in CNS damage and Ab protein production. To evaluate systemic inflammation after6-month oral bacterial inoculation, we tested plasma levels of 33 cytokines or chemokines in mice. Among these inflammatory markers, only MIP-1a and TNF-a levels were increased in the A. meyeri group compared to the control group . Plasma levels of MIP-1a were also increased in the A. odontolyticus group compared to the control N. elongata group . However, blood levels of the other microbial TLR-downstream proinflammatory cytokines including IL-1b, IL-6, IFN-g, IP-10, MCP-1, and MIP-2 were similar among the four study groups.We analyzed the correlation of A. meyeri, A. odontolyticus, and N. elongata with cytokine levels, and found that N. elongata enrichment in the saliva was directly correlated with levels of IFN-g in the cannabis smokers. However, after FDR adjustment, the p value was not significant.

No correlation was found between plasma cytokine levels and saliva enrichment of A. meyeri or A. odontolyticus. Infiltrating monocyte-derived macrophages in the CNS was related to the progression of neurodegenerative disease pathology. To investigate the potential mechanism of oral A. meyeri-mediated CNS abnormalities, we evaluated myeloid cell migration and infiltration by IHC using mouse brain tissues after oral inoculation of bacteria. Notably, macrophage infiltration was increased in the brain of A. meyeri-treated mice when compared to N. elongata or PBS-treated mice . In in vitro studies, A. meyeri, A. odontolyticus, and LPS significantly enhanced cell transmigration through microporous membranes in human macrophages via the MyD88 cell signaling pathway . Phagocytosis is a major function of antigen-presenting cells. Bacterial products activate antigen-presenting cells and decrease phagocytic capacity. We found that treatment of N. elongata significantly decreased phagocytosis in both human primary monocyte-derived macrophages and THP-1-derived macrophages. However, treatment of Actinomyces species bacteria maintained macrophage phagocytic capacity similar to those of unstimulated cells . Moreover, as expected, A. odontolyticus or N. elongata induced TNF-a, IL-1b, and IL-6 production in human primary monocytes . Unexpectedly, A. meyeri did not activate monocytes to produce TNF-a, IL-1b, and IL-6 .Long-term cannabis users may suffer disturbed brain connectivity, cognitive impairment, and psychological disorders, but the exact mechanisms are not fully understood. In the current study, we found that chronic cannabis use correlated with alterations of several taxa of the oral micro-biome.

Similarly, the former continental-scale meta-analysis of fossil pollen and archeological evidence indicates that the IP was among the last European areas – along with the British Isles and the Scandinavian region – where Cannabis was cultivated, and this occurred during the Roman Empire and the Early Middle Ages . However, these continental-wide analyses include only a few IP sites in their compilations. For example, Clarke and Merlin  mentioned a single, yet representative, site  where Cannabis was submitted to intensive cultivation and retting and used it to propose the arrival of Cannabis to the IP by 600 CE. McPartland et al.  retrieved their Iberian sites from the European Pollen Database  and other internet facilities and considered 10 IP sites, including two from the Balearic Islands . In this way, although the incoming of Cannabis to the IP may be placed within a rather general European context, the precise timing and pathways of arrival, as well as the internal and external dispersal trends, remain largely unknown. Due to the peculiar climatic, biogeographic and cultural features of the IP mentioned above, a thorough survey focused on this specific region to reconstruct Cannabis history is worth attempting. The potential of the IP for providing useful information in this sense is high, as demonstrated by some studies that have recorded relevant historical developments in the drying rack cannabis industry based on pollen analyses of lake sediments. Among them, the most significant examples were found in lakes Estanya and Montcort`es , where hemp was exploited since the Early Middle Ages.

The advantage of these sites is that the amount of Cannabis pollen deposited in the sediments is consistent with local cultivation and/or retting rather than with dispersal from regional and long-distance sources. Indeed, some aerobiological studies have demonstrated that relevant amounts of northAfrican Cannabis pollen can be transported to the southern IP in a few days . Similarly, a recent study of modern sedimentation in Lake Montcort`es  recorded significant percentages of Cannabis pollen, but the parent plant was absent from the region . This long-distance dispersal ability implies that only the presence of this pollen is not sufficient to infer the local occurrence of Cannabis populations. However, this is not the case for Estanya and Montocort`es, as we discuss at following. In the sediments of Lake Estanya, the first appearance of Cannabaceae pollen was recorded ca. 600 CE  during the Early Middle Ages . From then, the record was continuous until the 1990s. Hemp pollen was accompanied by other cultivated plants, such as Olea , Secale  and other undifferentiated cereal pollen. Hemp percentages remained relatively stable  until the 14th century, when they underwent a significant increase of up to 25% around the middle of the 18th century . This increase was interpreted in terms of hemp retting in the lake, coinciding with a local increase in the cultivation of this plant . This was supported by the study of proxies for water quality and non-pollen palynomorphs. This phase coincided with the maximum hemp production in Spain due to the high demand from the Spanish navy . After these dates, hemp pollen decreased abruptly to values below 10% during the 20th century.

The authors attributed this hemp crisis to a general decrease in cultivation due to the depopulation of the area during the first half of the 20th century. The first pollen records of Cannabis pollen in Lake Montcort`es sediments also occurred at approximately 600 CE and coincided with the disappearance of cereals , which indicates a shift in local cultivation practices from cereals to hemp . Further increases in wild grasses and weeds such as Artemisia  and Plantago  are consistent with the expansion of pastures. Hemp pollen experienced three main phases of abundance, separated by two phases of scarcity. The first two phases  were interpreted in terms of low-intensity cultivation/retting to cover local needs for fiber. The third phase, however, was characterized by significantly high abundances  and was difficult to explain in terms of only local consumption . As in Lake Estanya, this phase  was coeval with the maximum development of the Spanish navy and, as a consequence, of hemp cultivation across the entire country. The same abrupt decrease in hemp pollen was recorded at the end of the 19th century, which has been related to the dismantling of the royal navy, the onset of hemp importation from other countries, the substitution of hemp fiber by other materials such as cotton and synthetic fibers, and the decrease in human pressure . The further increase in hemp pollen in the late 20th century may have been due to the renewed interest in hemp, likely favored by EU subsides.The combination of the meta-analysis discussed above  and the case studies of Estanya and Montcort`es may suggest that wild Cannabis reached the IP during the postglacial period  and that cultivated Cannabis entered much later, by 600 CE. Notably, both entries would have proceeded from the north-eastern sector.

However, in the present state of knowledge, it is still premature to confirm these assessments. The lag of sufficient localities also hinders knowing what happened on the IP with Cannabis during the large gap between post-glacial times and the Middle Ages. The development of a thorough database for the IP, as a basis for further meta-analyses, is essential to understand when and how wild and cultivated Cannabis reached the IP, as well as what happened since those times. In addition to the information available from the above reviews and meta-analyses, other sources of information should be accessed. For example, many other sites are available in the compilation by Carri´ on  that have not been included in the former studies. This compilation gathered almost all pollen records available for the IP by the time of publication and is now being updated with new studies developed during the last decade.A number of these studies are not easy to locate, as they are available only in dissertations and local journals. Finally, some studies do not include Cannabis/Humulus pollen in the diagrams due to its scarcity, but the authors have data in their counting sheets and they can be recovered. Therefore, personal contact with palynologists working on the IP is also needed. All these information sources, along with others that may be located further, should be included in a thorough IP-wide study. Epilepsy is a common neurological disorder affecting 0.5–1% of children.

Approximately one-third of people with epilepsy will experience treatment-resistance which is defined as failure of adequate trials of two tolerated, appropriately chosen antiepileptic drugs to achieve seizure-freedom. Children unresponsive to conventional treatments face an increased risk of cognitive, behavioral, and psychosocial dysfunction that can have a negative impact on their health and development. This prognosis has led to strong consumer interest in and uptake of alternative treatments such as artisanal ‘cannabidiol -rich’ products as a way to manage seizures in children with epilepsy. However, such products are typically of unknown quality, composition, and safety, and their use may conceivably pose unpredictable health risks to these children. Despite increasing access to legal pharmaceutical-grade cannabis products globally, many consumers continue to use artisanal cannabis preparations. This may be done for various reasons including lower cost relative to the prescribed product, lack of awareness or knowledge of the patient access pathways, bias against pharmaceutical products, or perceived superior effectiveness and/or tolerability of artisanal products relative to the prescribed products. Artisanal cannabis oils and tinctures are often concentrated to increase the concentrations of active ingredients such as CBD. This, in turn, may result in unusually high levels of residual contaminants in the final product, risking possible toxicity with oral ingestion. The lack of quality control poses potential health risks to individuals via exposure to cannabis contaminated with pesticides, heavy metals, and residual solvents. This would be of particular concern when consumed by children, or immunocompromised or seriously ill adults, and occurs on a long-term basis. With many individuals continuing to self-medicate with artisanal cannabis preparations in Australia and the US, commercial greenhouse supplies contaminants may be unknowingly ingested by many vulnerable individuals suffering chronic illness, including children and adolescents with epilepsy. In a previous study, we collected individual samples of cannabis extracts from families in Australia who were using them to treat their child’s epilepsy, and conducted an analysis of cannabinoid and terpenoid content.

Contrary to family’s expectations, most cannabis products given to children as a way to treat their seizures contained low concentrations of CBD , while delta-9- tetrahydrocannabinol  was present in nearly every sample. To extend on this previous analysis, we further analyzed the samples for the presence of residual solvents, heavy metals, and pesticides, and compared the results to known toxicological standards. In the Australian context, pharmaceutical-grade cannabis products are strictly regulated, federally approved, quality-assured products that are only available on prescription via a medical doctor. All other cannabis products are illegal and unregulated– here referred to as ‘artisanal products’ – which are generally of unknown composition and are typically sourced via the illegal gray or black market.Samples  were collected between May 2016 and November 2017 across New South Wales and Queensland, Australia, from participants in the Paediatric Epilepsy Lambert Initiative Cannabinoid ANalysis  study. A total of 78 cannabis samples were collected from 41 families who were either currently using cannabis products to treat their child’s epilepsy  or who had previously used such products and now stopped . Of these, 37 families provided multiple samples. These included 68 liquid-based samples , six solidbased samples , three plant matter samples, and one crystal/powder-based sample. Aside from two families who had obtained a legal prescription, all other families were accessing unregulated artisanal cannabis preparations of unknown strength, composition, and quality either via local/homemade sources or international online suppliers. The two samples obtained on prescription were included in the contaminant analysis as they were representative of the types of products accessed by families at the time of the study. Samples were stored in a 80 C freezer and had previously undergone two freeze–thaw cycles for:  phytocannabinoid analysis, and terpenoid analysis, as part of the original study protocol. Further information regarding collection methods and the cannabinoid and terpenoid content of samples can be found in our prior publication. All participants provided written informed consent for the original study protocol while consent for the subsequent contaminants sub-analysis was obtained using an opt-out approach. Ethical approval for the secondary protocol and opt-out consent process was obtained from the University of Sydney Human Research Ethics Committee  and the Children’s Health Queensland HREC . Due to the sensitive nature of the information collected in the original study, all cannabis samples were deidentified for confidentiality and recoded to prevent any risk of participant identification. Therefore, information relating to specific cannabis samples  and the child  could not be linked to the contaminant analysis.

The analysis, including detection, identification, and quantification, of four types of heavy metals, 19 types of residual solvents, and 76 types of pesticides  was performed by a National Association of Testing Authorities -accredited analytical chemistry facility . All samples were analyzed using quality-control standards using a 10% replicate approach except those with a small sample volume which were completed in duplicate as a minimum. To account for the variation in sample volumes remaining from prior analyses in the original protocol, a representative sampling approach was chosen. The maximum number of analyses possible on each sample was determined based on volume available, ensuring at least 30 samples per contaminant group. Samples containing >3 g were analyzed for all three categories of possible contaminants; 2.5–3 g for residual solvents and pesticides only; 2.0–2.5 g for pesticides only; 0.7–1.9 g for residual solvents and heavy metals only; 0.6 g for heavy metals only; and <0.5 g for residual solvents only. Using this approach, 51/78 samples were analyzed for heavy metals, 58/78 for residual solvents, and 31/78 for pesticides. Contaminant analysis methods are described in brief in the Supplemental Files.The list of heavy metals and their associated toxicological limits were obtained from the Australian Government Therapeutic Goods Order No. 93 Standard for Medicinal Cannabis for heavy metals.

A placebo-controlled crossover study involving individuals with infrequent use given cannabis ‘edibles’ at different doses found dose-dependent acute impairments in attention, memory and psychomotor performance. Perceptible drug effect onset occurred 30-60 minutes after intake, peaked at 2-5 hours, and lasted eight hours or more . While the cognitive impairments observed were comparable to similar doses of inhaled cannabis the THC-blood concentrations observed were lower than peak concentrations reported in other studies on cannabis inhalation . On this basis, individuals with ‘edibles’ use could have been under existing limits for THC blood level for cannabis-impaired driving, despite their marked impairment being comparable to that from smoking or vaping THC. Furthermore, extending the evidence on the role of different use modes for cannabinoids, the pharmaco-dynamic effect patterns of CBD itself have been observed to be similar to those for THC products, yet generally also vary depending on the use mode/route employed . Moreover, a recent study reported students using cannabis products in multi-modal ways were at greater risk of cannabis-related problems, dependence, and alcohol co-use than those individuals with single-mode use .Systematic reviews suggest that individuals reporting frequent use of cannabis may develop tolerance to the acute effects of THC, especially its effects on memory, executive functioning, and psychomotor impairments, which are less pronounced in individuals with frequent than those with non-frequent use .

Tolerance is generally evident in a blunting effect on impairment, rather than its avoidance; it appears to be a result of neuroadaptation, a down regulation of cannabinoid receptors in response to frequent THC exposure . A recent meta-analysis confirmed a moderating effect of frequent cannabis use on the subjective impairment and psychosislike effects of THC . A double‐blind,pot drying randomized, placebo‐controlled study of the acute effects of cannabis use on neuro-behavioral functioning found that in subjects with occasional use, cannabis-induced alterations in brain functioning were associated with increased subjective intoxication and decreased behavioral performance; conversely, neuroadaptive processes were observed as facilitating reduced responses in individuals with chronic use . Other studies suggest that acute tolerance may be limited to persons with extremely high-intensity patterns of cannabis use . Individuals engaging in frequent cannabis use may also develop tolerance to the protective effects of CBD . Tolerance may lead to increased cannabis intake in order to achieve the desired level of intoxication, thereby increasing the risk of adverse effects. Some adverse neuro-cognitive effects of cannabis on memory, learning and mental state may reverse after a period of abstinence or substantial reductions in use . Reversible down regulation of brain functioning has been reported in animal and human studies, with structural levels returning to those of healthy controls within a few weeks, or even days, of non-exposure . A recent systematic review concluded that abstinence from cannabis use for periods of >72 hours diminished the neurocognitive deficits found in adolescent and young adult PWUC . Other studies have found reversals in key cognitive deficits but observed residual effects on higher-order cognitive functions and related brain networks .

Overall, conditions and measures of related studies vary considerably . In a sample of young cannabis using women, reductions in cannabis use frequency at 3- and 6-months post-baseline were associated with significant reductions in depressive symptoms, with the largest changes for more severe depressive symptoms at baseline . Furthermore, abstaining or reducing the amount of cannabis smoked can reduce respiratory problem symptoms .Key reviews have documented moderately but significantly increased associations between driving under the influence of cannabis and user-drivers’ involvement in MVCs that cause injury or death . Risk ratios may be higher if evidence is limited to drivers with acute impairments in relevant cognitive and psychomotor control functions . Similar risk associations have been confirmed for motorcycle crashes and occupational injuries . Using cannabis together with alcohol increases multi-fold the impairment of driving-relevant performance skills and MVC involvement risk Driving simulator and on-road performance studies confirm that acute cannabis use impairs driving-related reaction, tracking, and psychomotor control, including among youth drivers as a particular high risk group for driving-related adverse events . THC increases self-administration of nicotine in animals, suggesting increases in its rewarding effects . CBD reduces increased attentional bias towards cigarettes in humans who use both drugs, suggesting it may have anti-nicotine addictive properties . Adolescents who co-use tobacco and cannabis report more problems with and dependence on both drugs, consume more alcohol, and experience stronger withdrawal symptoms than those individuals with singular drug use . In large samples of young adults, co-users of cannabis and tobacco reported more intensive use and poorer physical and behavioral functioning than those without co-use ; similarly, among adults, cannabis use has been significantly associated with the initiation of cigarette smoking, smoking persistence, and relapse after cessation.Maternal tobacco co-use has been identified as a confounder for the possible effects of cannabis use on adverse neonatal outcomes, for example birthweight or gestational age , and predicts future use of cannabis and tobacco by offspring .

The concurrent use of cannabis and alcohol can have complex effects . Individuals reporting daily cannabis use who also used alcohol did not differ in brain structure from matched individuals with alcohol-only use; however alcohol co-use is a potential confounder in studies of long-term cannabis-related cognitive function . Concurrent adolescent cannabis and alcohol use may be associated with better neurophysiological and structural brain outcomes than alcohol-only use, but data are limited and effect dynamics uncertain . It is possible that THC exposure may acutely increase the rewarding effects of alcohol and produce quicker and more marked intoxication, and thus lower alcohol use. Co-using individuals may use both drugs more frequently, increasing the risks of co-morbid substance use and mental health problems, and poorer treatment outcomes than those not using both drugs . Comprehensive reviews suggest that frequent cannabis and alcohol co-use by adolescents is associated with greater neuropsychological impairments, adverse health and psycho-social outcomes, such as poorer academic performance and impaired driving. Concurrent use of cannabis and alcohol increases acute impairment, and increases the risk of MVC involvement and other injuries . Concomitant use of alcohol and/or tobacco with cannabis increases the risks of adverse cardiovascular events, including stroke . Interactions between cannabis and other psychotropic drugs, for example, psychostimulants, may negatively influence physical and mental health outcomes . As specifically relevant for prescription drugs, cannabinoids can inhibit the liver and other enzymatic systems, increasing the plasma levels and hence the toxicity of other psychotropic drugs via adverse drug-drug interactions .

Conversely, there may be some health-protective effects for individuals with high-risk use , but research in this area is underdeveloped. Both THC and CBD can produce drug-drug interactions and related adverse events, such as impaired neurological and cardiovascular functioning and infections . They both can interact with tricyclic antidepressants, central nervous system depressants, protease inhibitors, and warfarin therapy .Some reviews have found cannabis smoking to be associated with adverse cardiovascular outcomes such as acute myocardial infarction , arrhythmias, and ischemic attack , while other reviews have questioned the strength of the evidence . A systematic review found that the association with using large doses of THC was stronger for ischemic stroke than for other cardiovascular outcomes . Case studies have reported temporal relationships between cannabis drying smoking and adverse cardiovascular events, but the confounding role of tobacco and alcohol is unclear . While the evidence for cannabis-related cardiovascular outcomes is limited, it appears that THC exposure can exert substantial stress on the cardiovascular system, especially in individuals with novice or occasional use and consequentially limited tolerance to its effects . Systematic reviews have documented acute dose-response effects of cannabis use on tachycardia in young subjects without cardiovascular deficits . Similarly, cannabis smoking has been suggested as a trigger for AMI in young individuals immediately after use . Furthermore, risks for adverse acute cardiovascular events appear to be dose-dependent, and higher in individuals with frequent use of high THC-potency cannabis as well as in older PWUC and in individuals with pre-existing cardiovascular conditions .It is estimated that approximately half or more of the risks of developing substance use disorders is related to genetic susceptibility/heritability . These effects are partly explained by the additive effects of common variants on neurotransmission pathways and other physiological processes that are partially shared between substances . Comprehensive studies suggest a possible role of specific genetic predispositions for cannabis use problems, adverse psychiatric outcomes, and other substance use disorders .

Large genome-wide studies of cannabis dependence have identified independent regions with genome-significant polymorphisms . In a large genome-wide association study, eight independently associated polymorphisms explained a substantial amount of the variance in associations between cannabis use and risks of other SUDs and schizophrenia. Small but significant associations were found between polygenic risk scores for multiple SUDs and select mental health disorders, some indicating that those with a genetic risk for schizophrenia were more vulnerable to CUD than persons pre-disposed for other psychiatric conditions Overall, data suggest that individuals with an immediate or familial history of SUD or schizophrenia and depression are at elevated risk of developing chronic cannabis-related problems. Given the limitations of genetic risk diagnosis, such histories may serve as the best general indicators of increased risk. In those affected by mental health problems the prevalence of cannabis use is commonly elevated and associated with increased disease severity, progression or outcome severity . The causeand-effect dynamics involved between cannabis use, SUD, and mental health problems are complex, including possibly bi-directional relationships. The effects of cannabis may vary in response to other causes, and its use among those with mental health problems may also be a form of self-medication.Cannabis use has traditionally been twice as common in men as women, but the sex ratio of PWUC has substantially narrowed in more recent birth cohorts in many contexts . Fewer women than men, however, engage in intensive cannabis use, and some sex-based and suggestive gender differences in outcomes have been found, although the data may primarily reflect differential exposure levels . There are sex-related biological differences in the ECS and its role in the metabolic and endocrine systems, which may produce sex-based differences in the effects of cannabis on brain structures and functions and on mental health outcomes . Male PWUC develop CUD more often and typically express more problem symptoms than females. A series of double‐blind, placebo‐controlled pharmacodynamic studies comparing the effects of vaporized and oral cannabis use at different doses by sex found overall dose‐related increases in subjective drug effects and cognitive/psychomotor performance, heart rate, and blood-cannabinoid concentrations in female PWUC. Females exhibited greater peak-THC concentrations in blood and subjective effects as well as ratings of “anxious/nervous,” “heart racing,” and “restless” than males, suggesting differential effect profiles .

Women seem to experience greater and more prolonged sedation and psychomotor impairment from cannabis that also may increase their risks of MVC involvement . Female PWUC may have a higher prevalence of anxiety symptoms or disorder and an earlier onset of schizophrenia, although studies of depression outcomes are mixed . Women engaging in cannabis use, overall, may show a ‘telescoping effect’ in which they may more quickly transition from use initiation to CUD or other problems, although these dynamics may also include gendered differentials in social responses; furthermore, some studies suggest that women may experience more severe dependence and withdrawal symptoms . Male PWUC have been found to have twice the prevalence of cannabis-impaired driving as females .Cannabis use is increasing among older adults in North America but there are only very limited data on health outcomes in this specific age group . Human and animal data on ECS upregulation suggest that some age-related decrements may be balanced by neuro-protective effects or improved cognitive function in older PWUC. Reviews have found limited evidence for adverse effects on neuro-cognitive functioning . Systematic reviews of mental and cognitive health among older adult PWUC found only modest reductions in cognitive performance, and were concentrated in individuals with intensive and higher-dose use . A structural MRI study of frequent older-adult PWUC and non-using controls did not find any inter-group differences in in the brain’s total volumes of gray or white matter.

There were many hydroponic lettuce  researches reported , especially, in terms of ecotoxicological testing, lettuce has been recommended by the Environmental Protection Agency of USEPA  and the Food and Drug Administration, USFDA . Modified Hoagland nutrition and 2-fold ozone-treated sludge dilution solutions were used in hydroponic lettuce here, which was simple, rapid and economic. The domestic sludge was treated continuously by ozone until the concentration of fecal Escherichia coli was less than 1000 colony forming units 100 mL-1 , that is the water quality criterion in GB 5084 . The dilution ratio of the ozonetreated domestic sludge in the irrigation was optimized for lettuce growth. This study works on the scientific exploration of vegetable planting fertilized by the low-cost domestic sludge. This experiment was carried out from November 1, 2015 to January 9, 2016 in the greenhouse  of Agro-environmental Protection Institute, Ministry of Agriculture, China over a period of 70 d. Lettuce seeds of the cultivar Dasusheng were used in all experiments. The lettuce seeds were grown in the artificial substrate and irrigated with water. Three weeks later, when the seedlings grew to four or five true leaves, they were transplanted . Plant roots were washed with distilled water before planted. The average temperature is 15.6°C in the greenhouse, and the air relative humidity is 41.3%. And the characteristics of ozone-treated domestic sludge on the lettuce growth improvement in the water cultivation process were investigated.The representative five plants were removed from each hydroponics at 15 d intervals, and the leaf number, plant height, root length, root weight, fresh weight and dry weight were determined, respectively. The plant roots were cut off and weighted in a Thousandth Balance  after the surface water was absorbed by filter paper. The fresh weight was the weight of the whole plant and measured with Thousandth Balance  too. The chlorophyll content was determined directly using the SPAD-502 Plus Portable Chlorophyll Meter .

The soluble sugar was determined by the anthrone colorimetric method, and glucose is used to make the standard curve . One gram of plant samples was ground into homogenate, transferred to 20-mL scale test tube, kept in boiling water for 10 min. After the homogenate was cool, it was filtrated into volumetric flask. Then, 1-mL filtrate was put into 20-mL tube with stopper and mixed with 1 mL water, 0.5 mL anthrone reagent  and 5 mL concentrated sulfuric acid ,cannabis square pot then kept in a boiling water bath for 10 min. At last, optical density value was measured using Spectrophotometer  under the wavelength of 620 nm . The content of ascorbic acid  was determined by 2,6-dichlorophenol titration. A total of 200 g lettuce leaves were crushed and added to the same amount of 2% oxalic acid, then shaked for 5 min. And the solution was fixed to 100 mL with 1% oxalate. Then 10 mL of the above solution was taken and mixed with 10 mL 1% oxalic acid and 1 mL chloroform, then titrated to the end with 2,6-dichlorophenol indophenol dye . The nitrates were determined by Ultraviolet  Spectrophotometry . A total of 0.51 g samples of lettuce leaves were ground into homogenate with some distilled water, then the homogenate was washed into 100-mL volumetric flask with 30 mL distilled water. Another volumetric flask with 30 mL distilled water only was used as control. Then, 5 mL ammonia buffer , 30 mL distilled water, and 0.5 g powdered activated carbon were added into both flasks and mixed well. Subsequently, protein precipitating agent was added, mixed, and filtered after the sample and control flasks were kept still for 20 min. The absorbance was determined by the quartz color dish in the UV Spectrophotometer. The number of fecal E. coli was measured using enzyme substrate method . The sample was incubated at 44.5°C for 24 h, then the number of E. coli was got by UV irradiation. And the Colilert Reagent was provided by IDEXX, UK.Using biomass as a performance determinant, the lettuce under CK treatment showed the best performance, followed by the lettuces of T2, T1, T3 and T4 treatments.

This trend was observed for all of the agronomic traits determined with the exception of root weight. Root weight was followed the order of CK>T2>T3>T1>T4. The lettuce under CK had obvious advantages in biomass growth, however, its stalk was spindling, which might be caused by excessive nitrogen supply, small temperature differences and lower phosphorusus supply. The common nitrogen and phosphorus contents were 49–210 and 15–198 mg L–1, respectively . In this study, the nitrogen content in modified Hoagland nutrient solution was excessive in comparison with the phosphorus content. Using an analysis of variance, the lettuce cultured by modified Hoagland nutrition solution showed a significant advantage over the others cultured by ozone-treated sludge dilution treatments at all dilutions in the leaf number, plant height, fresh weight, and dry weight . Among all the ozone-treated sludge dilution treatments, the T2 was significantly better than the other three treatments  in the leaf number, plant height, root length, fresh weight, and dry weight. Therefore, from the point of view of lettuce agronomic traits, T2 was the most suitable treatment for lettuce growth and development among all ozone-treated sludge dilution solutions. First, the nitrogen and phosphorus contents in T2 dilution were within suitable range. Second, there were some copper  and zinc  in the hydroponics solution. The results also indicated that T1 had excessive Cu and Zn that limited the lettuce growth. It was also reported by other researches . The lettuce biomass results implied that the nutrients in the ozone-treated sludge dilution solutions could improve lettuce growth at low dilutions and inhibit lettuce growth at high concentration applications. This result might be attributed to the favorable buffering of the nutrient solution around plant roots in the low dilutions, which was similar to that in modified Hoagland nutrition solution. On one hand, it was deduced that the release of organic matter during sludge degradation caused a lack of oxygen to the root tissue. On the other hand, the heavy metal contents in T1 solution were higher than those in CK.

In other words, Cu and Zn contents in the nutrition solution of CK were lower than 100 and 200 μg L–1, respectively. The root elongation bioassay was one of the most straightforward test methods used for environmental monitoring in terms of simplicity, rapidity and economy . Nitrogen and phosphorus contents in T1 nutrition solution was higher than those in CK, but the root length of lettuce in T1 was lower than that in CK. The result was caused by the higher heavy metal contents in T1 solution. There was no significant difference between CK and T2 on the root length, however, the dry biomass of CK was higher than that of T2. It was as a result of lower nitrogen content in T2 than in CK. Additionally, high heavy metal concentrations in the sludge were also harmful, resulting in the decrease of root enzyme activity and the inhibition of root growth. The soluble sugar contents in the lettuce cultured with the ozone-treated sludge dilution solutions and the CK nutrition solution was determined . The soluble sugar contents of lettuce leaves in T2 treatment were the greatest, then followed by T3, T4, T1 and CK. According to the ANOVA analysis, the soluble sugar content of lettuce in T2 treatment showed significantly higher than that of other treatments ; while the soluble sugar contents in the T3 treatment showed significantly higher than that of CK, T1 and T4. There was no significant difference for CK, T1 and T4 treatments.As was known to all, chlorophyll absorbed energy from the light, and then used the energy to turn carbon dioxide and water into carbohydrates. The high soluble sugar content of lettuce in T2 may be the result of an optimal sludge concentration causing overall improvements in plant metabolic activity, transport of trace elements and enzyme activity. These improvements could accelerate adenosine tri-phosphate  synthesis and other enzymatic reactions, leading to increased photosynthesis where soluble sugar was the primary by product from this process.

Cu and Zn were the most likely toxicant elements in lettuce when exposed in the sludge dilution solution . The biological toxicity of ozone-treated sludge dilution solution in T1 was presented, which was caused from the higher toxic compounds  . The Cu and Zn contents were over the range of control standards, which resulted in the decrease of soluble sugar contents in T1 when compared with that in T2.The Vc content in lettuce cultured by various ozone-treated sludge dilution solutions and the CK nutrition solution were calculated by ascorbic acid measurements . The Vc content of lettuce in T2 was the highest among all the treatments, then followed by T4, T1, T3 and CK. And the Vc content of lettcue in T2 was significantly higher  than that of other treatments. No significant difference was observed among the T1, T3, and T4 ozone-treated sludge dilution treatments. The trend of Vc was similar to the trend of chlorophyll and soluble sugar contents for all treatments. Vc was especially found in vegetables and fruits and an essential nutritional element for human and cannot be synthesized within the human body. This vitamin must be obtained from external sources such as food. If the Vc storage content in human body was less than 300 mg, some symptoms would appear, such as increased capillary fragility and subcutaneous haemorrhaging to some degree . Therefore, Vc was an important index for lettuce quality evaluation. The Vc content in the lettuce from the T2 treatment was significantly higher than that of other treatments, demonstrating the advantages of the nutritional value in ozone-treated sludge applications when compared to the modified Hoagland nutrient solution.The nitrate contents in the lettuce leaves cultured by the ozone-treated sludge dilution and the CK nutrition solutions were determined. The results demonstrated that the nitrate content in the lettuce leaves under CK was the highest among all the treatments, followed by T1, T2, T3, and T4 treatments .

Based on the ANOVA results, there were significant differences  between CK and the ozone-treated sludge dilution treatments on the nitrate content in lettuce. Among the ozone-treated sludge dilution treatments, nitrate content in T1 showed significantly higher than that in the T2, T3, and T4 treatments . The nitrate contents of the cultured lettuce in the T1, T2, T3 and T4 were 34.3, 53.93, 55.34, and 68.60% lower than that in CK treatment, respectively. Nitrate content is one of the most important indices in vegetable safety evaluation. Normally, trim tray a certain amount of nitrate in vegetables is harmless to human health. However, nitrate can be converted into nitrite by plants, fungi and human gut bacteria, resulting in the formation of compound nitrosamine that is a strong carcinogen . In addition, excessive absorption of nitrate can lead to mental and developmental retardation, low levels of methemoglobin, or even death . According to the requirements of criterion in GB18406.1 , the nitrate content must be below 600 mg kg–1 in fruits and vegetables, 1200 mg kg–1 in root vegetables, and 3000 mg kg–1 in leafy vegetables. Because 80% of the nitrogen in modified Hoagland nutrition solution is nitrate, the cultivated plant will absorb and accumulate excessive nitrate after the ammonium nitrogen is exhausted . While, the plant can utilize ammonium nitrogen directly when cultivated by the ozone-treated sludge dilution solution due to the main nitrogen source of this solution . Thus, the nitrate contents of lettuce treated by the ozonetreated sludge dilution solution satisfied the nitrate limit  in leafy vegetables set by the GB18406.1- 2001 . As shown in Fig. 3-D, nitrate contents in all the treatments of this study were within security scope, and the nitrate contents of lettuce in T1-T4 were significantly lower than that in CK, which indicated that the lettuces cultivated with demestic sludge were security when evaluated with nitrate index only. The result was consisted with the nitrate contents in the nutrition solution, and the nitrate in CK was the highest. However, the leaves of lettuce in T4 are pale green or yellow, which is typical of nitrogen deficiency. Therefore, T2 and T3 were suitable solutions in terms of nitrogen requirements and security of plant.In this hydroponic experiment, we found that 2-fold ozonetreated sludge dilution solution could improve the quality of hydroponic lettuce more compared to the modified Hoagland nutrient solution.

While the federal government still categorizes cannabis as an illicit Schedule 1 substance , states are increasingly legalizing cannabis use, with 18 U.S. states and the District of Columbia legalizing adult recreational cannabis use and 36 states legalizing medical cannabis use as of May 2021 . These states include California, where voters approved medical cannabis use in 1996 and recreational cannabis use in 2016, with retail sales of recreational cannabis beginning on January 1, 2018 . As cannabis legalization spreads, many health professionals are concerned about negative health effects of possible increases in cannabis use , with particular fears focused on potential fetal harms from cannabis use in pregnancy . Studies investigating potential harms from cannabis use in pregnancy have documented a robust association between cannabis smoking and low birth weight . Some studies find increased risk of pre-term birth or small-for-gestational age associated with cannabis use in pregnancy , but others have not found these associations . Some studies have found associations between prenatal cannabis use and adverse neurocognitive outcomes  and increased psychopathology  in exposed children, especially when maternal cannabis use occurred after pregnancy recognition . However, most studies of harms associated with cannabis use in pregnancy suffer from methodological weaknesses, including an inability to adequately control for potential confounders including poverty  and poly-substance use including tobacco . In light of concerns about cannabis use in pregnancy, mobile vertical rack in 2019 the U. S. Surgeon General recommended total abstinence from cannabis for pregnant people .

The American College of Obstetricians and Gynecologists  recommends that prenatal care providers ask all pregnant people about their substance use, including cannabis, and that “women reporting cannabis use should be counseled about concerns regarding potential adverse health consequences of continued use during pregnancy” . However, adherence to these recommendations appears low . A few studies have examined pregnant people’s perspectives on and experiences with cannabis use in pregnancy. These studies have documented that pregnant people are uncertain but concerned about potential risks to their fetus from prenatal cannabis use , and that they seek information on risks and benefits of cannabis use in pregnancy from the internet as well as from friends and family . This research has also found that pregnant people would like to discuss cannabis with their healthcare providers but may be dissuaded due to concerns about being reported to child protective services  and potentially being separated from their newborn . Many pregnant people report receiving no counseling and education on health aspects of prenatal cannabis use from their healthcare providers , even after disclosing cannabis use . Instead, providers may emphasize legal consequences of use during pregnancy, rather than health-related aspects . Most of this research, however, was conducted in states and in time periods where recreational cannabis was illegal . A recent national study focusing on general  contexts found that people who use cannabis were more likely to disclose use to their healthcare providers in states where such use is legal.But research in the U.S. to date has not yet examined patient-provider interactions regarding cannabis use during pregnancy in a context of legalized recreational cannabis.

To fill these gaps, we conducted a qualitative study of people who used cannabis during pregnancy in California after legalization of recreational cannabis, to explore their experiences of their interactions with providers about cannabis. In May-August 2019, we conducted in-depth interviews for a qualitative study that sought to explore perspectives, decision-making, and experiences of pregnant and postpartum Californians who use cannabis regularly, in the context of legal recreational cannabis. This analysis focuses on participants’ experiences disclosing and discussing cannabis use with providers. A group of community advisors with expertise in prenatal care, preterm birth prevention, substance use disorder treatment, and community-informed research helped refine our interview guide, plan and conduct recruitment outreach, and interpret results. Study participants were eligible if they were currently pregnant or had been pregnant within the last year; had used cannabis regularly  in the last year or in the year before their most recent pregnancy; were 18 years or older; lived in California; and were Englishspeaking. Because research has shown that people who use cannabis during pregnancy in the U.S. come from all racial/ethnic groups and socio-economic positions , we aimed to recruit a heterogenous participant group, recruiting via cannabis dispensaries, healthcare providers, and social media. Several cannabis dispensaries in the San Francisco Bay Area posted or distributed study flyers. Providers in prenatal health and substance use disorder treatment clinics also posted flyers and/or referred patients to the study. On Facebook and Instagram, we recruited via local “cannamoms” groups and local cannabis user groups. We tracked demographic details of recruited participants on a spreadsheet and checked regularly to be sure that a range of racial/ethnic groups, socio-economic positions, and recruitment sources were represented. This led us to adjust recruitment after one month: after 9 of our first 14 participants reported that they were referred from a statewide group prenatal parenting program for Black women, we paused further participation from those in this program to ensure that we had a more demographically diverse sample. Interested participants took part in a 15-minute phone call with study staff for eligibility screening, verbal consent, and scheduling, followed later by an in-depth phone interview of up to one hour.

The first author conducted all interviews. A flexible interview guide  allowed us to cover domains relevant to our study questions while also exploring participants’ priorities and diverse experiences. Here, we report on interview domains covering participants’ patterns of cannabis use before and during pregnancy and disclosure and/or discussion of cannabis use in pregnancy with healthcare providers. Participants were given a $50 gift card in remuneration. Interviews were audio-recorded and transcribed verbatim. One participant declined to be recorded; for that interview, we used extensive notes taken during the conversation to inform development of themes, but did not use any direct quotations. We continued recruiting and interviewing until no new themes emerged in our interviews, suggesting we had reached thematic saturation . We conducted coding of transcripts via a two-step process: “chunking” text according to interview domains, and then detailed close coding within domains . We then conducted thematic analysis  of the coded text, using deductive and inductive methods. The first author conducted all coding and led all authors and community advisors in interpretation of results and articulation of major themes, through discussing codes and interview excerpts, followed by revising themes. We selected representative quotes from across the sample to illustrate each theme; the 15 quotes presented here come from 12 different participants reflecting a range of racial/ethnic groups, ages, and educational backgrounds. The study protocol was reviewed and approved by the University of California, San Francisco Institutional Review Board. All participants used cannabis at least weekly before pregnancy; most reported daily cannabis use, vertical grow rack both before and during pregnancy. More than half reported having reduced or stopped cannabis use upon pregnancy recognition. Some reported a mix of reducing and stopping; of these, some stopped using cannabis early in pregnancy but started again later ; others reduced early in pregnancy and then stopped or planned to stop a month or so before their due date.

A few reported that their use stayed about the same in pregnancy as before, or even increased during pregnancy. Most reported using cannabis to ease pregnancy-related symptoms of nausea/vomiting or lack of appetite, pain, or insomnia, or to cope with stress or trauma; some reported using to relax and enjoy themselves with others. This study finds that pregnant people who use cannabis in California continue to report barriers to open discussion of this use with their prenatal providers, despite state legalization of recreational cannabis. While a recent study found that pregnant people do find verbal screening for alcohol, tobacco, and other drugs acceptable and are willing to disclose their substance use to prenatal providers , previous research has found that pregnant people fear that providers’ knowledge of their use will lead to judgment and punishment, particularly reporting to CPS . Consistent with the older body of research, most participants in the current study reported being unwilling to disclose their cannabis use, due to fears of CPS reporting and potential consequences such as parent-child separation. Previous studies have suggested that such fears lead pregnant people who use drugs to physically avoid and/or emotionally disengage from prenatal care . Here, we extend those previous findings by identifying that pregnant people’s fears of being judged and reported to CPS by providers create barriers to comprehensive and compassionate discussions about cannabis use in pregnancy, even in the context of legal recreational cannabis. It is important to note that our participants’ fears of negative repercussions were centered around CPS report for cannabis use during pregnancy, not around the legal status of cannabis use per se. While few people are criminally prosecuted for substance use during pregnancy, about 1 % of all newborns are reported to CPS related to maternal substance use during pregnancy, including cannabis use . In our study, fears of CPS involvement were reported by participants across racial/ethnic groups, but in actuality there are stark racial inequities in this reporting, with providers reporting 4–5 times more Black than white newborns.While legalization of cannabis may reduce some racial inequities imposed by the racist “War on Drugs” , state legalization does not change the federal status of cannabis as a Schedule 1 substance, nor does it necessarily change the CPS reporting policy in the state; further, CPS reporting policies do not necessarily distinguish between legal and illegal substances . California has not changed their CPS reporting policy since legalizing cannabis . Our research suggests legalizing cannabis for recreational purposes does not resolve the barriers that CPS reporting requirements impose on patient-provider discussion of cannabis use in pregnancy. Our finding that few participants reported their providers asking about cannabis echoes previous research finding that providers consider cannabis use in pregnancy to be lower priority to address with patients than other substances used in pregnancy , and that many providers do not respond to pregnant patients’ disclosure of cannabis use . This silence may be sending a health message: our study concords with prior research suggesting that some patients interpret providers’ silence on the topic as an indication that cannabis is safe to use in pregnancy . Provider silence on cannabis use in pregnancy is inconsistent with ACOG-recommended practices and educational messages and may limit opportunities for nuanced and patient-centered discussions about risks and benefits of continued use.

Even when they do occur, though, patient-provider discussions of cannabis may not be nuanced and patient-centered. In our study, participants who discussed cannabis use with their providers reported hearing a wide range of health/risk messages, from endorsement of cannabis use, to recommended harm-reduction strategies, to what they experienced as threats of CPS reports. The spectrum of messages may reflect some providers’ attempts to acknowledge patients’ range of options on cannabis use in pregnancy . However, the inconsistency may also reflect providers’ uncertainty in the face of nascent and sometimes conflicting evidence on health effects of cannabis use in pregnancy . While this study was not designed to examine providers’ motivations for raising the possibility of a CPS report, this study strongly suggests that patients often interpret providers’ discussion of possible CPS report as a threat. Future research should examine providers’ behavior-change philosophies and approaches related to cannabis use in pregnancy, as well as their reasons for and approaches to discussing possible CPS involvement. This work has important implications. First, state-level legalization of cannabis does not address the CPS reporting policies that more commonly punish people who use cannabis during pregnancy. People concerned about pregnant people facing punishment for their cannabis use should focus on changing CPS reporting policies and not only general-population legalization policies. Second, in their committee opinion on cannabis and pregnancy, ACOG included a recommendation that providers inform patients “of the potential ramifications of a positive screen result [for cannabis], including any mandatory reporting requirements” . The findings from this study suggest that this recommendation, as currently phrased, may have unintended consequences, and thus, perhaps should be revised. Further, this study suggests that ACOG’s statement that “Seeking obstetric–gynecologic care should not expose a woman to criminal or civil penalties for marijuana use”  overlooks the realities of widespread CPS reporting policies and practices and the lived experiences and perceptions of pregnant people who use cannabis.