Hemp Growing

Cases in the deCODE sample met criteria for lifetime DSM-III-R or DSM-IV cannabis abuse or dependence or DSM-5 cannabis use disorder according to diagnoses made at the National Center of Addiction Medicine in Iceland, whereas controls were derived from the general population of Iceland . Exposure data were not available for some large groups ; therefore, controls were defined regardless of lifetime cannabis exposure across all datasets.Adverse mental health and social outcomes of cannabis use have been reported for individuals and societies . Cannabis use was associated with the use of other drugs , difficulties to reach life goals , adverse educational outcomes in adolescents , legal issues, and traffic accidents . On the one hand, there are genetic and neuro developmental risk factors ; on the other hand, there are potentially modifiable environmental risk factors of cannabis use . Parenting styles , substance use of parents and peers, academic and school related factors , and risk perception have been described as relevant psychosocial risk factors . In 2016, a global estimate by UNODC based on data from 130 countries estimated that 5.6% of the population aged 15–16 years had used cannabis at least once in the past year . In different regions of the world, the sale of cannabis has been legalized, leading to renewed interest in how this may affect cannabis use and associated factors . In Chile, a law is currently under discussion in Congress aiming to legalize home cannabis cultivation for personal recreational and/or medical use. In the past decade, there has been a public debate about legalization and important changes in legal practice to decriminalize cannabis cultivation. An increase of the prevalence of adolescent cannabis use in Chile was reported for the year 2013 compared to the years 2001–2011 . The prevalence of adolescent cannabis use in Chile was reported to be the highest in the Americas /InterAmerican Drug Abuse Control Commission , 2019. In line with the normalization theory , adolescents in countries with high prevalence of substance use are less likely to report risk factors than in countries with low prevalence.Therefore, risk and protective factors may have changed in prevalence and/or strength of association constituting new challenges for targeting prevention.

Risk and protective factors of substance use had been reported to be consistent between 1976 and 1997 in the US : several variables such as religiosity, political beliefs, truancy, and frequent evenings out were consistently linked to substance use over time among high school students. However, in the current context of marked changes of prevalence in adolescent cannabis use in Chile, the assessment of prevalence factors and their effect size over time may allow reaching a better understanding of the factors underlying the process in which the substance use is changing over time and then contributing to adjust prevention strategies and exploring if the factors associated to substance use vary across years. Factors associated with substance use in adolescents had been reported from Chile for one single year , but how these factors vary over time and in their strength of association with the prevalence of cannabis grow set up use has not been previously addressed. In Argentina, Chile and Uruguay, an increase of cannabis use in adolescents in recent years has been reported, and the association between risk perception and use has decreased. Meanwhile, perceived availability remained strongly associated with cannabis use, but other potential risk factors have not been investigated . The quantification of potential risk factors and their trends over time may allow targeting prevention strategies . The aim of the present research was to identify prevalence trends and associated factors of cannabis use in the past years among adolescents, and to assess trends of associated factors and the strength of association over time.Study participants were adolescent high-school students. The Chilean National Service of Drugs and Alcohol Use Prevention and Rehabilitation  carries out the nationwide school-based survey in students from 8th to 12th grade every two years, with a probabilistic, representative at regional  and nationwide level, stratified , multistage sampling design in clusters . The rate of reached sample was around 80% of the theoretical sample size. The detailed methodology is presented by SENDA in each survey report available online  with stability across the years from 2003 to 2017 and minimal variations. We obtained data from SENDA for the years 2003 to 2017 , 2018. SENDA offers the option of a self-administered questionnaire and a face-to-face interview. In the self-administered version, the students are supervised by a surveyor.

Once the schools and classes were defined, random samples of 20 students were selected from each classroom to participate in the survey /Inter-American Drug Abuse Control Commission , 2019.The survey questions included socio-demographic data, several types of substance use , tobacco and alcohol, perceived risk of substance use, satisfaction with school, school attendance, grades, relations with peers, teachers, and parents and extracurricular activities among others. We selected items that were consistently present across the years, relevant in practice and representing different areas of risk. The following variables were included in the analyses: 1) Cannabis use in the past year ; 2) Funding of the school: public  vs. private or mixed ; 3) gender; 4) age; 5) Use of alcohol in the past month ; 6) Use of tobacco in the past month ; 7) Age at first use of alcohol; 8) Age at first use of tobacco; 9) Unexcused absence from school  in the past year ; 10) School performance based on self-report was dichotomized as low  vs. high; 11) Sport activities, as the number of days per week doing sports as extracurricular activity; 12) Educational level of parents with three alternative categories: uncomplete secondary level, complete secondary level  and complete higher education; 13) Marital status of the parents; 14) Parental acquaintance with friends was assessed with the question, “In general, would you say that your parents  know your closest friends very well, fairly well or little?” ; 15) Parental rejection of alcohol use ; 16) Parental rejection of cannabis use ; 17) Having friends who regularly use alcohol ; 18) Having friends who regularly use cannabis ; 19) Perceived risk of cannabis use .Descriptive statistics were calculated for each year of the surveys, and for the variables: gender, age, school funding, cannabis use prevalence, alcohol and tobacco use prevalence; 95% confidence intervals  were calculated for prevalence rates. Mixed effects logistic regressions were performed for data at individual level, with data nested at the school level , and nested at the level of funding source of the schools. The multilevel logistic binomial regressions were conducted with cannabis use in the past year as dependent variable for each year separately. Adjusted odds ratios were calculated for each variable. The variables at the individual level were: Gender; age; age at first alcohol use; age at first tobacco use; alcohol use in the past month; tobacco use in the past month; perceived cannabis use risk; school performance; truancy; days of sport activities in a week; friends regularly using alcohol; friends regularly using cannabis; educational level of father and mother; parents’ marital status; parental acquaintance with friends; parental alcohol use rejection; parental cannabis use rejection.

Intraclass correlation coefficients were calculated from a null model for both the school level clusters and school funding level clusters. The command glmer of the lme4 package was used in R software to estimate the mixed effects logistic regressions. Variables with odds ratios on average higher than 1.5 across the entire time series were retained for further analyses. This threshold was introduced due to the large size of the data set and to avoid retaining significant odds ratios close to 1.0 that may be clinically irrelevant and irrelevant for prevention planning. Odds ratios smaller than 1.5 can be considered as small effect size and larger than 1.5 as moderate or large effect size . Adjusted odds ratios were calculated for the retained variables for each year of data collection to assess changes of the association over time. Also, interactions between year and each one of the retained variables were analyzed by multilevel mixed effects logistic regressions for all pooled data to assess how the associations between variables and outcomes were affected by time in each survey cycle, using the first year of the series as reference. The prevalence of the retained variables was described as trends over time. Trends of prevalence data and odds ratios over time were plotted for the retained variables and each trend was tested for its fit to linear or higher models, and the F-statistic, degrees of freedom , R-squared and p values were reported. As quality control, before the analyses, data points of participants who answered in at least two occasions in an inconsistent way for each substance were eliminated , for instance, inconsistent answers about date of last use of cannabis, lifetime use and/or use in the past month.The interaction of each one of the retained prevalence factors and year of data collection was calculated, with the year 2003 as reference. specific differences over time in the association of each factor with cannabis use were observed. For the use of alcohol in the past month, we observed a significant negative interaction from 2007 to 2017 showing a decrease of the association with cannabis use over time. For the use of tobacco in the past month, a similar pattern of negative interactions was observed between 2007 and 2015. For the factor friends who regularly use cannabis, we observed negative interactions from 2007 to 2017. For truancy, negative interactions were seen from 2009 to 2017. For low outdoor cannabis grow risk perception, the interaction for 2009 was negative, but thereafter positive. In contrast, low parental cannabis rejection was the only factor that showed positive interactions from 2007 over time until 2017 . Table 3 shows the interactions observed between years and prevalence factors.Our research showed that cannabis use among adolescents increased substantially from 2003 to 2017.

We identified the factors most strongly associated with adolescent cannabis use and present prevalence estimates over time for those prevalence factors. Furthermore, we inform the strength of association over time for each of the most important factors. Although having friends who regularly use cannabis decreased in the strength of association with cannabis use, the variable continued to have the strongest effect size. An important increase in the magnitude of association with cannabis use was seen for low parental rejection of cannabis use. Interaction analyses for each year with each of the factors associated with cannabis use, showed trends since 2007 with a decrease of the association between cannabis use and the factors alcohol use in the past month, tobacco use in the past month, cannabis use in friends, and since 2009 for truancy. However, we observed an increase in the association between cannabis use and low parental cannabis rejection since 2007. Overall, the most important prevalence factors show significant changes in the strength of association since 2007 compared to the reference year 2003. Interestingly, this precedes the major increase in the prevalence of cannabis use observed between 2011 and 2013.This study comprised nationwide survey data of more than a decade with large sample sizes. We show for the first time trends for the prevalence and the strength of association with cannabis use of possible risk factors in a Latin American country. The study also has limitations: even though the surveys were presented in a consistent way over the years, the data were based on self-reporting. Repeated cross-sectional data do not allow establishing causal links between the increase of cannabis use and the associated variables. The variables assessed in this research were mainly on the individual level and limited to the items continuously included in the national surveys over the years.In the US, the prevalence of cannabis use among adolescents in the past year increased between 1991 and 2015, while the prevalence of alcohol use decreased, and the prevalence of any other illicit substance use also decreased . In Europe from 2000 to 2015, the prevalence of cannabis use in the past month among adolescents showed heterogeneous trends in different regions: decrease in Northern Europe in linear trends, increase in Southern Europe in linear trends, decrease in Eastern Europe in a concave trend and increase in the Balkans in a convex trend.

The band positions and intensities were extracted from the spectra of the THCA/THC and CBD powder standards whereas the IR bands from the CBDA cannabinoid were taken from the mentioned reference. These spectra were additionally used and compared with the spectra of the native and decarboxylated flowers and extracts that markedly helped in the band assignments . The most abrupt spectral difference evidenced upon decarboxylation of the flowers is depicted by the increase of the intensity of the bands around 1510, 1430, 1260, 1180, 1040 and 835 cm 1 . The obtained result infer that the emerging bands most likely arise from the vibrations within the THC and CBD units whose content increased upon heating, as the presence of the corresponding acidic forms is majorly reduced. Thus, the medium band at 1510 cm 1occurs from both the CBD and THC and intensity increase upon flower decarboxylation infers increase of their content. In addition, the striking rise of the band at 1424 cm 1 is attributed to the vibrations from the THC molecules since its intensity dominates in the IR spectrum of the pure THC and the CBD lacks this IR absorption band . A similar conclusion is derived for the bands at 1267, 1038 and 835 cm 1 in the decarboxylated flower spectrum that are the strongest band in the THC and either very weak or absent in the CBD counterpart . Furthermore, the bands at 1621 and 1578 cm 1 are blue shifted in the heated samples in comparison to fresh THCA dominant flowers  and pure THCA spectrum . This outcome strongly reflects that, upon heating, the THCA conversion to THC might be successfully monitored by infrared spectroscopy even in the complex matrix. Similarly, the recent Raman spectroscopy work for non-invasive and non-destructive differentiation between hemp and cannabis attributed the bands at 1623 and 1295 cm 1 to THCA/THC species assigning the former one to their aromatic ring vibration. On contrary, the heated flowers  contracted the intensities of strong 888 and 620 cm 1 bands found in the fresh CBDA rich flowers  that are obviously attributed to the CBDA molecules. Namely, these bands are crucial to determine the presence of the CBDA compound  appearing as the strongest peaks in the pure sample. Moreover, their absence in the THCA counterpart infers that these bands are analytical signatures to follow the transformation of CBDA into CBD.

It is also worth mentioning that the IR spectra of the decarboxylated flowers made possible to discriminate between CBDA and CBD on one hand and the THCA and THC on the other. Moreover, the spectra of the decarboxylated flowers and the fabricated extracts are practically identical . Thus, the band discussion for the spectrum of the decarboxylated flower is also valid for the bands in the spectrum of the cannabis extract. This approach derived from the IR results for the native and decarboxylated flowers was further con- firmed by the chemometric model encompassing the most discriminating bands at 1580, 1430, 1183 and 1040 cm 1 as predictors for THC concentration .Fourteen MIR spectra acquired from different cannabis grow system extract samples were used to construct the calibration set whereas the remaining 20 spectra were used for the prediction set. The CBD and THC concentrations in the samples varied between 0.38– 39.2% and 18.93–86.99%, respectively . Only the spectral region of 1800–400 cm 1 was used for the statistical modeling because the ATR diamond crystal exhibit two-photon broad IR absorbance bands between 2600 and 1900 cm 1 that reduce the signal-to-noise ratio , and the MIR region above 2600 cm 1 did not contain any specific bands originating from the molecules of interest. The preliminary analysis of the models revealed that Savitskzy-Golay smoothing and the second derivative of the native MIR spectra resulted in bestfit parameters for R2Y, R2X  and Q2 . The overlaid spectra from the calibration and prediction set, colored according to the THC and CBD content of the samples are presented in Fig. 4a and b. Considering that CBD and THC were not the sole components in the extract and that the samples originated from different sources , it is logical to assume that some transformation of the spectra will be needed to separate and potentiate the specific bands with quantitative relationship to the components of interest. Therefore, in the further part, only the model based on the above mentioned transformation will be presented and discussed. Three main components were extracted from the PLS model for quantification of THC with 0.934, 0.951 and 0.909 for R2X, R2Y and Q2. The score scatter plot for this model reveals distinctive pattern of the sample variances that can be traced to the concentration of THC in the samples. Indeed, these plots reveal how the X variables are related to each other. In this model, there is a clear trend of distinction among the spectra along the t1 vector related to the THC concentration of the samples, thus pointing out the dominant role of the first component in the overall prediction capability of the model. Furthermore, the VIP plot reveals the spectral regions with the utmost importance in the regression model. The bands with VIP factor larger than 1, are usually considered as important both for explaining the variations in the X matrix as well as to correlate with the Y variables. The spectral regions around 1040, 1425, 1183 and 1577 cm 1 demonstrate the largest VIP factors in the model and should be considered as main predictors for the THC concentration. The latter could be additionally confirmed with the coefficient plot , where the mentioned spectral regions are assigned with the largest regression coefficients. The plotted results of actual  versus the predicted THC concentrations  are presented in Fig. 5d, and the RMSEE  of 4.67% indicates the fit of the observations to the model. The RMSEcv for this model is 5.25% and it is an analogous measure to RMSEE, but estimated using a cross-validation procedure.

The RMSEE and RMSEcv are descriptors for the absolute accuracy of the model, and the values reported here should be expected, taking into consideration the variable origin of the samples , number of samples, the employed concentration range, and the real limits of the analytical technique . Three main components were also extracted from the CBD quantification PLS model with 0.936, 0.991 and 0.972 for R2X, R2Y and Q2. In this model, the score scatter plot  also presents a distinctive pattern related to the CBD concentration in the samples that follow a diagonal line between both score vectors , indicating that both the first and second component has significant capabilities for prediction of the Y variable. The VIP plot  demonstrated that the same spectral regions of the previous model , with an addition of the region around 880 cm 1 . These regions bear the largest VIP factors, and at the same time, the mentioned spectral ranges are assigned with the largest regression coefficients . The plot of actual versus predicted CBD concentrations  reveals a better fit of the points relative to the previous THC model with 1.21 and 2.62% for RMSEE and RMSEcv. The predictive capabilities of both models were evaluated separately on a prediction  set of 20 extract samples of various origin and the results are presented in Fig. 6a and b. The root mean square error of prediction,  for THC and CBD PLS quantification models were 3.79 and 1.44%, respectively, thus con- firming the previous accuracy descriptors and ruling out the possible bias of the calibration models.The PLS models for the quantification of THC and CBD in decarboxylated Cannabis flowers also employed the second derivatives of the raw MIR spectra  with Savitsky-Golay smoothing. The overlaid spectra from the 45 samples used in the calibration and prediction set, colored according to the THC and CBD content of the samples are presented in Fig. 7a and b. As in the previous case, such transformation was chosen as the most optimal regarding the main fit parameters  in comparison to the raw, SNV and first order derivative MIR spectra models. Such data transformation is often considered as a necessity in cases where spectra from complex matrices are obtained and the main quantification related bands are overlapped with other components present in the sample. The THC PLS quantification model was build using transformed spectra acquired from 15 decarboxylated samples with various THC content and origin . Five main components were extracted from the model explaining 97.2% of the variations in the X-variables, and producing a high correlation coefficient R2Y = 0.992 with appropriate predictability . The score scatter plot of the second and third component vectors reveal the THC content related pattern, where the THC content increases as a function of the score in both components . The model VIP plot  exposes the bands that are related to the THC content in the flowers. The spectral regions around 1620, 1610, 1578, 1425, 1180, 1038, 1010 and 825 cm 1 which are similar to the ones reported in the extract PLS models, are also assigned with large VIP factors. The coefficient plot confirms the previous findings, where the above mentioned spectral regions with the highest VIP factors,marijuana grow system are also assigned with the highest regression coefficients . The RMSEE and RMSEEcv derived from the actual versus predicted THC concentrations plot  were 0.43 and 1.53%.

The complexity of the sample , the variability of the samples in regards to their origin and horticultural maturity, as well as the nonuniformity of the plant material and the flower-ATR crystal contact should be considered as main factors that govern the accuracy descriptors. Five main components were extracted for the PLS modeling for CBD content quantification of the Cannabis flowers with R2X = 0.969, R2Y = 0.994 and Q2 = 0.66. As in the previously described model, the score scatter plot of the second and third main components vector presents a distinctive pattern associated with the CBD content in the samples . The bands around 1440, 1185, 1100, 1010, 911, 888, and 826 cm 1 demonstrated the largest VIP factors in the MIR spectra . The mentioned bands were assigned with the highest regression coefficients , thus confirming their association with the CBD content. The actual versus predicted plot  of the samples demonstrates a satisfactory level of correlation and the accuracy model parameters RMSEE and RMSEEcv were 0.21 and 1.41%. To evaluate the predictive capability of the above mentioned PLS models for quantification of THC and CBD in decarboxylated Cannabis flowers, a separate prediction  set of 30 samples of different origin was employed. The correlation plots of actual versus predicted THC and CBD content are presented in Fig. 9a and b, and the models RMSEP was 2.32% and 1.33% for quantification of THC and CBD, respectively. The RMSEP values are in good agreement with the accuracy descriptors of the models and con- firm the presented predicting capability of the models in a separate independent set of samples.To our knowledge, this study is the first to use a validated questionnaire to assess the association between female sexual function and aspects of cannabis use including frequency, chemovar, and indication. In this survey of more than 400 women, we found a dose response relationship between increased frequency of cannabis use and reduced odds of female sexual dysfunction. In addition, while the increase in index scores was small , increased cannabis use was associated with improved sexual desire, arousal, orgasm, and overall satisfaction as well as overall improved FSFI scores as compared with less frequent users. Older women and those with more comorbidities tended to have more sexual dysfunction. Importantly, our study did not find an association between cannabis chemovar , reason for cannabis use, and female sexual function. As cannabis use has been shown to be associated with increased sexual frequency in the United States, it is possible this may cause positive effects on sexual experiences.7 Much of the research focusing on sexual function and experiences with regard to cannabis began in the 1970s and 1980s. Cannabis’ potential positive effect on female sexual function was noted as early as 1970 by Tart19 who sought to describe the common experiences of cannabis users. He noted in interviews with college students that orgasms are improved, arousal increases, and “sexual feelings are much stronger” leading to more satisfaction.

The sample size was based on power analysis and previous relevant studies.A total of 357 questionnaires were distributed between January and February 2020 during lectures and 296 questionnaires were returned . Two participants were excluded because their field of study was other than nursing. Finally, 294 respondents were included in the sample. The “Attitudes, Beliefs and Knowledge towards Medical Cannabis Questionnaire”  included 54 items for data collection purposes.Sixteen items were used to assess student attitudes and beliefs towards MC; and, twenty items assessed knowledge on MC effectiveness. MC education/training was assessed by 3 items. A section for reporting demographic, educational and personal data was included. The data collection tool used for this survey evidences internal consistency across multiple locations with Cronbach’s alpha values ranging from 0.767 to 0.831.The instrument was translated from English to Greek and back translated. Cultural adaptation of the translated version was performed by a group of experts including five academic and clinical instructors. The study was designed according to the Declaration of Helsinki and the protocol was approved by the Ethics Committee of the NKUA Department of Nursing . Permission was obtained to use the tool for data collection purposes. Each questionnaire was accompanied by a cover letter providing details about the researchers’ affiliation, contact information and study purpose. Assurance was provided about the voluntary nature of participation and anonymity of collected data. Also, it was clearly stated that returning a completed questionnaire was considered informed consent to participate in the study. Senior undergraduate participants  reported more positive attitudes towards MC use for mental health, fibromyalgia and terminal illness treatment purposes than junior undergraduate participants . Present study results provide the opportunity to compare studies elsewhere of nursing students.Moreover, other data show neutral attitudes towards MC among physicians.Differences between these studies and present Greek findings may be attributed to cultural differences and other factors including the nature and scope of prevailing legislation and regulations. Present study results evidence junior undergraduate respondents are more inclined to believe serious physical health risks are associated with cannabis use. This finding is consistent with that of Khamenka et al.,Chan et al. and Gritsenko et al. who reported the majority of undergraduate medical students believe cannabis use poses serious physical and mental health risks.

The NKUA Nursing Department offers 3rd year students a 3 h lecture on medical cannabis through an elective course titled “Psychoactive Substances”. Consequently, because of the elective nature of the course, few undergraduate students each year receive theoretical education on MC. This may partially explain the present finding that most of the undergraduate participants reported that they should receive formal education on MC laws and regulations. Moreover, undergraduate survey participants were more likely to report a need for MC academic education and clinical practice purposes than postgraduate survey participants. The dearth of MC undergraduate education has been reported in multiple locations.Undergraduate respondents, compared to postgraduates, tend to be less positive about MC effectiveness for medical conditions. Also, they report less personal cannabis use for recreational purposes. The latter issue  is consistent with the findings of Khamenka et al.among Belarus undergraduate medical students who reported less personal cannabis use. Overall, personal cannabis grow system and other substances use tends to be associated with more positive attitudes towards MC benefits. For example, in the study by Vujcic et al.,on undergraduate medical students in Belgrade, the majority of those students believed MC use is safe and associated with health benefits. This result was found associated with positive attitudes towards cannabis use legalization and personal cannabis and alcohol use. Current study postgraduate respondents were more likely, than undergraduate students, to report family member medical and/or recreational use. Moreover, most undergraduate respondents agreed that they should receive MC academic and clinical education/training, including information about laws and regulations, during their nursing studies. These results are consistent with findings of other international studies.Social workers are on the front line dealing with hurmful substance use on individual, family and society levels. The potential increase of MC use among the general population as additional states approve its use, can influence social work practice linked to substance use disorder and criminal justice, health care and child/social welfare institutions and systems.In these domains, social workers have a significant role; therefore, there is ample justification that they should be trained about MC potential benefits and harms. Changing policies and regulations are expected to position social work professionals with significant roles and responsibilities linked to MC. However, little is known about social work student attitudes and beliefs about MC- aspects that would contribute to curriculum development. The aim of this study was to assess MC attitudes and beliefs among social work students from the United States and Israel.

The MC regulations of these two countries differ; and, therefore, it is hypothesized that differences exist between the study groups in terms of the factors studied. Based on college/university level MC education,we believed a cross-national comparison of social work students will reveal MC attitude and belief differences attributed to culture and experience with MC. Drawing on research of student attitudes and beliefs about MC,a data collection instrument was modified for cross- national social work survey purposes. Questions were developed in English, translated to Hebrew and back translated to English to ensure content and vocabulary were appropriate to the students surveyed. This process involved native Hebrew and English-speaking university social work faculty members. The resulting questionnaire used in this survey consisted of 40 short and simply worded questions about MC effectiveness for various conditions, risks, benefits, treatment, training and research. Detailed information about the instrument have been recently published elsewhere.The study was conducted during the 2018–2020 academic years in two institutions of higher education – one in the southern region of Israel and the other in New Jersey . The survey also included a question about student recreation cannabis use. This was included because students’ recreational use has been found correlated with positive attitudes, beliefs and knowledge about medical cannabis including education and training.The aim of this study was to assess medical cannabis attitudes and beliefs among a cross national study cohort of social work students. Overwhelming support was found for MC and substantial acceptance of its therapeutic value. These findings are similar that found among other health professionals such as oncologists and pharmacists.The present study did not evidence any difference based on gender and students who reported personal cannabis use, compared to non-users, were more likely to recommend MC for treatment. Students, regardless of country, who used cannabis were less inclined to believe cannabis use poses serious physical or mental health risks. Finally, despite the beliefs about its use, both groups of students reported a dearth of formal education about MC. Some differences were found between the two groups of students. In most cases, US students reported more favorable attitudes toward MC than those from Israel. The decision to use US and Israeli students for comparison stems from both similarities as well as differences between the two cultures. For example, the State of Israel’s culture is distinctly US orientated; and, ’American’ values, practices, and culture influence many living conditions in the country including political traditions and economic policies among others.Moreover, despite cultural differences, both US and Israel share values that originated in Western society and guide social work studies and practice.

Future studies should include cultural factors such as student substance related norms to deepen the understanding of the similarities and differences found in the current study. There is an ethical dilemma that needs to be addressed with respect to student expressed use of cannabis for recreational purposes when they know it is not legal in areas where they are residing. In the United States, the National Association of Social Workers  Code of Ethics does not specifically address the issue of MC; however, the Code’s preamble highlights the dual focus social work professionals have on individual and society.For example, Baker & Randolph conducted a study to examine the ethical dilemmas that face social workers when they provide to clients who use MC.These researchers found that even though social workers must practice under the NASW Code of Ethics by promoting the self-determination of clients, the dispute over the medical cannabis laws creates controversy for the profession regarding this basic tenet. Furthermore, they point out that social workers should be aware of where and how their clients are acquiring MC. If the client is obtaining it illegally, this places the social worker in the ethical dilemma of knowing his/her client is breaking the law. Despite all of this, the NASW Code specifies the professional values of a social worker including service, social justice, the dignity and worth of all people, as well as the integrity of the profession. These values are also reflected in the Israeli social work code of ethics.Therefore, although there is a lack of uniformity of the acceptance of MC, under the codes of social work ethics inboth the US and Israel, it is clear that social workers have a role to serve people in need,advocate for both clients and society-at-large, and to practice in an honest and trustworthy manner.Education on MC should address medical, social, and ethical issues related to it. This will provide social work students with a comprehensive understanding of the substance and promote their ability to relate to dilemmas that might arise while addressing individuals in need. Notwithstanding their lack of knowledge and training, the vast majority of survey respondents reported that they would recommend MC for their clients. This may be explained by the fact that social workers do not have the legal competency to authorize such use ; therefore, potential professional and legal ramifications are not at stake. Indeed, previous studies reported those peoplelegally eligible to certify for MC use tend to hold more permissive and favorable attitudes about marijuana grow system use for medical conditions.Likewise, since only two universities were included in this study the findings may not be generalizable to other Israeli or US students due to age, cultural and religious differences. Similarly, the majority of Israeli respondents were undergradate students while all of the US students were graduate students. There may be differences in these two samples based on the differing academic levels. Additionally, the survey relies on self-reporting which can lead to biases from respondents that may not accurately represent their attitudes about MC.

Despite these limitations, this study provides information that can guide additional research to further explore attitudes about MC among professionals and potentially influence policy change. Medical cannabis  is legal in many countries, with much regulatory variability. The legality of MC has changed considerably over the past several decades, particularly with evidence of its value for chronic illnesses and related symptoms.1 For example, cannabis or cannabinoids have been proven to be useful for the treatment of chronic pain, chemotherapy-induced nausea and vomiting, and for improving multiple sclerosis spasticity.For nearly three decades, Israel has been officially using the substance to treat selected medical conditions. More recently, Thailand has become the first country in Southeast Asia to approve medical cannabis. As these countries move forward with the substance for medical purposes, key questions persist about the nature of knowledge, attitudes, and beliefs about MC among medical students who will become clinical practitioners, medical consultants, and health service decision-makers. For centuries, the chemicals in cannabis and cannabinoids have been used for medical purposes. The psychoactive compound of cannabis, THC or tetrahydrocannabinol, is linked to a sense of euphoria or a “feel good” condition, which may encompass positive effects for certain conditions, but is also associated with potential negative effects, such as psychotic symptoms or cognitive impairment.A second compound is cannabidiol or CBD, which is non-psychoactive and is considered to be associated with many therapeutic effects.MC has been found useful for chronic neuropathic pain,reducing chronic or neuropathic pain in advanced cancer patients, and as an adjunct to traditional analgesic therapy.Despite these positive results, the potential benefits of cannabis-based medicines for chronic neuropathic pain may be outweighed by their potential harm when used in combination with opioids.Indeed, increased anxiety and depression have been reported among such patients, including those who use tobacco, alcohol, cocaine, and sedatives.

Pre-legalization, Indigenous communities identified a lack of culturally-specific educational materials on the health effects of cannabis; these should be developed, and could be implemented as a harm reduction strategy . Increased treatment availability will also be important. Given the high prevalence of use among youth, this population may be at increased risk of developing cannabis use-related problems ; early-onset use, in addition to high frequency use and use of high-potency products, has been identified as a major risk factor for subsequent health harms . At present, evidence-based treatment options in Canada for cannabis use disorder are limited . Ensuring Indigenous Canadians’ access to treatment can begin with increased access and funding for culturally-specific mental health and addictions services, as a gap in these services has been identified by Indigenous communities . Our systematic review has several potential limitations. First, our review focused on the prevalence of cannabis use and its associated factors in Indigenous Canadians, but we restricted inclusion to publications that reported data on cannabis use prevalence. Therefore, our review may not represent the full scope of research on factors associated with cannabis use in this population. Second, publications focusing on groups other than on-reserve First Nations were limited in number and had small sample sizes, reducing the generalizability of our findings. Third, bias affecting external validity  was common among our included publications; all but two had at least one item at high risk of bias in this section. To increase the generalizability of our findings, we focused our summary of prevalence results on publications with the largest sample sizes and the fewest items at high risk of bias. Fourth, the interpretability of our findings on associated factors is limited given the largely cross-sectional nature of the available data, which renders the directionality of associations unclear.Because of the massive scale of the Covid-19 pandemic, Covid treatment research is subject to intense politicization, frequent media scrutiny, and continued public interest.

As thoroughly described in a recent JAMA Viewpoint Article , public scrutiny into drug development research has the potential to introduce a new set of incentives into the research process, which can, in turn, disrupt science-based regulation and the delivery of evidence-based treatments. These dangers became abundantly apparent through the US experience with hydroxychloroquine. When influencers and politicians began to endorse hydroxychloroquine as a treatment for Covid based upon early observational and preclinical studies, many in the public, including patients, physicians, and policy-makers, were quick to embrace hydroxychloroquine as an effective treatment, even though observational and preclinical studies are incapable of causally proving a drug’s safety or efficacy. This unearned enthusiasm for hydroxychloroquine led to shortages for those who required the drug for approved indications  and even cases of poisonings . Another observational study  subsequently found a positive association between hydroxychloroquine use and mortality as well as other adverse events, which may have made recruitment for hydroxychloroquine randomized controlled trials more challenging . Concerningly, the cacophony of contradictory observational and preclinical evidence presented in the media led some members of the public to adopt a dogmatic attachment to the drug’s effectiveness or ineffectiveness in line with their political identity . Since hydroxychloroquine was first suggested as a possible Covid treatment, a large-scale RCT, similar to what would be required for FDA drug approval, along with five smaller RCTs have all failed to find that hydroxychloroquine is an effective treatment for Covid. The authors of the large-scale RCT stated on June 5th, “this result should change medical practice worldwide and demonstrates the importance of large, randomised trials to inform decisions about both the efficacy and the safety of treatments” . Despite this causal evidence, many in the public still believe that hydroxychloroquine is an effective treatment , detracting from other potentially effective preventive measures and treatments and fueling conspiratorial theories about pharmaceutical interventions overall .Owing to the political and social history of cannabis grow facility, the safety and efficacy of medical cannabis and cannabis derived products is a political, as well as scientific, discourse. Many patients, physicians, and policy-makers want cannabis to be a safe and effective medication and are willing to endorse cannabis’ safety and efficacy with little supporting evidence . Media outlets frequently and widely cover the results of cannabis research, and like with hydroxychloroquine, many in the public are primed to accept favorable findings, regardless of their methodologies, as truth.

Because observational and preclinical studies generally take less time and cost less money than large-scale RCTs, interested parties, particularly “Big Marijuana” companies, are able to sponsor dozens of non-causal studies and publicize their findings, providing more ammunition to their political allies . The dissonance between positive observational trial results and federal cannabis prohibition have caused many in the public to form their own conclusions about the underlying motives for cannabis policy . Some become distrustful of the actors and systems instituting prohibition, including policy-makers, pharmaceutical regulators, and the pharmaceutical industry. Because their situations are similar, medical marijuana researchers can potentially learn some lessons from the experience of hydroxychloroquine researchers. Perhaps none is more important than the notion that researchers and regulators should only accept results from large-scale RCTs as evidence of a drug’s safety and efficacy regardless of political pressure or competing findings from other forms of research. Much of the harms related to hydroxychloroquine could have been averted if physicians and researchers insisted on proof of safety and efficacy from large-scale RCTs and if the FDA had imposed greater restrictions on use related to non-approved indications. Similarly, an insistence on large-scale RCTs to confirm the safety and efficacy of cannabis and cannabis-derived products, as well as stricter regulatory controls on unsubstantiated health claims made by marijuana marketers, could avert potential public health harms related to inappropriate medical cannabis use. Further, to the extent that cannabis and cannabis-derived products are truly safe and effective for certain conditions, large-scale RCTs can confirm these benefits and give policymakers, physicians, and patients the confidence to allocate appropriate treatment.To the layperson, other forms of research can appear to have equivalent or even greater value compared to large-scale RCTs . This is particularly true for observational studies. Observational studies can have thousands more participants than even large RCTs. They often use complex-sounding statistical techniques, like propensity score matching or growth models, while RCTs are statistically straightforward. Observational studies involve “real users” as opposed to clinical study test subjects. While some are aware of the concept of confounding, many can be appeased by adjustment for confounders in the analytical rather than design phase of the study. Despite their veneer of credibility, observational studies have no causal interpretations and, instead, can easily provide biased effect estimates. Large-scale RCTs are the only method that can reliably provide causal estimates of an effect . Consider, for example, a treatment that has no effect. The treatment is tested in 100 different trials, each with 1000 participants. The relationship between the treatment and the outcome of interest is confounded by 20 variables , which could be, for example, gender, race, age, height, weight, and blood pressure.

For simplicity, assume that each confounder is randomly distributed around 0.4  for those not receiving the treatment and 0.6  for those receiving the treatment. The effect size of each confounder on the outcome ranges between 0.5 and 5 , with an equal probability of either increasing or decreasing the outcome. To avoid overfitting, I include a random error centered at 0 with a standard deviation of 10. Observational researchers rarely know all potential confounders or even have access to data on all known confounders. Assume, then, that the researcher knows and collects data on, on average, 30%  of the confounders, and adjusts for all of them. Many researchers would consider an observational study with six confounders “well-controlled”, and yet it is reasonable that 10 continuous and 10 dichotomous variables confound a given relationship. However, if we simulate this circumstance, approximately 85 of the 100 trials would produce an estimate significantly different from 0, even though the treatment truly has no effect . Each of these 85 trials may be publishable in separate peer-reviewed journal publications, but none of them would be accurate. Indeed, if the research or publication process is biased in one direction, cannabis grow system it may appear that the literature consistently shows a relationship in that direction. Large-scale RCTs eliminate the dangers emerging from unknown confounders. Because participants are randomized to receive either the treatment or a control and because the sample size of both groups are large, all third variables, including known and unknown confounders, balance between groups.1 In other terms, it is not possible for potential outcomes to correlate with the treatment when the treatment is randomly assigned. In the above example, this is analogous to adjusting for all 20 known and unknown confounders. If we simulate that case, approximately 95 of the 100 trials produce results consistent with the treatment’s true effect size. Other study designs have related problems. Small-scale RCTs, for example, do not necessarily balance confounders or potential outcomes; without help from the law of large numbers, the different treatment arms can, by chance, be correlated with known and unknown confounders and potential outcomes . Many initial safety trials do not have a comparison group altogether, and so the effect can be confounded by time or disease progression. Animal models and preclinical studies frequently fail to produce comparable results in humans due to the immeasurable number of confounding biological systems . For these reasons, large-scale RCTs are almost always required for drug approval by regulatory bodies in developed countries around the world. It should be noted that, in the United States, the 21st Century Cures Act has allowed for some flexibility in the study design and statistical analyses of trials used to test new medical devices and drugs’ safety and efficacy. Even in these cases, however, FDA guidance on Bayesian analysis affirms the importance and necessity of random assignment to treatment and a sufficient sample in late-stage investigational new drug trials . It is true that, strictly speaking, large-scale RCTs are not the only way to establish causal evidence . For example, natural experiments, which exploit random or quasirandom assignment occurring in the real world, can have many of the same benefits as RCTs  and potentially better generalizability.

However, true natural experiments, particularly for the use of pharmaceutical products, are rare. Further, when a natural experiment is found, one needs to be convinced that assignment to the treatment is truly random, or at least orthogonal to potential outcomes conditional on adjusting for observed confounders, before accepting the results as causal. In virtually all cases, that argument requires at least a small leap of faith . Consequently, large-scale RCTs are the only study design that can reliably produce causal evidence. Large-scale RCTs have another key benefit over observational, early clinical, or natural experiment designs: it is challenging for researchers to intentionally bias their studies to find favorable results. For both pharmaceutical and marijuana research, researchers often have a considerable interest – financial, ideological, or otherwise – in producing findings that suggest the drugs they test are safe and effective. Dishonest researchers may, for example, selectively choose which confounders to include in their models in order to find a spurious but statistically significant result . Large-scale RCTs essentially remove the option for researchers to act in this way. Potential outcomes are balanced through the randomization procedure, and so the researcher merely has to perform some simple and straightforward analytics in order to assess whether the drug had an effect or not. She cannot purposely introduce bias into her model by omitting a confounder. Simply put, with large-scale RCTs, there is little room for dishonest researchers to play statistical games with their data. It should be noted that not all large-scale RCTs are properly formulated or conducted to produce clinically meaningful results, and the mere presence of a study that brands itself as a large-scale RCT is insufficient to determine whether a drug is safe and effective or not . For example, in trials that are inappropriately conducted, randomized groups may differ in post-randomization experiences or randomization may not be properly generated at all.

Importantly, the full-spectrum cannabis extract totally relieved thermal hyperalgesia, mechanical allodynia and withdrawal latency in CCI rats. In contrast, treatment with purified CBD or purified THC, given at the same dose existing in the extract, showed only a partial anti-nociceptive effect. Thus, this study suggests that full-spectrum cannabis extract has a better analgesic effectiveness than CBD or THC alone in rats with neuropathic pain. Intriguingly, the authors also found that the anti-nociceptive effect of the full-spectrum cannabis extract was independent of CB1 and CB2 receptors. Indeed, the anti-nociceptive effect of the full-spectrum cannabis extract was mainly due to the activation of the vanilloid receptor, TRPV1. This conclusion was supported by the finding that treatment of animals withCB1 and CB2 receptor blockers could not abolish the protective effect of the full-spectrum cannabis extract. Conversely, TRPV1 receptor antagonist, capsazepine, completely blocked the effect of full-spectrum cannabis extract suggesting a TRPV1-dependent mechanism . Overall, this study clearly demonstrated that the beneficial effects of the full-spectrum cannabis extract was superior to purified THC or CBD in the treatment of neuropathic pain and that this effect was not mediated via the classical CB receptor-mediated signaling. The anti-nociceptive effect of full-spectrum cannabis extract has been confirmed in streptozotocin-induced diabetic neuropathy in rats. Treatment of these animals with full-spectrum cannabis extract significantly ameliorated mechanical allodynia and the physiological thermal pain perception. Of importance, the observed effect was independent of hyperglycemia, suggesting a direct neuronal effect. Indeed, evidence suggests that the anti-nociceptive effect may be due to the activation of the neurotrophic factor, nerve growth factor , by one or more components within the cannabis extract. In addition to the anti-nociceptive effect, full-spectrum cannabis extract protected against oxidative stress-induced neuronal damage in these diabetic rats.

Collectively, this study supports the concept that the combination of cannabinoid and non-cannabinoid compounds, vertical grow rack as present in the aforementioned extract, produces a profound benefit in the treatment of neuropathic pain . In addition to the pre-clinical studies, full spectrum cannabis extract such as Sativex has been investigated in numerous clinical trial on patients with MS-related symptoms . These trials are either double-blind randomized placebo-controlled parallel-group trials, an uncontrolled open-label or non-interventional trials that have studied the effect Sativex as a monotherapy or as an add-on therapy on patient with MS-related symptoms. Notably, Sativex reduces neuropathic pain, muscle stiffffness and spasticity, bladder dysfunction, and improves sleep quality in MS patients. Importantly, the effect of Sativex on MS-related neuropathic pain was more pronounced when administered as an adjuvant therapy. Overall, these trials confirm the notion that full spectrum cannabis extract such as Sativex is effective for the treatment of MS-related neuropathic pain. While small scale clinical studies suggest that full-spectrum cannabis extract like Sativex is safe and effective in the treatment of MSassociated symptoms such as neuropathic pain, this might not necessarily hold true for all other cannabis products. Indeed, purified oral THC lacks beneficial effects for the treatment of neuropathic pain associated with MS . In addition, oral products with purified or high THC content produces cognitive dysfunction, undesirable psychological effects and tachycardia. Thus, care should be taken in the interpretation of the effectiveness and safety of the types of cannabis products used in treating neuropathic pain.While the major undesirable effects of THC containing products are cognitive dysfunction, particularly the loss of short-term memory consolidation, anxiety, tachycardia and hunger, these are obviously not common adverse effects of full spectrum cannabis extract like Sativex. In fact, given that full spectrum cannabis extract consists of a variety of cannabinoids and terpenes, we postulate that these cannabinoids and terpenes can help minimize the undesirable effects of THC. In support of this notion, CBD was shown to reduce unpleasant THC-induced effects such as psychological reactions, anxiety, tachycardia and hunger  through the more traditional CB receptor-mediated pathway. Indeed, the reduction of the unpleasant THC effects are mediated by the following mechanisms:  CBD appears to compete with THC for CB1 receptor binding site and acts as a CB1 receptor antagonist or reverse agonist and  CBD suppresses the activity of CYP2C and CYP3A enzymes involved in the metabolism of THC in the liver, which subsequently inhibits the hydroxylation of THC to its 11-hydroxy metabolite.

Of note, 11- OH-THC is 4 times more psychoactive compared to THC , and thus reducing the formation of 11-hydroxy metabolite by CBD should minimize the unpleasant psychological reactions of THC. In addition to CBD, α-pinene, a bicyclic monoterpene, was shown to aid the memory and minimize cognitive dysfunction via blunting the activity of acetylcholinesterase in the brain. Together, the absence of the major undesirable effects of THC is an important advantage of full spectrum cannabis extract like Sativex. Nevertheless, side effects such as somnolence, dizziness, confusion, fatigue, dry mouth, white and red buccal mucosal patches and nausea have been reported in patients on Sativex. In contrast to Sativex, the presence of CBD in some cannabis grow racks extracts, particularly the oral extracts, can sometimes exacerbate some of the psychological effects of THC  which might be due to the profound effect of CBD on the hepatic first pass metabolism of THC whereby CBD elevates the blood level of THC . Thus, oral broad spectrum CBD extract  might be safer than oral THC or THC/CBD cannabis extract products. Nevertheless, while highly purified CBD extract lack any psychoactive adverse effects, a risk of hepatotoxicity, in addition to suicidal ideation have been reported with a chronic high dose of extracted CBD. Other adverse effects such as fatigue, somnolence and gastrointestinal disturbances have been also reported.Cannabis sativa L.  is one of the oldest cultivated plants in history with multifarious applications, ranging from the textile, construction and paper industries to the nutritional, pharmaceutical and cosmetic sectors. While the stems provide cellulosic and woody fibres of very high quality, and the seeds are a rich source of fatty acids and proteins for the feed and food industries, the leaves and inflorescences are a gold-mine for phytochemicals. The rich spectrum of bioactive compounds can be exploited for several pharmaceutical applications . The plant is known for its therapeutic usage as antiemetic, analgesic, and appetite stimulant or to treat epilepsy, glaucoma, and Tourette’s syndrome . In total, a broad spectrum of more than 500 phytochemicals has been identified from the leaves, flowers, bark, seeds, and roots. This includes numerous cannabinoids, flavonoids, and terpenoids, as well as sterols , which are of industrial interest. The phytochemical spectrum, however, varies significantly with chemovar and plant part , and also with agronomic and environmental factors . Traditionally, stems, inflorescence and seeds were the most used plant parts. In medicine, the major focus has always been on cannabidiol  and Δ9 -tetrahdydrocannabinol  as bioactive compounds, which are mainly present in the flowers, as well as the leaves. Thus, the roots have been investigated less with respect to the reported pharmaceutical potential. Nonetheless, the roots have historically been used for the treatment of fever, inflammation, infections, as well as arthritis . Recently, the presence of phytocannabinoids has been reported in hairy roots for the first time, although in almost negligible amounts compared with the rest of the plant .

Naturally occurring triterpenoids are described as being of therapeutic value because of their anti-cancer, anti-inflammatory, antiulcerogenic or antiviral activities . The first characterized triterpenoids from ethanolic root extracts were friedelin and epifriedelinol, reported in 1971 . Recently β-amyrin was discovered to be accumulated in hemp roots as well . Of the identifiedtriterpenoids, friedelin seems to be the most abundant , which was reported to exhibit anti-inflammatory, antipyretic and analgesic effects in mice and rats . Triterpenoids have been extracted from cannabis roots by conventional extraction with ethanol , ethyl acetate , n-hexane, and petroleum ether . Supercritical fluid extraction  has not yet been described for triterpenoids from cannabis roots. However, the extraction with supercritical carbon dioxide in combination with EtOH has been reported for triterpenes from other plants . Furthermore, SFE can be considered an environmentally friendly and highly efficient alternative, compared with volatile solvent extraction . Antioxidant activity of naturally occurring triterpenoids has been determined in several studies. Cai et al.  observed DPPH , ABTS, and superoxide anion free radical scavenging activity in extracts from medicinal fungus S. sanghuang. In particular, friedelin, isolated from Azima tetracantha Lam. leaves showed very promising scavenging effects on DPPH, hydroxyl, superoxide, nitric oxide, and suppressive effects on lipid peroxidation . Additionally, phytosterols are known to be antioxidants and β-sitosterol, campesterol, as well as stigmasterol, have been reported to act as modest radical scavengers in solution . Currently there are no studies available on the antioxidative capacity of hemp root extracts, where triterpenoids and phytosterols have been identified. This study presents the extraction of phytochemicals from hemp roots and the identification of heretofore undescribed secondary metabolites to ascertain the exploitation potential of this plant part, which is usually treated as waste. The predominant triterpenoids friedelin and epifriedelinol were directly quantified from the root extracts of three different hemp chemovars by GC–MS/FID analysis. Moreover, the extraction efficiency of the target triterpenoids by conventional extractions with EtOH and n-hexane as well as a supercritical CO2 extraction is discussed herein for the first time. Furthermore, the influence of different harvest times and drying conditions on the triterpenoid concentration for one chemovar was monitored. In addition, in vitro  and cellular antioxidant activity assays of the ethanolic cannabis root extracts were measured for the first time, due to the reported antioxidant activities of the accumulated secondary metabolites in hemp roots. The roots of three type III Cannabis sativa L. chemovars , Futura 75 , Felina 32 , and Uso 31 , were cultivated in the fields  of BioBloom  in 2019.

The crop was planted in rows with an average plant density of 35 plants per m2 . All three chemovars were grown organically in close proximity on a 60 ha plot. For Futura 75, three individual samples, which varied in harvest times and drying conditions were analysed. The hemp roots of Futura 75 , were collected in July 2019, air dried and stored at room temperature. For comparison of chemovars, Futura 75 , Felina 32 , and Uso 31 , were harvested in August 2019 and received the same postharvest treatment as sample A. The third sample of Futura 75  was harvested on an agricultural scale in October 2019 after the vegetative period and after the harvest of the aerial parts. Sample C was heavily washed with the help of a steam cleaner and dried for 30 h at 45◦C in an agricultural drying facility and stored at room temperature until analysis. For analysis, the complete hemp roots were washed with water and chopped to smaller sized parts. The pieces were shock frozen with liquid N2 and milled by a Retsch ZM 100 with sieve  at 14,000 rpm . The pulverized material was lyophilised until constant weight and stored in a dark place for further experiments. Qualitative and quantitative analysis of the chemical constituents was carried out with an Agilent 7890A GC-System coupled to a mass detector and a flame ionization detector . An Agilent HP-5MS GCcolumn  was used for the separation. The initial flow was set to 1.3 mL/min and helium was used as a carrier gas. The samples were injected without split. The temperature program for the analysis was as follows: 1 min at 100◦C as initial conditions, 10◦C/min ramp up to 325◦C, and 15 min hold at 325◦C. The FID was operated at 350◦C. Electronic ionization  was used for the detection mass spectrometry. Source and single quad temperature were 230◦C and 150◦C. The total ion current  was measured between 35 to 750 m/z after a solvent delay of 6.5 min. The method was developed and modified according to recent literature for the separation of triterpenoids . For the quantification with GC-FID, an analytical grade standard of friedelin was purchased from Sigma-Aldrich . A stock solution  in chloroform was prepared and diluted for calibration. The triterpene epifriedelinol was expressed as mg friedelin equivalent per g dried hemp root. The identification of the compounds was performed by comparing fragmentation patterns with an intern mass spectrometric library, National Institute of Standards and Technology  database , and corresponding literature data or the purchased pure standard substance.

This approach can help to overcome the main sources of bias from classical observational approaches, by providing a more reliable estimate of the likely underlying causal relationship. There are limitations to this study that should be considered. First, the ALSPAC cohort suffers from attrition, which is higher among the socially disadvantaged . Furthermore, polygenic scores for tobacco smoking initiation were associated with drop out in the ALSPAC . We attempted to minimize the effect of drop-out by using multiple imputation, FIML, and inverse probability weighting which assume MAR missing patterns. Although it is not possible to test the MAR assumption, it was made more plausible as a number of SES variables were found to predict whether participants attended the clinic or not . Second, tobacco and cannabis use were self-reported. However, there is evidence to suggest that self-reported assessments are reliable and valid methods , and the assessment of tobacco and cannabis use yearly over 6 years in a latent variable framework helps to account for measurement error . Third, while the longitudinal approach for each substance used in this study has a number of advantages over using measures at a single timepoint, it was not possible to examine cannabis use without tobacco use as most cannabis users use cannabis in combination with tobacco . We therefore cannot rule out the possibility that observed associations between cannabis use and cognitive functioning are exacerbated by the combined use of cannabis and tobacco. Fourth, different measures of tobacco and cannabis use for the observational and MR analyses were used. Along with deriving latent classes of tobacco and cannabis use, we used the largest GWAS consortia  which has identified 341 genetic instruments for ‘smoking initiation’, and the GWAS conducted by Pasman and colleagues which identified 8 genetic instruments for lifetime cannabis use which are continuous measures. To our knowledge it is not currently possible to use a nominal exposure  and consequently the effect sizes are not directly comparable. Fifth, it is likely that both the one- and two-sample MR analyses areunderpowered. However, findings using weak instruments tend to bias findings towards the null in the two-sample setting and toward the outcome-risk association in the one-sample setting . Sixth, the main limitation of one- and two-sample MR is that the quality of the pooled results in the GWAS consortia is dependent on the individual studies.

Another limitation is that the same sample may contribute to both GWAS  which was the case in the current study as ALSPAC was in both the exposure and outcome. This will bias the MR estimate towards the observed estimate. However, as the MR found no clear evidence for an effect, this suggests it was not biased by overlapping samples. See Lawlor and colleagues  for a more comprehensive description of limitations associated with MR studies. Finally, it is possible that the direction of the association could work in both ways, that is, impairments in cognitive functioning may precede  tobacco and cannabis square pot use.We were able to include a number of measures to maximize the robustness of our findings:  ascertaining the temporal order of exposures and outcomes;  controlling for premorbid working memory and brain insults prior to measures of tobacco/cannabis use helped to reduce the possibility of cognitive impairments, or lower cognitive abilities in childhood, influencing tobacco/cannabis use; and  it is possible that a common risk factor is influencing both tobacco/cannabis use and lower cognitive function, however MR methods helps to protect against this possibility by minimizing bias from reverse causation and residual confounding.Overall, there was observational evidence that adolescent tobacco and cannabis use were associated with subsequent cognitive functioning, highlighting impairments in a range of cognitive domains, including working memory, response inhibition and emotion recognition. Our findings lend support to the developmental vulnerability hypothesis, in that, tobacco and cannabis use in adolescence, when the brain is undergoing critical development, may have neurotoxic effects. Better powered genetically informed studies are required to determine whether these associations are causal. In order to rule out the possibility of deficient cognitive functioning preceding substance in adolescence, future research should use an equally robust approach to examine the alternate hypothesis. This study lends support to public health strategies and interventions aimed at reducing tobacco and cannabis exposure in young people.In the last two decades and owing to serious adverse effects associated with the use of opiate medications and nonsteroidal anti-inflammatory drugs , the two major pharmacological groups used in pain management, more attention has been paid to cannabis-based extracts and cannabinoid-based products to fill the gap left by analgesics currently available in the clinic .

Increasing evidence from human clinical trials has demonstrated that cannabis-based therapeutics can minimize neuropathic pain intensity and provide effective remedies for chronic pain management . However, the clinical use of herbal cannabis is opposed by several limitations including the psychoactive adverse effects  and associated harm to individuals and the public health, the complex and variable chemical content with the associated lack of consistency and standardization, possible microbial and pesticidal contamination, as well as the lack of solid evidence of effectiveness. Therefore, there is a critical need for robust research on herbal cannabis and its ingredients to evaluate the medical potential of the active ingredients alone and in complex mixtures . Potentially bioactive cannabis-derived compounds not only include cannabinoids but also terpenes, which comprise more than 150compounds out of the 500 plus constituents of Cannabis Sativa, the most commonly used cannabis species . Based on the fact that different cannabis varieties are able to induce various physiological effects, as has been observed among cannabis users, the socalled “entourage effect” has been proposed to refer to the additive or synergistic contribution of terpenes to the pharmacological effects shown by cannabinoids . In a recent study that investigated the ability of terpenes found in C. Sativa to activate TRPV1 in HEK cells, a mixture of terpenes was found to remarkably promote intracellular calcium influxes. In addition, betamyrcene  and, to a lesser extent, nerolidol  were identified as the major contributors to the calcium influx activity. MC activity was completely dependent upon the presence of TRPV1 protein and thus the TRPV1 antagonist capsazeine could effectively bloke MC-induced calcium influx. Furthermore, based on molecular docking data, MC binds to TRPV1 to via a hydrophobic, non-covalent interaction . MC , a monoterpene and the most abundant terpene in cannabis, and NL , a sesquiterpene, have both demonstrated anti-nociceptive and anti-inflammatory effects . In addition to these two terpenes, betacaryophyllene  , a bicyclic sesquiterpene found in cannabis, has been reported to act as a specific agonist against cannabinoid receptor 2 , which presents in peripheral organs, outside the CNS . This interesting activity, beside other mechanisms of action, make CPh a potential therapeutic candidate in the management of neuropathic pain . However, the volatile and hydrophobic nature of these terpenes result in poor solubility and low bioavailability, limiting their in vivo pharmacological efficacy. To address these limitations, we have recently developed polymeric nanoparticles  that successfully encapsulated these three terpenes . The new nanosystems were fabricated using poly-poly , a block co-polymer of a hydrophilic chain of PEG linked to PLGA a biocompatible, biodegradable, Food and Drug Administration -approved co-polymer based .

It is anticipated that the encapsulation of the cannabis-derived terpenes in PLGA NPs will equip them with a wide range of qualities such as enhanced solubility and stability, promoted absorption by biological membranes, sustained release, and ultimately improved therapeutic efficacy . In this work we sought to study the impact of the of MC, CPh, and NL encapsulation on their potential effectiveness in pain management. To this end, we tested the terpene-loaded PEG-PLGA NPs in HEK293 cells  that express the nociceptive transient receptor potential vanilloid- 1 ion channel , a non-selective ligand-gated cation channel that is involved in the sensation of scalding heat and pain . This ion channel is a member of the TRPV subfamily of the transient receptor potential  channels, a family of membrane calcium channels that are activated by a variety of exogenous and endogenous physical and chemical stimuli . TRPV1 is identified by its responsiveness to capsaicin and its analogues , but TRPV1 also responds to noxious temperatures , low pH , and to some endogenous compounds; in particular, the endocannabinoids. TRPV1 antagonists include capsazepine and ruthenium red . TRPV1 is expressed in both peripheral and central nervous systems, predominantly in primary sensory neurons involved in pain perception, in addition to several nonneuronal cells such as immune cells and smooth muscle cells . Both antagonism and agonism of TRPV1, and other TRP channels, can induce analgesia, via inactivation and chronic desensitization of this nociceptive ion channel making it a target for pain treatment . The activation of TRPV1 leads to an influx of Ca2+ via the plasma membrane, thus generating changes in intracellular Ca2+ concentration. It was also found that TRP channels are present in intracellular organelles and control the release of intracellular Ca2+ . Influxes of Ca2+ were monitored by the fluorescent indicator Fluo-4 acetoxymethyl. We used similar experimental conditions to acquire fluorescence images of cells treated with the terpenes-loaded NPs. Additionally, the cytotoxicity of the free and encapsulated terpenes was assessed. The terpene-loaded PEG-PLGA NPs were synthesized and tested in HEK cells that express TRPV1. The calcium signaling assay utilized in this work enables the measurement of calcium influx, as a result of TRPV1 activation. Fluorescence intensity changes were monitored using Fluo-4, which was used to measure intra-cellular free Ca2+ concentrations . Our work was based on the findings of Jansen et al. who demonstrated that cannabis-derived terpenes, predominantly MC, activate TRPV1 channels inducing calcium fluxes . We obtained the HEK TRPV1 cells from the same research group. However, we had to introduce some modifications to the calcium signaling assay developed by Jansen et al. in which a more sophisticated and sensitive instrument  was employed. Thus, a higher count of cells  and higher concentrations of terpenes  were involved. Similar high concentrations of terpenes have previously been reported in the literature. For example, linalool has been found to activate human TRPA1 at an EC50 of 117 μM . In addition, the experiment duration was set to 1 h to provide enough time for drug release from NPs and trim tray for weed interaction with the receptors. Our results confirm the findings of Jansen et al. regarding free MC, and the relatively small effect of free NL on TRPV1. Moreover, this work demonstrates that the PLGA-based nano-formulations significantly enhance the calcium influx induced by the three terpenes.

In general, this improved effect may be explained by the solubilization of the lipophilic terpenes in the core of the nanocapsules, thus improving their ability to interact with the TRPV1 channels. Furthermore, the likely slow drug release, as generally observed for lipophilic substances encapsulated in PEG-PLGA NPs , may explain the time-dependent enhancement of fluorescence intensity shown by the terpene-loaded NPs. Interestingly, NL-loaded NPs demonstrated a two-phase response characterized by a small peak followed by a drastic logistic phase pattern  reaching a calcium signal similar to that exhibited by ionomycin. In fact, the two-phase response suggests that the generation of calcium signal by the encapsulated NL may be provided by a more complex mechanism. The first small peak may result from the terpene that is released immediately by the nanoparticle formulation followed by a slower but extended release of the terpene. However, as this pattern was not observed by the other two terpenes, it is also possible that the high intercellular concentration of NL achieved by the nano-formulation induces other mechanisms for increasing calcium concentration in the cytosol. One possible mechanism is the mobilization of calcium from endoplasmic reticulum in which functional TRPV1 channels are located and serve as intracellular Ca2+ release channels . A more in-depth investigation is needed to clarify the mechanism underlying effect induced by NL-loaded NPs, which is not within thescope of the current work. Moreover, the high-level responses seen by the combinations of the three terpenes may provide an evidence of a synergistic effect. It is noteworthy that shifts in intracellular Ca2+ have been found to promote cell death, through apoptotic or necrotic pathways .

Governments have imposed widespread restrictions on public life to cope with the pandemic worldwide. The resulting “social distancing” policies and other measures to contain the incidence of COVID-19 infections led to isolation and solitude for many individuals. Men are disproportionately affected by severe COVID-19 disease progression and show a higher mortality due to COVID-19. However, there is evidence from the scientific literature that women may be more affected by the economic, social and psychological consequences of the pandemic. Sectors with a high share of female employees  were disproportionately affected by lockdown related closures, short-time work and job losses. Women are also more likely to work in atypical jobs with lower social security coverage or part-time, which contributes to lower financial security. In the pandemic, at least in families with “traditional” gender roles, the main burden of child care at home was on women because of closed schools and child care . In addition, employees in health care and other essential services  are also mostly female and have been exposed to stress, high workload levels and an increased risk of infection during the pandemic. Additionally, in a student population, perceived stress with regard to COVID-19 was shown to be higher in female than in male individuals. Since the beginning of the pandemic, the impact of the COVID-19 situation on mental health in the population has been discussed. At the beginning of the pandemic, researchers drew attention to the necessity to address the public mental health consequences. Some authors argued that a “psychiatric pandemic” was co-occurring with COVID-19. In the meantime, numerous studies in various countries showed that the COVID-19 situation has negatively affected mental health. Population-based studies in Germany found evidence that depressive symptoms, anxiety, sleep disturbances and psychological distress increased as a response to COVID-19.

Research with repeated cross-sectional designs indicated that the implementation of contact restrictions was associated with increased levels of depression and anxiety that seem to have persisted even during the easing of those restrictions. Women experienced higher levels of depression and anxiety than men during the first COVID-19 wave. This corresponds to previous research demonstrating gender differences regarding depression, anxiety and insomnia because of the pandemic . Psychological distress and mental health problems are well-described risk factors for increases in the use of alcohol and other substances. Besides the potential negative effects for individuals,cannabis grow equipment significant increases in alcohol use are also a public health concern. In the German general population, per capita alcohol consumption is high by global standards. In the group of women in Germany, 13.1% drink alcohol in a hazardous pattern, defined for women as more than 10 g pure alcohol per day on average . Among women, alcohol consumption increases with higher socioeconomic status. Women with a higher socioeconomic status are twice as likely to drink hazardously than women with a middle or low socioeconomic status . A number of publications document changes in alcohol consumption under COVID-19 pandemic conditions for different countries, e.g., for the United States, the United Kingdom, Poland, Australia and France. These studies have shown that between one fifth and one quarter of adults increased their alcohol use after the pandemic started. Corresponding to those results, retailers in various countries have reported an increase in the sale of alcoholic beverages since the beginning of contact restrictions or lockdowns. In contrast, a very recent study in 21 EU countries showed that in most countries, with the exception of Ireland and the United Kingdom, there was a decrease in alcohol consumption. However, a reduction in alcohol consumption was less common among people who were particularly stressed by the pandemic. Other studies also found significant associations between higher levels of psychological distress, or depressive or anxiety symptoms and an increase in alcohol use. Among women, psychological distress related to COVID-19 has been significantly associated with the quantity of alcohol use, such as the number of drinks had at the last heaviest drinking event and the number of drinks on a typical occasion. For women, social distancing policies and the resulting loss of social support has been associated with an increase in hazardous drinking during the first lockdown in the USA. Those increases in alcohol consumption under pandemic conditions were interpreted as a dysfunctional coping mechanism for distress caused by the pandemic.

The analysis refers exclusively to the female part of a population-based German sample as it is hypothesized that women have been psychologically burdened by the COVID-19 pandemic differently to men due to their professional, family and social situation. In addition, women and men are known to differ in the extent and pattern of their drinking behavior. The objective of this analysis is to examine whether alcohol consumption changed in a German population-based sample of women under conditions of the COVID- 19 pandemic. In addition, the extent of depressive symptoms, anxiety and COVID-19 specific fears and their influence on alcohol, nicotine and illicit substance consumption are analyzed.A population-based and cross-sectional online survey with a self-selected convenience sample was conducted from October until December 2020. The survey covers the period of the “second wave” of the COVID-19 pandemic in Germany. During this phase, government mandated contact restrictions to contain the pandemic in Germany were relatively strict. Schools remained closed, public life was significantly restricted and people’s daily lives changed significantly. Inclusion criteria were at least 18 years of age and German language capabilities, since the survey was only available in German. Participants were recruited via social media, institutional newsletters and online press releases. Participation was anonymous and there were no financial compensations or other incentives for participation. Electronic informed consent was obtained prior to the start of the survey. Participation was voluntary and anonymous, and participants could withdraw from the study at any time. The study was conducted in accordance with the Declaration of Helsinki, and the Ethics Committee of the University Hospitals Essen has approved the study . The Foundation of University Medicine Essen  funded the study. The Open Access Fund of the University of Duisburg-Essen funded the publication of the study.In this population-based sample of women in Germany, nearly one quarter of those who use alcohol increased their alcohol use.

Nearly one third of smokers increased their nicotine use and more than forty percent who used other substances increased their sub-stance use during the COVID-19 pandemic. One in five women reported major depressive symptoms and nearly one quarter at least mild symptoms of generalized anxiety.Depressive symptoms and specific COVID-19-related fears did not contribute significantly to an increase in alcohol or nicotine use. The proportion of approximately one quarter of the participants who reported an increase in their alcohol corresponds with the results of previous studies, which found similar rates of alcohol use during the first wave of COVID-19. The most significant increase in alcohol consumption in the 35–55 year old group may be explained by the fact that in this group the stress of childcare, homeschooling or caring for elderly relatives may have been more prevalent. Due to the ongoing social distancing policies, the opportunity to drink alcohol at parties, bars, restaurants or events decreased markedly. This may explain the decrease in alcohol consumption in the youngest age group, in which almost the same number of women reduced as increased their alcohol consumption. Due to the social distancing measures, it is likely that the increased alcohol consumption primarily occurred in private settings with family members, closest friends or alone. Social distancing and self-isolation came along with the disruption of daily routines, boredom, loss of daily structure and lack of social contacts, which were identified as motives for a rise in alcohol consumption during the pandemic. A US study also found that the longer people spent time at home, the higher the risk of binge drinking at home. The relief of negative emotions and stress caused by the pandemic might have been a further motivator to drink more alcohol. Increases in alcohol consumption can negatively affect physical health in various ways; it is a leading risk factor for global disease burden and causes substantial health loss. Alcohol use is an important cause of traffic accidents and self-harm among young people and promotes various types of cancer. Alcohol use also adversely affects cardiovascular diseases such as hypertension in a dose-dependent manner. In the context of COVID-19, the negative health impacts of alcohol use are important to consider as both cardiovascular diseases and cancer increase the risk for severe COVID-19 disease progression or mortality. With regard to nicotine, its use is also highly correlated with mental stress in women. In addition, external reasons may also have led to an increase in nicotine consumption. Contact restrictions and working from home meant that many people stayed mainly in their home environment. For smokers, this may mean that the smoking bans in public and reduced social control  disappeared and may have led to an increase in cigarette consumption. Active smoking is a well-studied risk factor for the development and worsening of COPD, asthma and chronic respiratory diseases. Non-smokers in households with smokers may also have been more exposed to secondhand smoke during the pandemic and associated “stay at home” policies. Passive smoking increases the risk of asthma,mobile grow system reduced lung function and respiratory tract infections in children.

Tobacco use has a special role in the context of COVID-19 because of its negative impact on several preexisting conditions that promote the risk of severe COVID-19 disease progression. In the small subgroup of participants who use any illicit substances, predominantly cannabis, consumption increased considerably more than for alcohol and nicotine. These results were contrary to a Belgian sample that found no changes in cannabis use. However, the results are consistent with a longitudinal Dutch study that also found an increase in cannabis use during COVID-19, but no increase in the severity of cannabis use disorder  in daily consumers. In this study, mental well being was reduced and contributed significantly to changes in cannabis use. In Canada, self-isolation was associated with an increase in consumption in male cannabis users; coping with depression motivated the use of more cannabis than pre-pandemic, and an increase in cannabis use was associated with financial concerns and lower education.Symptoms of generalized anxiety were the only mental health factor that predicted an increase in alcohol and nicotine use in this sample. Previous studies have shown diverse findings regarding alcohol use and anxiety under COVID-19 conditions. An Australian study found an association between anxiety and alcohol use, whereas another study in the United Kingdom found no correlation between alcohol use and anxiety in an adult sample who were in self-isolation. In general, the association of alcohol use and symptoms of anxiety and anxiety disorders are well documented. Although the COVID-19 pandemic is a novel situation, research on other collective stressful events such as SARS 1 in 2003 or the economic crisis in 2008 demonstrated that those events were associated with an increase in alcohol use, partly mediated by depression and anxiety symptoms. Evidence of specific COVID-19-related anxiety as an influencing factor is less clear. In contrast to generalized anxiety, specific fear of COVID-19 did not contribute significantly to explain changes in substance use in our study. This corresponds to findings from a US study, which also found that the subjective fear of virus infection was not associated with an increase in substance use. Another international study group found, however, a significant association between COVID-19-related fear and increases in substance use among Russian, Belarusian and Israeli students during the first wave of COVID-19. The finding that depressive symptoms do not significantly contribute to the increase in alcohol consumption is rather unexpected since previous studies showed the opposite effect. In general, an increase in depressive symptoms is a risk factor for alcohol use and vice versa. Major depression and alcohol use disorder  are closely associated. The presence of either disorder doubles the risk of the second disorder. Co-occurrence of AUD and depressive disorders is associated with greater severity and worse prognosis for both disorde. In our female sample, one in five reported depressive symptoms above the cut-off in the PHQ, indicating that COVID-19 negatively affects mood and mental well being, but drinking alcohol to cope with depression does not seem to be the preferred option.

The head-motion estimates calculated in the correction step were also placed within the corresponding confounds file. All resampling can be performed with a single interpolation step by composing all the pertinent transformations . Gridded resampling was performed using ants Apply Transforms , configured with Lanczos interpolation to minimize the smoothing effects of other kernels . Non-gridded  resampling was performed using mri_vol2surf . Many internal operations of fMRIPrep use Nilearn 0.5.0, mostly within the functional processing workflow. For more details of the pipeline, see the section corresponding to workflows in fMRIP rep’s documentation. Data analysis was conducted in AFNI Version AFNI_20.0.18 ’Galba’ . The first level general linear model was conducted via 3dDeconvolve to generate contrast maps for each individual participant, including a regressor-of interest for each of the 4 task conditions . Six motion parameters  were included as regressors of nointerest, as were the six a CompCor parameters.This generated beta-weight values at each voxel location for each of the four task conditions to carry forward to group analysis . Following first-level analysis, data were smoothed using a 6 mm gaussian kernel , for a final average smoothing level of 8.18 mm. For each of the following analyses, a whole-brain mask excluding the cerebellum was used. All analyses were performed using the AFNI function 3dLME , a group analysis program that performs linear mixed effects  analysis on data with multiple measurements per participant. The primary analysis tested the effects of cannabis use and MDD diagnosis on emotion regulation. The model was specified as follows: task condition , cannabis use , MDD diagnosis , including two- and three-way interaction terms, were included as variables of interest. Medication use , age, and number of alcoholic drinks consumed in the last 28 days as regressors. Sex was not included as a regressor due to high collinearity with cannabis use. Numeric variables  in this analysis and all subsequent analyses were mean-centered. A random effect of participant was included in the model, and a marginal sum of squares was used. Three secondary analyses were then conducted. First, we examined the interaction between emotion regulation style and task-condition in the full sample. Similar to the main analysis, an LME model was specified with a condition × ERQ score interaction term, and age, alcohol, and medication use included as regressors. The ERQ score involved subtracting the maladaptive emotional style  from the adaptive style . Thus, higher ERQ scores indicated more adaptive emotion regulation than lower scores.

Two participants were excluded from this analysis due to missing ERQ score data. Next, we examined the relationship between HAM-D score and BOLD-signal activation during the emotion regulation task. Here, only individuals with an active MDD diagnosis were included . The LME model was specified with a condition × HAM-D score interaction, and age, alcohol, and medication were included as regressors. Finally, the effects of early-onset cannabis use on task-related BOLD signal activation were examined. Here, we only included individuals who actively used cannabis . We tested our hypothesis that early-onset cannabis use would have pronounced negative effects by grouping subjects into early-onset  versus late onset . LME analysis is well-suited for such unbalanced groups . We then identified where early-onset cannabis users had greater or lower activation than late-onset users. The LME model was specified with a condition × age of onset interaction,vertical grow system and age, alcohol, and medication were included as regressors. For second-level analyses, the minimum cluster-size threshold was determined in two steps. First, we estimated the smoothness of the residuals for each subject output by 3dDeconvolve using the autocorrelation function  option , and the mean smoothness level was calculated. Next, minimum cluster size was determined using a 10,000 iteration Monte Carlo simulation  at a voxelwise alpha level of p = 0.05. Correction for multiple comparisons at p = 0.05 was achieved by setting a minimum cluster size of 64 voxels. Posthoc contrasts were FDR corrected. The current study used an fMRI paradigm of positively- and negatively-valenced emotional scenes to investigate the individual and combined effects of MDD and frequent cannabis use on emotion regulation. We also conducted several secondary analyses to explore how the various characteristics of emotion regulation, MDD, cannabis use and age of onset of cannabis use further contribute to emotion processing in the brain. Although we did not see a three-way interaction, both MDD and cannabis use showed a complete reversal of activity levels relative to their controls in response to the different conditions of the emotion regulation task. Specifically, while participants without MDD showed higher activation to the positive attend condition vs. the other three, those with MDD showed low activation to this condition, with the other three showing higher levels . Similarly, participants who did not use cannabis showed higher activation levels in response to the negatively vs. positively valenced conditions, while the opposite was true for cannabis users . The fact that we saw this reversal in all four conditions strongly suggests that both MDD and cannabis use affect several aspects of emotion processing. That is, we observed a change in both positive and negative, and effortful and passive emotion processing. Prior research has shown the effects of MDD and cannabis use on specific types of emotion processing, such as dysfunctional activity during active emotional reappraisal . The present results indicate that both MDD and cannabis use may have a more global effect than previously thought. Both of these effects were observed in the left temporal lobe. While these results were not predicted and are in need of replication, both theleft MTG and STG have frequently been associated with emotion processing , and have previously shown decreases in activity levels in individuals with MDD during emotion processing . Both regions are also involved in multisensory association . Given that the present stimuli were complex emotional scenes, it is possible that the interactions with MDD and cannabis use in each area reflect differences in multisensory representation. Individuals with MDD showed a reduced representation of positive stimuli during the attend condition, a difference that was eliminated with effortful emotion regulation. Thus, it is possible that individuals with MDD may be successfully augmenting positive representations, while being less successful in their attempt to regulate negative representations. In contrast, cannabis users showed an increased representation of positive stimuli and suppression of negative stimuli, and these mood-altering effects may reflect some of the participants’ motivation for ongoing cannabis use.

The difference between the observed effects, namely regulation versus representation of valence, could be why the specific area of temporal lobe differs. Finally, although both MDD and cannabis use affected emotional processing within the temporal lobe, the difference in specific regions may account for why we did not observe a threeway interaction. Although several regions of the frontal cortex showed activation differences among emotion regulation task conditions, there were no interactions with MDD or cannabis use. Models of both depression and of cannabis use predict the under-activation of frontal regions, specifically the vlPFC, dlPFC, and dmPFC. During healthy emotion regulation, we also observe suppression of these areas . Because the individuals with MDD are already experiencing suppression in these regions, it is possible that the amount of change during the emotion regulation task was not enough to appear different from non-depressed participants. We also found that higher ERQ scores, which represent a greater ability to adaptively control one’s emotions, correlated with less activity in the right frontal lobe. This was observed across all task conditions, indicating that better emotional control leads to less effortful emotion processing overall. While this may seem intuitive,mobile grow systems it may be surprising that there was no interaction with condition; for example, Greening and colleagues  found suppressed BOLD activity in individuals with MDD during negative regulation compared to healthy controls, but no difference in positive regulation. However, here, even in the ‘attend’ conditions, individuals with low ERQ scores showed more effortful processing than those with high scores. This consistency may reflect that emotion processing occurs even when passively viewing emotionally laden images . Poorer emotional regulation has been linked to MDD , and correlates with increases in activity in frontal regions when viewing emotional images . Thus, these results fit well with previous literature, and suggest that even passive emotional processing is more effortful for those with poorer regulation, which may be a neural representation of less adaptive emotion regulation strategies . The relationship in the left MTG between HAM-D and task condition in individuals with MDD was driven by the steep increase in activity in response to the ‘negative reduce’ condition with increasing score. This relationship echoes the results found when comparing individuals with and without MDD , which showed a similar increase in activity in this condition. Notably, a similar relationship was not found in the other three conditions, highlighting the fact that even within a group of persons with MDD, there are individual differences in levels of depressive symptoms that affect different aspects of emotion regulation. Finally, our emotion regulation task showed activation within the expected network of regions involved in emotion processing, specifically the left inferior parietal lobe, the left middle frontal gyrus, the right insula, and the left inferior frontal gyrus. In both the left inferior parietal lobe and left inferior frontal gyrus, the ‘negative attend’ condition had significantly lower levels of activation than the other conditions. The left middle frontal gyrus showed lower activity to negative versus positive conditions, and the insula showed increased activation in the ‘negative reduce’ condition relative to the others. All four regions have shown differential activation during viewing of emotionally negative stimuli compared to neutral stimuli , and are thought to belong to a larger network of regions involved in the initial appraisal , regulation , and the final generation of regulated emotional states. However, although the regions showing an effect of task condition were part of the well-studied emotion processing network, the areas we found to be modulated by MDD, cannabis use, or characteristics of these two factors  were outside of this network. The fact that these effects extended beyond typical emotion processing areas during the present task indicates that both MDD and cannabis use have far-reaching consequences for the brain, perhaps affecting domain-general processes .

One limitation of the present study is that our analysis of early-onset cannabis use did not identify any significant effects of age of onset, with only a main effect of condition, implying these results were similar across age groups. This was surprising, as early-onset cannabis use was previously associated with increased connectivity between the default mode network and reward-processing areas in the same sample , though the early age of onset group was defined differently. Additionally, a recent review paper reported that adolescent exposure to cannabinoids can lead to dysregulation of emotion and reward processing in rats . One possible explanation for the lack of effects in this area is the low number of participants in this analysis; only 12 individuals were considered “early” cannabis users, which may not have been a large enough sample to detect differences between early and late cannabis use. A second limitation is that we did not study the effects of comorbidity with other psychiatric illnesses. Data on comorbidities were collected and reported; as can be seen in Table S1, there was a large range of psychiatric comorbidities within the sample of individuals with MDD. Because of the large variation in the type of comorbidities observedwithin the sample, we do not have reason to believe that any one diagnosis could be driving the results observed here. However, comorbidity of MDD with other psychopathologies can impact emotion regulation and should be considered in future work. Tobacco and cannabis are among the most commonly used substances by adolescents worldwide. In 2019, 27.1% U.S. high school students and 22.3% of U.S. high school seniors reported past-30-days use of tobacco products and cannabis, respectively, with 2.4% and 6.4% of U.S. high school seniors using cigarettes and cannabis on a daily basis, respectively . Cannabis is often used in combination with combustible tobacco by young people. Approximately 14% of young adults in the U.S. report combustible tobacco and cannabis co-use within the past month .

To assess the statistical heterogeneity between studies, we used the I2 statistic, which provides an estimate of the percentage of variability due to heterogeneity rather than chance alone . The chi-squared test was used for significance testing. A visual inspection of the funnel plots was used to detect publication bias . The robustness of the conducted analyses was examined by conducting sensitivity analyses including only highquality studies. Furthermore, meta-regressions for potential moderators were planned . To our knowledge, this is the first meta-analysis of observational studies that focuses on the link between negative symptoms, cannabis and nicotine. Novel results are revealed based on a pool of more than ten thousand patients. Current non-abstinent cannabis users were not different from nonusers with regard to negative symptoms.Since nicotine was consumed by all participants in all cannabis studies, it is important to note that no association was found between nicotine use and negative symptoms. Thus, our findings support a specific effect of cannabis abstinence on negative symptoms. Regarding positive symptoms, we observed borderline significant results with a very small effect size, suggesting a possible association with current cannabis use; however, this effect became nonsignificant when including only high-quality studies. In addition, we found that nicotine users reported higher levels of positive symptoms than nonusers, a result that had a very small effect size and was essentially driven by the ‘nicotine as main drug of choice’ group. For cannabis, the overall results revealed the absence of a specific association between current cannabis use and the severity of negative symptoms. No difference was found between the subgroup using only cannabis and nicotine and the subgroup using cannabis as a main drug of choice. These findings are consistent with the meta-analysis by Large and colleagues  that also reported no significant differences between current cannabis users and nonusers. The similarity of the results is of note because there were considerable differences in the methods and included studies. Overall, we included a larger set of studies, but we restricted the included groups to patients with schizophrenia and excluded patients with broad first-episode psychosis. An earlier meta-analysis by Potvin and colleagues  also restricted the inclusion criteria to patients with schizophrenia and suggested that cannabis users would show less negative symptoms than nonusers. However, only three cannabis studies could be included in that meta-analysis, and in one study, subjects had to be abstinent for at least three weeks.

Overall, our study does not confirm Potvin and colleagues findings and shows that for patients with schizophrenia, there does not seem to be a significant difference in the severity of negative symptoms between current cannabis users and nonusers. A key finding of the present study is the observation that patients with schizophrenia and chronic cannabis use who have recently stopped using cannabis show less severe negative symptoms than patients with schizophrenia who do not use cannabis grow racks. To the best of our knowledge, this finding has not yet been reported in a meta-analysis of cross-sectional data. Some evidence comes from a meta-analysis of longitudinal studies that showed a small trend-level effect, suggesting that cannabis discontinuers show less severe negative symptoms than continuous users and nonusers . A recent poster by Ihler and colleagues reported that experiential negative symptoms related to amotivation improved after 12 months of follow-up in the group who discontinued cannabis compared to continued use . The findings for recent cannabis abstainers have to be considered with caution, because most studies had small sample size and the only large study reported a small effect size . However, the study was rated as having a high risk of bias and the low effect size in this study can be explained by less restrictive criteria for abstinence, in particular the lack of urine drug screening to verify abstinence. Importantly, all of the abovementioned results remained largely unchanged when restricting the analyses to high-quality studies. An important limitation of our results concerns the fact that it was not possible to conduct a meta-regression with the amount of cannabis used as an independent variable because only a few studies reported the grams of cannabis used per day, and only one study estimated the THC content. However, the dose dependence of cannabis effects remains of major importance and needs further evaluation with respect to negative symptoms .Our results suggest that patients with schizophrenia who use nicotine do not report different levels of negative symptoms than nonusers, with the effect size being close to zero. This finding is consistent with a recent meta-analysis by Huang and colleagues that also found no association between nicotine and negative symptoms . Here, we expand the findings by Huang et al. by using a larger sample of studies to show that this absence of an association occurs in studies including patients using nicotine only as well as in studies including patients using nicotine as a main drug of choice. The available data did not allow us to perform a meta-analysis of nicotine abstainers compared to nonsmokers. Boggs and colleagues report a small nonsignificant decrease in negative symptoms following one week of nicotine abstinence , indicating that further research is needed. Here, we report that patients with schizophrenia who current use cannabis do not differ from nonusers regarding the severity of negative symptoms. One interpretation of the absence of an association in the current users would be that cannabis simply does not exert any effects on negative symptoms. While this interpretation would not be in line with the hypothesis concerning the amotivational effects of cannabis use, it must be considered that the evidence for the negative effects of cannabis on motivation remains heterogeneous .

It may also be difficult to detect the effects of cannabis consumption on negative symptoms because patients with schizophrenia will often suffer from a combination of primary and secondary negative symptoms. Thus, the potential amotivational effects of cannabis as a secondary symptom may account for only a part of the overall negative symptomatology shown by the individual patient. Alternatively, it is conceivable that in chronic cannabis users with schizophrenia, the stimulating and blocking effects of cannabis on the reward system offset each other and result in the absence of an effect on negative symptoms . However, these considerations cannot account for the second important finding reported here, i.e., that recent cannabis abstainers show less severe negative symptoms than nonusers. This finding is consistent with the reduced susceptibility of developing negative symptoms among patients with schizophrenia who use cannabis grow system. Previous reports have suggested that cannabis-using patients with schizophrenia have better cognitive functioning than nonusers, particularly with respect to premorbid cognitive functioning . Furthermore, a recent study conducted by Mallet and colleagues has found that patients with heavy cannabis use before the onset of psychosis showed significantly less neurological soft signs, less negative symptoms and better cognitive functioning in different domains than their non-heavy user counterparts . It has therefore been hypothesized that cannabis-using patients constitute a subgroup that has lower biological vulnerability, which also results in a reduced susceptibility to developing negative symptoms. Another explanation suggests that cannabis-using patients might more easily access cannabis due to better premorbid social functioning, which could also be related to a reduced susceptibility to developing negative symptoms . Thus, cannabis-using patients with schizophrenia have less severe negative symptoms when they abstain from the drug. When using the drug, this difference may be obscured by the amotivational effects of cannabis . Importantly, the abstinence duration of at least three weeks required in the abstinence studies seems to be sufficient to alleviate the negative effects of cannabis on motivation. This timeframe is consistent with positron emission tomography studies in healthy cannabis users that show reduced dopamine release in the associative striatum in current users . Interestingly, in earlier studies with the same minimum duration of abstinence as in our abstainer studies, dopamine release in the striatum was not different from nonusing controls . Therefore, the time period of abstinence required in our recent abstainer group is consistent the normalization of dopamine release in the striatum.

We found a borderline significant association of current cannabis use with positive symptoms without significant subgroup differences between cannabis and nicotine groups and cannabis as the main drug of choice groups. However, the effect size was very small and might be of questionable clinical significance. These results differ to some extent from those reported by Large and colleagues, who found a medium effect size for the association of current cannabis use with positive symptoms . Several differences between the two meta-analyses must be noted. First, we included a larger number of studies than Large, but we did not include studies with patients experiencing broad first-episode psychosis, which may lead to stronger effects of cannabis on positive symptoms. Second, in the first-episode studies included in the Large meta-analysis, not all patients were receiving antipsychotics. The fact that we were focusing on stabilized populations treated with antipsychotic medication might have led to a weaker association of cannabis with positive symptoms. Third, our analysis allowed us to differentiate the groups ‘cannabis and nicotine’ from cannabis as the main drug of choice, but this differentiation did not have an impact on effect size. Furthermore, we were able to specifically address the recent cannabis abstainer group. In contrast to the findings for negative symptoms, this group did not significantly differ from the nonuser group. Overall, our results show only a very limited cross-sectional association between cannabis use and positive symptoms. Our results show that overall nicotine use is associated with more severe positive symptoms, although the effect size was very small. In the subgroup analysis, the effect was significant only for the ‘nicotine as a main drug of choice’ group. Importantly, this subgroup effect remained significant when considering only high-quality studies, while the overall effect became nonsignificant. Huang and colleagues reported a somewhat larger effect size for the association of nicotine use with positive symptoms . Our meta-analysis included a larger number of important studies and allowed a clear distinction of ‘nicotine only’ and ‘nicotine as a main drug of choice’ subgroups. Our subgroup analysis suggests that the observed association with positive symptoms might be more strongly related to the concomitant use of other drugs along with nicotine. However, we cannot exclude the possibility that nicotine use alone could increase the severity of positive symptoms to some extent. Our results only suggest a very limited cross-sectional association of continued cannabis use with positive symptoms. The acute psychosisinducing effects of THC have been well documented and seem to at least be partially related to increased dopamine release in the striatum . However, the long-term effects seem to depend on a large number of parameters, including the duration and intensity of the exposition as well as the proportion of THC and cannabidiol .

Our data suggest that the effects of ongoing cannabis consumption are to some extent offset by ongoing antipsychotic drug treatment. Although our data provide little evidence for a specific association of nicotine use with positive symptoms, it has to be noted that there is some evidence that psychotic-like experience have been associated with the smokers’ status in the general population after adjustment for confounding factors . Moreover nicotine has been suggested to increase positive symptoms via increased dopamine release and the increased metabolism of antipsychotic drugs . There was a small but highly significant association in the nicotine as the main drug of choice group. A mechanistic interpretation of the finding is difficult because substance use in this subgroup was very heterogeneous across the different studies. The main limitation of our meta-analysis is the nature of the included studies, which employed heterogeneous methods. It should be noted that the number of patients included was much higher in the nicotine groups than for the cannabis groups. Therefore, future studies with large sample size could change the results for cannabis users and recent abstainers. Nevertheless, this is the largest meta-analysis on the topic so far, and we were able to conduct sensitivity analyses including only high-quality studies that confirmed the main findings. Several limitations concern the case and control definition, such as differences in population, inclusion criteria and methodology across the included studies.

Catatonia may also present as part of a primary psychotic disorder, general medical condition, or relating to substance abuse.This case describes a catatonic state associated with psychosis and mania postulated to be induced by vaping cannabis oil. We acknowledge that it is difficult torule out an underlying BPD in this case and that his cannabis use could have induced a mood episode or was simply incidental to the presentation, especially given that catatonia is seen most commonly in BPD mood episodes. In addition, it is more likely for patients experiencing a manic episode to engage in risky behavior such as substance use, and the patient may not have noticed the onset of mania when he began to engage in cannabis use. However, we still fifind his case to be compelling in that he never experienced psychosis, mania, or catatonia outside of episodes of high-potency THC use, which the patient reported preceded the start of his acute psychiatric symptoms. In addition, it is atypical for a patient with BPD to have never experienced a depressive episode or not have a family history of mood disorders. Ultimately, it would be difficult to diagnose BPD in this patient unless he has future mood episodes in the absence of precipitating substance use. There were no general medical conditions found that we could contribute to the development of catatonia. He also had no residual symptoms of psychosis that would be expected of a primary psychotic disorder in the periods between his two admissions. Lastly, the patient denied that he had used any illicit substances other than cannabis before either hospital admission that could have contributed to the development of catatonia. Regarding cases of cannabis-induced catatonia, the literature draws from scattered case reports only. One case was found involving a 17-year-old patient with cannabis dependence and catatonia who eventually was diagnosed with schizophrenia.11 Another case published in 2011 touts itself as the “only report of cannabis-induced catatonia” found at that time in the literature. This case involved a 30-year-old patient with increased use of pot for growing marijuana for three weeks before admission for catatonia. This patient had a history of five prior episodes of catatonia with no interepisode psychiatric symptoms, several of which were associated with increased cannabis use.

Catatonia has also been associated with abrupt withdrawal of heavy cannabis use in one case report. In this case, a 32- year-old man who reportedly smoked approximately 20 g of cannabis daily for many years was incarcerated. Three weeks later, he was admitted for catatonia after he had ceased talking and eating and had a Bush-Francis catatonia rating scale score of 30. He required six weeks of treatment before his symptoms fully resolved.13 Although cannabis use is common in patients with BPD, the association between cannabis use and bipolar symptomology remains equivocal. This is also a point of interest given that individuals with BPD have increased rates of cannabis use compared with patients with other psychiatric disorders and the general population. Cannabis use disorder prevalence is also higher in patients with BPD, specifically 7.2% in patients with BPD compared with 1.2% in the general population.14 Authors of a 2018 review on cannabis use and mood disorders concluded that there is moderate evidence to support earlier onset and increased exacerbations of BPD symptoms in patients with problematic cannabis use.15 However, a more recent review from 2020 concluded that some studies found a significant association between cannabis use and BPD onset and progression, whereas other studies did not, highlighting the need for more longitudinal research in this area.16 While the general body of literature regarding the effects of high potency cannabis remains limited, we do have a possible model in the form of synthetic cannabinoids . One recent case report links the use of SCs to the development of catatonia in two patients.17 Similar to our patient, these two patients also experienced psychosis and related catatonic symptoms. These compounds, commonly called K2 or spice, bind as full agonists to CB1 and CB2 and elicit cannabimimetic effects similar to those of THC. However, SCs have been shown to bind to cannabinoid receptors with potencies 2–100 times greater than traditional herbal cannabinoids and are associated with greater risks of adverse psychiatric symptoms such as agitation and psychosis.

Moreover, SCs do not contain any psychoprotective CBD, which is also similar to high-potency THC products. One could postulate that despite the difference in binding potentials, receptor saturation through high-potency herbal THC products may result in similar symptoms experienced with SCs. It would follow that higher rates of psychosis and catatonia seen in SC users may also be seen in those vaping highpotency cannabis oil.Our review of published literature found five case reports  of hospitalizations associated with cannabis oil vaping. Of particular interest, one patient also developed catatonia and was treated with lorazepam similar to our case. However, this patient had been administered antipsychotics, which itself can be a risk factor for the development of catatonia. Four cases reported prominent symptoms of psychosis, includingcommand auditory hallucinations, persecutory and paranoid delusions, incoherent speech, and poor selfcare. In four of the cases, clinicians attempted treatment with risperidone. Interestingly, two cases reported cardiotoxicity with diaphoresis, hypertension, and tachycardia. In one case, the patient required sedation becuase of seizures. Psychiatric disorders are cited as one of the most common reasons for using medicinal cannabinoids. However, a recent systematic review and meta-analysis found that there is insuffificient evidence to suggest that cannabinoids improve depression, anxiety, or psychosis. In fact, it is well established that cannabis use, especially of products with highly concentrated THC, increases the likelihood of developing psychotic disorders in individuals at risk and predicts higher psychosis relapse rates.A recently published large multicenter case-control study of patients with first-episode psychosis found that the greatest risk factors for psychosis were daily use of cannabis and use of high-potency cannabis .

The odds of developing psychosis among daily low-potency cannabis users  were 2.2 times higher than for never users. The odds of psychosis among users of daily high-potency cannabis users were 4.8 times higher than for never users. Assuming cannabis use caused these patients’ psychosis, the study investigators estimated that 20% of new cases of psychotic disorders could have been prevented if daily cannabis use were abolished.24 Furthermore, there is ample evidence that initiation of cannabis use in adolescence is associated in a dose-dependent fashion with the emergence andseverity of psychotic symptoms. Those adolescents who initiate use earlier and use at higher frequencies show more significant symptoms of psychosis and poorer treatment outcomes. These associations are more robust for those patients with a strong family history of psychotic disorders.25 One concern highlighted extensively by the media is the rise in vaping-related lung injuries. National and state data from patient reports and product sample testing show THC-containing e-cigarette or vaping products are linked to most e-cigarette or vaping product use– associated lung injury cases. As of February 4, 2020, a total of 2758 hospitalized e-cigarette or vaping product use–associated lung injury cases and 64 deaths had been reported to the US Centers for Disease Control and Prevention. Among these cases reported to the Centers for Disease Control and Prevention , 82% reported using THC-containing products with 33% using THC-containing products exclusively. Of these cases, 52% were younger than the age of 24 years.Owing to this large rise in vaping product use among adolescents,container for growing weed the US Food and Drug Administration  issued an enforcement policy in January 2020, which prohibits the production, distribution, and sale of all flflavored cartridge-based e-cigarettes with the exception of menthol and tobacco flflavors. In accordance with the FDA, the change is an attempt to limit the alarming rise in the use of e-cigarettes by teens, who overwhelmingly prefer flflavors. However, to date, the FDA’s efforts to improve the safety of vaping devices has focused only on the regulation of nicotine vaping products.

Our case raises concerns about the potential for increased psychiatric toxicity from vaping highly concentrated THC products. Numerous studies continue to show the relationship between cannabis use and the development of psychosis; however, there is currently no clear relationship between the onset and progression of BPD owing to cannabis use or the development of catatonia. Based on our case, one could hypothesize that the use of highly concentrated THC products could result not only in psychosis but also episodes of mania and catatonia that may have not been seen in the past when lower-potency THC use was more the norm. High-potency cannabis use may result in more severe psychiatric side effects, similar to SCs in which several cases of catatonia have been documented. There is currently no available research to guide the public about what level of THC is benefificial for any medical condition or what level may result in medical and psychiatric toxicity, though it is apparent that daily use and high-potency THC use  result in higher psychosis risk.This is alarming in light of recent data showing increasing numbers of adolescents and adults initiating and using cannabis products daily.8 The vaping of concentrated cannabis oils is also growing, especially among adolescents, further increasing exposure to high-potency THC. Current evidence suggests that this trend will likely lead to more cases of psychosis and need for acute psychiatric treatment.4 More education about these risks should be made available to the public and legislators should consider regulations to limit the concentrations of THC and types of cannabis products offered in dispensaries until more research is available regarding their safety. Our case also highlights the need for more research into the potential medical and psychiatric complications from the use of newer, highly concentrated THC products. More attention should also be given to the possible negative medical consequences of vaping THC products such as e-cigarette or vaping product use– associated lung injury. We propose based on our case that high-potency cannabis products may have signififi- cantly more psychiatric toxicity than traditional lower potency products, and future research should be aimed at clarifying this potential association.Modern civilization has extensive utilization of multiple pharmaceutical drugs such as Non-steroidal anti-inflflammatory drugs  for the reprieve of pain, as analgesics and antipyretics, sex hormones, antiepileptic , blood lipid-lowering and b-blocker agents.

NSAIDs are the class of drugs that are used more abundantly because these are over the counter drugs and can be easily purchased from the market without specific prescription. More common drugs in this class are acetylsalicylic acid, paracetamol, ibuprofen, naproxen and diclofenac.Moreover, many common pharmaceuticals are available with extensive utilization in medical care having paracetamol as a base ingredient and are used with different formulations and considered safe, except for high dosage. The structural formula is given in Scheme 1. As the use of these drugs is unavoidable and these pharmaceutical compounds are excreted in urine and other biological wastes as active metabolites, either directly or indirectly, in high fractions. These wastes are constantly being discharged into municipal wastewaters which results in contaminated aquatic surroundings, surface and ground waters, and finally into the drinking water supplies. Despite their very low concentrations, these are hazardous for human beings especially for infants, and cannot be removed employing conventional water treatment techniques such as chlorination. Advanced oxidations, reverse and forward osmosis can be used to remove these contaminants but these processes are expensive; hence, large scale application for municipal water treatment is uneconomical. Up to now, membrane fifiltration, UV-degradation, ultrasonic degradation and electrochemical degradation are the reported processes for the removal of NSAIDs from surface or drinking water. The combination of catalytic decomposition along with ultrasonic degradation was studied by Soltani et al.,.Results elucidated that the dispersion of stonewaste  improved the pore volume and specific surface area of ZnO catalyst which significantly improved the paracetamol degradation effificiency up to 98.1%. Mirzaee et al., investigated the electrochemical decomposition of paracetamol in an ultrasound environment. Using Iron anode improved the degradation potential of the modified hybrid process  as compared to individual processes.