In the PYS dataset,we combined parent and child information on child predictor variables to obtain a best estimate of the child behavior.For example,a behavior was counted when either the parent or child reported the behavior.Item scores were recoded as “Yes” or “No” where necessary to make them uniform across studies.For example,the Child Behavior Checklist [CBCL] has response options of 0,1 or 2 then item scores were recoded as Yes or No.We undertook separate analyses for each gender.We first determined which items were predictive of the outcome.We next summed significant items into an index,examined AUC,and computed sensitivity,specificity,and positive predictive power for the summary screening score.If the variance accounted for by these indicators proved too low,we repeated the procedure for “new items”.In the final analyses,three of the studies used CBCL items,and one study used data based on self-reported antisocial behavior,MFQ,and the Child Symptom Inventory.The items from the CBCL,the MFQ,and the CSI were highly comparable.The intercorrelation results of the predictor items showed that some items were significantly negatively correlated with the outcome variable,and other items correlated with the outcome non-significantly across all three datasets.This reduced the number of viable items in the Pittsburgh datasets to 14.The Michigan group derived their own scale of 9 items.In brief,a procedure very similar to that described here for the three Pittsburgh datasets was used.We intercorrelated available predictor variables that overlapped with those originally identified across externalizing,hyperactivity/impulsivity,internalizing,and temperament items with the outcome variable.This method was used to reduce the item pool,based on predictive accuracy.An intermediate,reduced set of items considered in the subsequent analyses are presented in Table 2.In prediction analyses with early-onset marijuana use as the outcome,the most predictive items were three externalizing characteristics: destroys things belonging to his/her family or others,steals outside the home,growers equipment and lying or cheating.We used these items to construct a preliminary 3-item scale.
We the determined whether we could improve upon this 3-item scale by adding each of the intermediate sets of individual items.The greatest improvement was seen with the addition of “disobedient at school”.The addition of parent smoking also improved the prediction results in all data sets.Table 3 compares the performance of this “5-item Screener” across both the construction and validation datasets.Considerable replication of results was shown across the nine analyses.Eight of the nine AUCs showed statistically significant findings.The AUCs were moderately strong,ranging from 0.59 to 0.74.In most instances,the AUC reduction from construction to validation analyses was low in magnitude.However,in the case of the PYS boys,the validation sample result was a non-significant finding.Table 3 shows that across all analyses,almost all the results held equally well for boys and girls.The proposed cut-off score of the 5-item Screener was selected based on balancing sensitivity and specificity.The resulting categorization of youth at high risk for early-onset marijuana use was based on the best possible sensitivity and specificity according to the performed AUC analyses.Table 3 reports the sensitivity and specificity across the nine analyses,which varied somewhat across the data sets.The results show that the optimal cut-off score in 4 out of the 9 analyses is 1.5 or 1.6,and.5 in another set of 4 analyses.Thus,a score of 1 or 2 on the screener optimally identified children at high risk for early-onset marijuana use.Table 4 shows the more detailed results of the analyses with information about sensitivity,specificity,PPV,NPV,and overall accuracy for 5-item Screener scores.We interpret these results as indicating that a threshold or “cut off” score of 2 or more would provide acceptable results.To further address whether internalizing items would enhance the accuracy of the 5-item Screener for predicting early-onset marijuana use,results with a scale including the 5-item Screener and two added internalizing items are presented.A comparison between Tables 3 and 5 shows that the addition of internalizing behaviors did not systematically improve the AUC analysis results.The additional items resulted in marginally lower AUCs in six out of the nine analyses.Thus,the addition of internalizing items failed to improve the 5-item Screener.Using the 5-item Screener,subsequent analyses were conducted to investigate the prediction of other substance use outcomes.Specifically,we investigated the extent to which the screener predicted alcohol use and illicit drug use at age 15 and older.Because of measurement limitations,the analyses only focused on the CEDAR and the MLS data sets.
The 5-item Screener applied to the CEDAR data set significantly predicted monthly alcohol use by the 15th birthday,illicit drug use by the 15th birthday,and the onset of a DSM-IV defined substance use disorder involving an illicit drug by the 18th birthday.We also examined two longer-term outcomes at an average age of 16.6 in the MLS data set.The 5-item Screener significantly predicted frequency of cigarette use in the past month,and frequency of problems associated with drinking in the past year.Thus,these results held for both and girls.Lastly,we examined in the CEDAR data set whether the inclusion of two internalizing items improved the prediction when added to the 5-item Screener on the longer-term outcomes.The results show that the inclusion of internalizing items did not improve predictions when added to the 5-item Screener and,instead,slightly reduced the AUC.s the legalization of cannabis continues to be liberalized for medicinal and recreational purposes,its consumption is expected to continue to rise.As of 2020,cannabis has been legalized in 33 states for medicinal purposes and in 11 states for recreational use.Yet,its distribution and use remain largely unregulated.According to the 2015 National Survey on Drug Use and Health in the United States,approximately 22.2 million Americans aged 12 and older reported current marijuana use within the past month,with a predominant prevalence of use in males between the ages of 18 and 25 years old.Research on cannabis both as medical therapy and on its adverse health effects is still nascent.Findings on the effects of cannabis use on male sexual health appear paradoxical.While enhanced sexual arousal and experience have been reported in some cannabis users,habitual cannabis use has been linked to erectile dysfunction.In one study,chronic cannabis smokers demonstrated penile vasculopathy on veno-occlusive plethysmography.With studies suggesting potential adverse effects on erectile function,the impact of cannabis on ED requires further investigation.An explanation for the paradox between the reported enhancement in sexual experience and impairment in erectile function with cannabis use may be attributed to the ubiquity of endocannabinoid receptors,cannabinoid receptor type 1 and type 2,throughout the body.
Cannabinoids,such as cannabidiol and THC,modulate the activity of dopaminergic and oxytocinergic neurons via brain CB1 receptors involved in the regulation of pleasure responses and sexual arousal.Findings of vasculogenic ED associated with cannabis use may be due to the activation of CB1 and CB2 receptors in the peripheral vasculature,which has been found to promote atherogenesis and endothelial dysfunction.The dried flower and leaves of Cannabis sativa,one of the most commonly consumed cannabis strains,contains over 100 pharmacologically active cannabinoids with different potential therapeutic properties and side effects.However,as the cannabinoid compositions in the different strains of cannabis are not standardized,the elicited physiological effects may be unpredictable as well.While purified THC has been studied for clinical use,investigations on marijuana,or Cannabis sativa,plant extracts for medicinal use may be more challenging due to the varying cannabinoid constituents.The Western dietary pattern,which is high in saturated fats and simple carbohydrates,has been associated with chronic systemic inflammation and the development of risk factors such as hypertension,obesity,and dyslipidemia found in vascular disease.Furthermore,in rodent models,a high-fat diet has been found to induce changes within the corpora cavernosa suggestive of vasculogenic ED.These adverse effects may likely be due to the generation of increased reactive oxygen species from the lipid-laden contents in an HFD.In a saturated endogenous anti-oxidant system,a redox imbalance can occur,leading to an increase in oxidative stress that results in the deleterious endothelial changes observed in vascular dysfunction.Although the relationship between cannabis consumption and metabolic conditions such as diabetes and dyslipidemia has not been established,cannabis use has been linked to high caloric intake and cardiovascular dysfunction.Thus,findings that suggest cannabis use and Western diet can negatively impact cardiovascular health may also imply possible harmful effects on erectile function as well.Thus,it is vital to determine whether the combination of diet and cannabis use may have an additive or synergistic effect on erectile tissue health.This study seeks to investigate the effects of HFD and the addition of either MJ or purified THC extract on the erectile tissue of mice.
Given that MJ extract contains a mixture of different cannabinoids of uncertain biochemical consequence compared to purified THC,we hypothesize that MJ extract may enhance the inflammatory process brought on by an HFD and lead to observable deleterious changes within the corpora cavernosa.Our results demonstrate that the development of fibrosis appeared most pronounced in the corpora cavernosa of mice given an HFD combined with oral MJ as evidenced by a decrease in SMC to collagen ratio,an increase in myofibroblast proliferation in the tunica albuginea,plant benches and a reduction in anti-oxidative stress expression.These findings suggest that in the setting of chronic HFD,the addition of MJ consumption may synergistically enhance inflammation and hasten penile fibrosis.In contrast to the effect of MJ extract,the addition of purified THC extract did not appear to exacerbate fibrotic changes.THC may mitigate the inflammatory response,which correlates with the benign impact that is found in the mouse corpora cavernosa of this study.The histological changes seen within the corpora cavernosa of mice fed HFD þ MJ are similar to alterations seen in both vascular atherosclerotic changes and cavernosal venoocclusive dysfunction.Whether brought on by chronic insults from smoking,diabetes,or obesity in vascular atherosclerosis or the aging process in corporal veno-occlusive dysfunction,a persistent inflammatory state triggers the apoptosis of SMCs and accumulation of collagen.In the penis,these findings are consistent with the progression of fibrosis associated with ED.Previous investigations alluding that the dysregulation of CB1 and CB2 receptors can result in atherosclerotic plaque formation in the peripheral vasculature provide insight into the corpora cavernosa histopathology of mice treated with HFD þ MJ.Activation of CB1 receptors can lead to the production of lipid-laden macrophages and reactive oxygen species.While antagonism of CB2 receptors found in immunomodulatory cells can dampen the recruitment of proinflammatory cytokines and myofibroblasts,agonism of CB2 receptors in the corpora cavernosa may reduce reactive oxygen species.The cascade of events brought on by CB1 and CB2 receptor modulation results in the plaque formation seen in vascular endothelium injury,remodeling,and eventual fibrosis.These mechanisms may also be at play in the fibrosis observed in the corpora cavernosa of mice fed HFD þ MJ in this study.The increase in fibroblast to myofibroblast transition in the connective tissue of the tunica albuginea and the accompanying decrease in cavernosal SMC to collagen ratio was significant in the HFD þ MJ group.MJ,the extract of Cannabis sativa used in this experiment,contains a multitude of natural cannabinoid constituents.This may have led to the non-specific binding of the unidentified constituents to the endocannabinoid receptors,resulting in the activation of the inflammatory cascade and leading to the increased myofibroblast expression.This increase also suggests that MJ may exacerbate the fibrotic progression already underway within the corpora cavernosa oxidative stress already brought on by HFD.Previous studies using animal models suggest that THC may have anti-inflammatory and anti-oxidative properties,presumably via CB2 receptor interaction.
THC has been shown to slow the disease progression in rodents induced with rheumatoid arthritis,atherosclerotic plaques,and hepatic fibrosis.In line with these studies,in this experiment,the corpora cavernosa of mice given a diet and THC extract did not demonstrate as a significant reduction in HO-1 expression as in those given a diet and MJ extract.This finding may explain the lack of architectural changes found in the corpora cavernosa of mice administered either NCD þ THC or HFD þ THC.The reduction in oxidative stress and minimal adverse tissue changes suggest the therapeutic potential of THC as an antioxidant,although more studies are needed.Furthermore,while it appears that purified THC can exert anti-inflammatory and anti-oxidative effects applicable for clinical use,caution may be needed with the use of whole cannabis plant extract in which the cannabinoid constituents are unidentified and unquantified,such as with MJ in this experiment.As the legalization of cannabis continues to expand for medicinal treatment and recreational use,further delineation of the beneficial and detrimental properties of cannabinoids and their CB1 or CB2 receptor proclivities is warranted.Additionally,with respect to male sexual health,identifying the presence and localization of endocannabinoid receptors within the corpora cavernosa may further elucidate the effects of cannabis and its components.