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False negative reports of a general substance-related problem can include statements that the person did not take the substance when he or she had been using, admissions of use but denial of high levels of consumption or associated problems that occurred, or a person admitting to substance related difficulties but denying an overarching problem with the substance . For alcohol, the focus of the current analyses, the latter might be a form of denial that is especially problematic for clinicians who only ask general questions about substance use and problems rather than using standardized screening questionnaires, like the Alcohol Use Disorders Identification Test . In such situations, the clinician might ask questions like “How much do you drink?” or “How would you describe your drinking pattern?”. The answer they might receive from many individuals who fit the definition of an AUD could be something like “I’m a moderate social drinker”. Much of the literature on denial has focused on underlying mechanisms that contribute to false negative reports regarding SUDs. Possible mechanisms include deliberate and conscious lies to avoid negative views from others or consequences of the behaviors and false negative reports from cognitive difficulties in correctly appraising the dangers of the substance use . Other theories reflect psychodynamic defense mechanisms where persons facing substance-related psychological stressors subconsciously “defend” themselves by denying that the substance problem or adverse event occurred . It is likely that multiple factors contribute simultaneously to denial ,trimming tray and the literature suggests that the underlying mechanisms might differ with different drugs and for different situations . The current analyses focus on inaccurate denial of current AUDs in individuals who report themselves as light or moderate social drinkers. To prepare for the study we searched the literature for specific characteristics of individuals who evidence denial.

Regarding demography, the most consistent data were seen for race/ethnicity where a relatively scant literature indicated that a range of denial-related behaviors were more common for African American and Hispanic American subjects than for European Americans . Marital status and education level did not consistently relate to the probability of denial , although one study suggested more denial among lower educated individuals . Even more inconsistent results were seen for the relationship to denial for sex, age, socioeconomic status or income . We found no published studies regarding whether an individual’s report of specific AUD criteria items were more likely to relate to inaccurate recognition or reluctance to admit to an overall alcohol problem. Optimally, the impact of specific criteria should be evaluated while also considering the relationship of denial to drinking quantities, the number of alcohol problems, and whether an individual has alcohol abuse or dependence in DSM-IV. Our group recently reported a phenomenon that might overlap with denial. That paper searched for characteristics of San Diego Prospective Study probands with AUDs whose young-adult offspring erroneously reported no significant alcohol problems in that parent . The attributes of the person who denies their own overarching alcohol problem might be similar to characteristics related to lack of recognition of his alcohol-related difficulties by his offspring. Items associated with an offspring’s incorrect report of their father’s problems included the lack of endorsement of four specific AUD criterion items. These included probands denying spending a great deal of time to obtain, use, and/or recover from alcohol , not endorsing decreasing important activities due to alcohol , and not admitting to continuing to use alcohol despite physical and/or psychological problems or despite social and/or interpersonal problems . This paper uses data from two SDPS generations to evaluate characteristics associated with denial of global ratings of problem drinking in individuals who admitted to specific abuse or dependence criteria.

The analyses test five hypotheses: 1) Based on clinical experience and the literature we estimate 30%–50% of SDPS AUD subjects will not rate themselves as falling into problem drinking categories; 2) The lower the number of AUD criteria endorsed the greater the chance of denying having a general problem with alcohol; 3) The lower the maximum drinks endorsed the greater the probability of denying having a general problem with alcohol; 4) Individuals with alcohol abuse will be more likely than those with alcohol dependence to deny having a general problem with alcohol; and 5) The absence of the four criterion items that related to false negative reports by offspring of their proband father’s AUD will also relate to that father’s own denial of a general problem with alcohol including D5 ; D6 ; D7 ; and A4 . Following University of California, San Diego Institutional Review Board approval, randomly mailed questionnaires were used to recruit 453 SDPS probands as drinking 18-to-25-year-old male UCSD students who never met criteria for an AUD, SUD, bipolar disorder or schizophrenia and did not currently have a major depressive or anxiety disorder.Beginning in 1988, the 453 probands began participation in every five-year personal follow-ups using a semi-structured interview reviewing substance use and problems based on the Third-Revised and Fourth Diagnostic and Statistical Manuals . The questions were extracted from the Semi-Structured Assessment for the Genetics of Alcoholism. Fifteen-year follow-ups included the Self Report of the Effects of alcohol questionnaire, the Impulsiveness Subscale of the Karolinska Scales of Personality and the Zuckerman Sensation Seeking Scale . The SRE records numbers of standard drinks required for up to four effects including a first effect, feeling dizzy or slurring speech, unstable standing, and unplanned falling asleep. SRE-5 scores for the first five times of drinking and is generated by the total drinks in that period needed across effects divided by the number of effects endorsed. SRE-T scores reflect the average across first five, heaviest drinking period, and recent 3-month drinking. Higher average drinks needed for effects indicates lower response per drink and higher future risk for alcohol problems . As probands’ biological children reached age 18, they were personally interviewed every five-years using SSAGA-based questions. The first interview following their 18th birthday included the impulsivity and sensation seeking questionnaires, and, for those with experience with drinking, the SRE.

Analyses include all 94 AUD male probands and all 176 offspring who met AUD criteria in the five-years prior to the index interview and these participants were not chosen as proband-off spring pairs. Their SSAGA-like interviews queried their recent five-year quantities, frequencies and problems associated with substances, including all 11 DSM-IV substance-related criterion items. We added a final question to the alcohol section which asked: “Since your prior evaluation , how would you label your own drinking pattern overall?” The options included: 1) nondrinker/abstainer; 2) infrequent/occasional light social drinker; 3) moderate social drinker; 4) frequent/heavy social drinker; 5) problem drinker/alcoholic; and 6) recovering alcoholic. The follow-up rate in the SDPS was over 90 %, and maximum likelihood procedures were used to address missing data with Little’s MCAR test showing data missing completely at random . Tables 1,2,3, respectively, describe AUD proband and AUD offspring demography, personality, and substance-related variables for all relevant participants combined and then separately for subjects who rated themselves as falling into categories 1–3 regarding their drinking pattern overall versus those who rated themselves as categories 4–6 . The deniers were reporting categories that might indicate to clinicians that a patient does not have problems with alcohol. The first step, univariate comparisons of Groups 1 versus 2, used F-tests for continuous variables and x2 for categorical data. Tables 2 and 4 present our key results involving backwards elimination logistic regression analyses using variables that significantly differentiated between deniers and non-deniers in Tables 1 and 3. Finally regarding methods, for both probands and offspring data, multicollinearity was assed using both simple correlation matrixes among the variables and evaluating for variance inflation factors . For correlations, values greater than or equal to 0.80 and for VIF values greater than 5 indicate possible multicollinearity .Table 1 for probands and Table 3 for offspring each first present data for the entire relevant sample and then separately for Group 1 denier and Group 2 non-denier participants. Self-ratings of their general alcohol status among AUD probands included 0% nondrinkers, 12 % infrequent/occasional light social drinkers, 55 % moderate social drinkers, 25 % frequent/heavy social drinkers, 6% problematic drinkers/alcoholics and 2% recovering alcoholics. AUD offspring self-ratings were 0% non-drinkers, 24 % infrequent/occasional light social drinkers, 58 % moderate social drinkers, 13 % frequent/heavy social drinkers, 2% problematic drinkers/alcoholics and 3% recovering alcoholics. Table 1 demonstrates that overall most AUD probands were European American, had ever married, 70 % had children, and their average education was 17 years. On average, probands endorsed 2.5 AUD criteria and 52 % were alcohol dependent with the remainder meeting alcohol abuse. Thirty-one percent had used cannabis in the recent five-years, 4% met cannabis use disorder criteria, 17 % smoked cigarettes,10 % used other illicit drugs, including 2% who met SUD criteria on that substance. Among AUD probands, 67 % were classified as deniers of problematic drinking . Significant alcohol-related univariate comparisons between probands in Groups 1 and 2 revealed that deniers were less likely to have alcohol dependence, reported lower average maximum drinks,grow tent kit and were less likely to endorse five AUD criteria, including dependence criteria D4, D5, and D7, along with abuse criteria A1 and A4. These included three of the four criteria predicted in Hypothesis 5.

Deniers were also less likely to have SUDs for noncannabis drugs. While not noted in the table, the correlation between a false negative family report of a father with an AUD in the prior paper and an AUD father being a denier in the current analysis was 0.28 . Table 2 presents results predicting AUD proband denier status using a backwards elimination logistic regression analysis that included variables that differed significantly across deniers and non-deniers in Table 1. Four variables contributed significantly to the analysis including three of the criteria predicted in Hypothesis 5 along with a SUD on illicit drugs other than cannabis. Tables 3 and 4 focus on 176 AUD offspring who were primarily European American, 40 % of whom were women, 29 % had ever been married, and individuals who reported on average 15 years of education. Sixty-two percent met interval criteria for alcohol dependence, they reported on average 11 maximum drinks per occasion and endorsed an average of four AUD criteria. One in five smoked cigarettes in the prior 5 years, 80 % used cannabis,19 % had a cannabis use disorder, and 37 % had used other illicit drugs, including 3% who developed a SUD on those substances. Comparisons of Groups 1 and 2 revealed that the 82 % who were deniers were slightly younger and had lower proportions with alcohol dependence, lower average maximum drinks, and fewer AUD criteria endorsed compared to non-deniers. Group 1 deniers were also less likely to endorse every specific AUD criterion except for D3 . AUD offspring in Group 1 on average reported fewer drinks required for effects across the time frames , were less involved with other drugs and had lower scores on sensation seeking. Group 1 and 2 offspring comparisons were repeated for the 106- male offspring, 84 of whom were deniers. Here, results were generally consistent with those in Table 3. Analyses using the 70 female offspring alone could not be adequately interpreted because there were only 9 non-deniers. Table 4 describes the backwards elimination regression analysis predicting denial in AUD offspring using variables that differed significantly across Groups 1 and 2 in Table 3. Like Table 2, significant predictors of denial involved indicators of less intense alcohol involvement and less use and/or problems with other drugs. The five specific variables in Table 4 included only one that contributed to Table 2 and one variable noted in Hypothesis 5 , but D6 had not entered the regression analysis for probands. The three other variables included lower proportions of deniers who smoked, reported alcohol withdrawal, or met criteria for alcohol dependence. If regression analyses were limited to the 106 AUD males, denial remained associated with lower levels of both alcohol and drug related problems, but the specific items for male offspring included a lower average maximum drinks per occasion, lower cannabis use, and deniers had a lower average age. Within the same interview session 67 % of SDPS probands with current AUDs and 82 % of current AUD offspring endorsed enough alcohol problems to meet DSM-IV AUD criteria but denied having a general alcohol problem.

Two waves of surveys were administered at varying times by each cohort between May 11th, 2020 and February 15th 2021. Given our objective to explore associations of alcohol and other drug use, we conducted a cross-sectional analysis of survey respondents who had complete information on alcohol use and the covariates of interest. If people responded to more than one wave of the survey, we used their first survey. We explored incorporating alcohol consumption prior to the start of the COVID-19 pandemic but 75% of the respondents were missing this information which limited this analysis. The primary outcome was alcohol use, categorized into three groups based on participant responses to the United States Alcohol Use Disorders Identification Test – Consumption questions , modified to ask about drinking in the past 30 days rather than past year . We denote the three groups as; no alcohol use , low-risk alcohol use, and hazardous alcohol use based on terminology best practices .The third question asks about heavy episodic drinking . Heavy episodic drinking was defined as reporting drinking ≥ 4 drinks for women or ≥ 5 drinks for men in a single occasion , 2016. Hazardous alcohol use was defined as averaging ≥ 7 drinks per week for females and males ≥ 65 years of age, ≥ 14 drinks per week for males < 65 years of age or reporting heavy episodic drinking on any occasion in the past month. Low risk alcohol use was defined as reporting any alcohol use below the thresholds for hazardous use. No alcohol use was defined as reporting no alcohol use in the past 30 days. Demographic covariates included age, sex assigned at birth , and self-reported race/ethnicity. We also included two indicators of socio-economic status: employment status and current food insecurity. Respondents were classified as employed if they endorsed being employed full time,roll bench employed but with a reduction in hours, furloughed, or working “without formal employment” . Current food insecurity was defined as endorsing either not having enough money for food, or rationing food.

Mental health variables considered were anxiety measured on the Generalized Anxiety Disorder-7 categorized as none-low anxiety , resilience as classified by the Brief Resiliency Scale categorized as low , normal , or high resiliency , self-reported disruptions to mental health care during the pandemic, and level of worry about the pandemic. Patients reported their level of worry about COVID-19 on a scale of 1–10, and patients who reported a level of ≥ 5 were classified as having substantial worry. HIV status was self-reported at the time of the survey. Current drug use was ascertained using the second question of the Alcohol, Smoking and Substance Involvement Screening Test modified to ask about the past-month frequency of use . ASSIST provides 5 levels of frequency of use and participants werecategorized as self-reported past month use for each of the following substances: tobacco, stimulant , non-prescribed opioid , and cannabis. Participants also reported whether they were currently receiving any substance use disorder treatment . Participants who reported being in substance use disorder treatment also reported whether there had been any disruptions to their treatment which could include missed in-person or telemedicine visits with clinicians or disruption in medications. Overdose was defined as self-reporting an overdose event in the past 30 days at the time of the survey. Lastly, because of broad differences in the six cohorts’ geographic and social profiles due to different study goals, cohort was included as an adjustment variable, as was survey wave . We did not adjust for calendar month in which the survey was completed due to high collinearity with cohort. We determined the proportion of individuals who reported no alcohol use, low-risk use, and hazardous use in the past 30 days. We examined associations between the covariates listed above with low-risk alcohol use and with hazardous alcohol use using multi-nomial logistic regression, with no alcohol use as the reference category. Age was included as a linear covariate in the model. On visual inspection of the relationship of age and prevalence of hazardous or low-risk alcohol use relative to no alcohol use, the rate of prevalence decrease for each increasing year of age was different for those ages < 50 and ≥ 50.

We accounted for this by adding a knot at age 50 which allows for separate slopes to be calculated for ages < 50 and ≥ 50. We report the results of both crude and fully adjusted models . A post-hoc secondary analysis was conducted to measure the association between opioid and stimulant use patterns and alcohol use. A total of 2121 participants completed a survey. Of these, 14 participants were excluded due to missing alcohol use information on their survey. We excluded 123 participants that were missing information on any covariates of interest. Table 1 provides the study population characteristics. The median age of the study sample was 42 years, and a majority were male and non-Hispanic Black . Current employment was reported by 43% of participants and 28% reported some limitations to their access to food. At the time of the survey, 42% reported having HIV. Overall, 45% of the sample reported no alcohol use in the past 30 days, 33% reported low-risk alcohol use, and 22% reported hazardous alcohol use. Current tobacco use and cannabis use were relatively common and there was substantial use of stimulants and opioids as well. Of 351 participants who used either opioid or stimulants, 224 used stimulants only, 77 used opioids only, and 50 used both opioids and stimulants. Of the 17% of participants who were receiving substance use disorder treatment, 69% experienced disruptions to their treatment. Ten participants reported recent overdose. Table 2 shows the proportion of participants who reported current drug use and recent overdose by alcohol use category. Compared to participants with no alcohol use, participants with low-risk alcohol use had higher prevalence of stimulant use and cannabis use and similar levels of tobacco use , opioid use , and recent overdose . Among participants with hazardous alcohol use, there was a higher prevalence of tobacco , stimulant , opioid , cannabis use and overdose compared to participants with no alcohol use. Multinomial logistic regression estimates a ratio of prevalence ratios . In the crude analyses adjusted only for cohort, the prevalence of low-risk alcohol use relative to no alcohol use decreased with each year of age before the age of 50 and also after the age of 50 . The prevalence of low-risk alcohol use relative to no use was statistically higher among males and among employed participants , and lower among participants with HIV .

With respect to drug use, cannabis had the largest association with low-risk alcohol use relative to no alcohol use , but any drug use was associated with a higher prevalence of low-risk versus no use: tobacco , stimulants , and opioids . Participants receiving substance use treatment had a lower prevalence of low-risk alcohol use relative to no use . Among those in substance use treatment, there was a non-significant increase in the relative prevalence of low-risk alcohol use among those whose treatment was interrupted . Participants with recent overdose had a non-significant increased prevalence of low risk alcohol use relative to no use . Self reported race, food insecurity, and survey round were not significantly associated with the prevalence of low-risk relative to no alcohol use, nor were the mental health indicators of low-risk-to-severe anxiety, resilience, interruptions to mental healthcare, or worry about the pandemic. In the fully adjusted model , the prevalence of low-risk alcohol use relative to no use decreased with each year of age before 50 but not after 50 . The prevalence of low-risk alcohol use relative to no use remained higher among males and employed participants , and remained lower among participants with HIV . White participants had a lower prevalence of low-risk alcohol use relative to no use compared to non-Hispanic, Black participants. After adjustment, opioid use and tobacco use were no longer significantly associated with higher prevalence of low-risk alcohol use relative to no use ,drying rack cannabis but cannabis maintained the strongest association followed by stimulants . Receiving substance use treatment was still associated with a lower prevalence of low-risk alcohol use compared to no use . In our multi-cohort study of people with and at risk for HIV with high prevalence of drug use, we found that nearly a quarter of participants reported drinking above recommended levels set by NIAAA. As expected , drug use was relatively common and higher compared to the general population . However, the significant relationship between hazardous alcohol use and stimulant use is notable. Stimulant use in the last month was reported by 13% of all participants, while one-in-four participants with hazardous alcohol use reported stimulant use; when compared to people who did not report stimulant use, stimulant use was associated with a nearly 3-fold increase in prevalence of hazardous alcohol use compared to no use. Overdose deaths involving stimulants is rising and recognizing the strong relationship of hazardous alcohol use with stimulants should lead clinicians to screen for both alcohol and stimulant use when patients report using one those substances. Additional studies examining the temporal relationship of alcohol and stimulant use are needed to understand this relationship. Alcohol sales surged at the start of the COVID-19 pandemic with a 54% increase in sales in March 2020 . Multiple nationally representative surveys showed that alcohol spending and consumption increased . The prevalence of hazardous alcohol use in our study is comparable to U.S. general public which potentially suggests that, when considering alcohol use alone, these cohorts are similar to the broader community . However, we believe this finding should be a cause for specific concern for the End the HIV Epidemic plan . Alcohol use is associated with behaviors which increase the risk of HIV transmission, less adherence to anti-retroviral treatment, and lower retention of care among people with HIV which could hinder the national goal of stopping the HIV epidemic . At the same time that alcohol use is increasing, surveillance data shows that drug overdoses are now at the highest levels ever recorded . In both US and Canada, most overdose deaths involve heroin tainted by illicitly manufactured fentanyl and represent a continuation and worsening of the opioid overdose epidemic. However, stimulant use, including cocaine and methamphetamines, was rising prior to the COVID-19 pandemic, and stimulants are now involved in nearly half of overdose deaths .

In our study, stimulant use was strongly associated with both low-risk and hazardous alcohol use. Understanding the context and patterns of people’s use of alcohol and stimulants could inform harm reduction approaches as simulant use becomes more widespread. Other drug use including tobacco, cannabis, stimulants, and opioids was associated with increased prevalence of low-risk or hazardous alcohol use relative to no use. This result is consistent with previous studies demonstrating an association between hazardous alcohol use and other drug use . The drug most strongly associated with low-risk or hazardous alcohol use was cannabis, indicating the rarity of cannabis use in the absence of alcohol use. Opioid use alone was only weakly and not statistically significantly associated with hazardous alcohol use; the association between opioid use and stimulant use together and low-risk alcohol use was weaker and not statistically significant. People often mix opioids and stimulants, specifically cocaine, and combining both drugs could be a marker of more intense drug use and thus also more intense alcohol use. The co-use of opioids and alcohol raises the risk of overdose ; one-in-seven opioid overdose deaths involved alcohol . Given the association between these three substances in our study, further public health surveillance of hazardous alcohol use and its identification and treatment when caring for people who use opioids and stimulants could inform harm reduction approaches as simulant use becomes more widespread. For participants who had current substance use treatment and for those who have HIV, there was a lower prevalence of hazardous alcohol use. Given the cross-sectional nature of the study, we consider several potential explanations. For participants undergoing substance use treatment, they could be more motivated to not drink just as they are motivated to engage in substance use treatment .

Medicinally, Cannabis acts as an analgesic, anti-emetic and appetite stimulant. Recreationally, it is an anxiolytic producing a sense of euphoria. However, Cannabis has also been identified as a risk factor for inducing acute psychoses in healthy individual and schizophrenia in individuals susceptible to mental illness. Schizophrenia is a chronic mental disorder with cognitive, emotional and behavioral disturbances, affecting ~1% of the global population. Te complex psychiatric condition is manifested through an array of negative symptoms, such as anhedonia and alogia, as well as through positive symptoms like disordered thoughts and catatonia. Psychosis, comprising of episodic delusions and hallucinations, is an additional symptom of schizophrenia and may also be brought on by illness, extreme stress or drug use. Drugs that trigger psychotic symptoms in humans, such as the hallucinogenic phencyclidine and the sedative ketamine, have been found to initiate repetitive stereotyped circling when administered to zebrafsh. Interestingly, rotational swimming has not been observed following administration of other psychotropics like lysergic acid , 3,4,5-Trimethoxyphenethylamine or 3,4-Methylenedioxymethamphetamine. Consequently, this distinct behavioral stereotypy has been attributed to a mechanism shared between PCP and ketamine, namely antagonism of the glutamate N-methyl-D-aspartate receptor. Glutamate is the predominant excitatory neurotransmitter in the central nervous system and acts as a precursor to the main inhibitory neurotransmitter γ‐aminobutyric acid. Together they work to maintain an excitation/inhibition balance. Inhibition of the ionotropic NMDAR impedes further excitatory signaling and may give rise to the repetitive stereotyped circling. Tis NMDAR hypofunction is also a prominent clinical hallmark of psychosis and schizophrenia, and thus the animal behavior stereotypy has potential as a measure of psychosis-like behavior. Hereafter,ebb flow the psychosis-like behavior refers to the circling behavior as a psychopharmacological response relevant to human psychosis.

Similar to PCP and ketamine, the main psychoactive component of Cannabis, Δ9-tetrahydrocannabinol , causes circling in rats. THC binds Gi/o-protein coupled cannabinoid receptors in the brain and periphery although CB2R expression has also been reported in the midbrain dopamine neurons. Since administration of the CB1R antagonist SR-141716 eliminates the THC-induced circling in rats, the behavior is hypothesized to be mediated through CB1R. Among a broad range of downstream effects, CB1R activation inhibits NMDAR signaling, suggesting a comparable mechanism behind the repetitive stereotyped circling as NMDAR antagonists. However, another pivotal target of THC relating to its rewarding effects is the brain’s dopaminergic system. Although the exact signal transduction path remains unknown, THC increases dopamine signaling along the mesolimbic pathway from the midbrain ventral tegmental area to the nucleus accumbens of the forebrain. In addition to the above-mentioned glutamate hypothesis of schizophrenia, there is also long-standing empirical support for hyperactive DA signaling as a basis for psychosis etiology. Given the high prevalence of Cannabis use and its influence on both glutamatergic and dopaminergic neurotransmission, animal models of its psychotomimetic effects are valuable tools for elucidating the endocannabinoid system’s role in psychosis. Zebrafsh have a highly conserved eCBS and display neurobehavioral similarities with rodents following NMDAR antagonism. As zebrafsh lack DA neuronal expression in the midbrain, DA neurons in the basal diencephalon are a proposed functional counterpart to the mammalian mesolimbic DA system. Te considerable homology between the zebrafsh CNS and the human CNS, combined with their rapid development, accessibility to molecular genetic dissection and in vivo imaging, make them an attractive choice in the biomedical field as they permit high-throughput screenings of genetic and pharmacological manipulations of embryos, larvae and adults.

Making use of these beneficial traits, this present study firstly aims to produce and quantify THC’s effect on zebrafsh stereotyped behavior using a newly developed computational method to quantify the Repetition Index . Secondly, the effect of neurotransmitter imbalance on the behavioral stereotypy was investigated through co-administrations of THC with NMDAR agonist NMDA and GABAA receptor antagonist pentylenetetrazol respectively. Thirdly, to validate if the behavioral stereotypy is mediated via CB1R or CB2R, THC was tested with the selective CB1R inverse agonist AM251 and with the selective CB2R inverse agonist AM630. Finally, to determine if the circular swimming is indicative of a psychotic state, THC was co-administered with the antipsychotic sulpiride. Overall, a zebrafsh model of THC-induced behavioral stereotypies is presented, which is a valuable tool for future in-depth studies of the mechanistic relationship between Cannabis use and risk of mental illness at cellular and molecular levels.Using a new analytical method that we have developed, this study demonstrated that 1 μM THC administration in adult zebrafsh triggered a shift from typical navigational locomotor patterns to a repetitive circling behavior, which was ameliorated by the antipsychotic sulpiride . This behavioral phenotype appears analogous to THC’s efect in rats and the efect of NMDAR antagonists in zebrafsh models of psychosis. Notably, it did not occur in the ethanol control group or in the experimental conditions without THC. Harnessing this behavioral stereotypy through a quantitative measure of RI rather than through manual scoring, eliminates issues of experimenter bias and broadens the possibilities of standardized screens of antipsychotic drugs and for clarifying the enigmatic relationship between endocannabinoids and psychosis/schizophrenia. Cannabis has had a medicinal role for millennia and has lower dependence potential compared to other common drugs of abuse like nicotine or alcohol. Teories connecting Cannabis-use and psychotic episodes began to surface in the 1980s and since then, research has put forward bidirectional associations between Cannabis consumption and psychosis, where high frequency use, early onset of use and use of Cannabis containing high THC concentrations act as mediating factors.

Te susceptibility to psychosis-like symptoms varies across Cannabis consumers as it involves a complex interplay between environmental factors and genetic predispositions. Polymorphisms of genes involved in DA metabolism, e.g. COMT and DAT1, are of reoccurring interest as they may increase the vulnerability to neuronal over-excitation by DA in the prefrontal cortex and give rise to executive dysfunctions and psychoses. As cannabinoids increase dopaminergic signaling, by interrupting glutamate and GABA neurotransmission, Cannabis-use may entail long-term risks in those with dysfunctional DA metabolism. Cannabis is an atypical drug with contradicting responses, especially in zebrafsh where there are reports of anxiogenic effects in adults and biphasic responses in larvae depending on the dosage. Here we present a concentration-dependent THC-induced behavioral stereotypy which is partially attenuated by NMDA, in a nonlinear fashion . This hints of an indirect glutamate modulation of the behavioral phenotype in question, corroborating previous zebrafsh studies with the NMDAR antagonists PCP, ketamine and MK-801. Tepharmacological amplifcation of NMDAR excitation and thereby an increased glutamate release, may have counteracted THC’s NMDAR antagonism. Likewise, inhibiting GABAAR using PTZ showed trends of lowering the RI . A combined depression of glutamate by THC and GABA by PTZ could have maintained the excitation/ inhibition balance of the CNS and prevented repetitive circular locomotion. However, the potent nature of PTZ caused convulsions at 2 mM . Therefore, RI reductions could be due to a general PTZ efect on locomotion and not a direct counteraction of THC. Expanding the dose response analysis of THC, NMDA and PTZ and performing absorption, distribution, metabolism and excretion analysis in zebrafsh will shed further light on the observed concentration-dependent effects. Regardless of the possible THC-mediated shift in CNS excitation/inhibition balance, THC’s effect on the current behavioral phenotype appeared to be CB1R-independent and CB2R-dependent in zebrafsh. Te CB1R specific inverse agonist AM251 was ineffective at lowering the RI when co-administered with THC, to a value not significantly different from the control condition . This was surprising as it contradicts CB1R’s central role in cannabinoid modulation of rodent locomotion, cognition, behavior and reports of CB1R antagonists reversing THC’s effects. CB1R is also known to directly regulate NMDAR via the HINT1 protein,cannabis drying and is colocalized with cholecystokinin basket cells, a type of GABA interneuron in the PFC. Trough these interactions, CB1R agonists may diminish NMDAR activity and inhibit GABA release from CCK-basket cells, leading to a disinhibition of excitatory pyramidal cells. Consequently, downstream DA excitation is potentiated and causes an imbalance in cortical functioning, which is a clinical feature of schizophrenia. Despite the multitude of CB1R pathways for THC to exert its efects on glutamate, GABA and downstream DA signaling, reports of THC as a multi-target ligand may better explain the non-CB1R mediated THC behavioral stereotypy. Te CB2R inverse agonist AM630 given with 1 μM THC reduced the frequency of circling and significantly lowered the mean RI of 1 μM THC alone to a RI not significantly different from the controls . In addition, AM630 prevented the THC-related reduction in velocity during immersion . CB2R modulation of zebrafsh locomotion is complex, as larvae lacking CB2R have been shown to swim less in light periods and more in dark. Te CB2R knockouts also avoided open spaces, thereby displaying an anxiety-like behavior compared to WT larvae. Zebrafsh carry two CB2R duplicates , as opposed to one CB1R, that could exhibit different functional activities compared to CB2R of other species. Although CB2R are mainly expressed in immune cells of the peripheral nervous system, their expression has also been reported in the central nervous system, e.g., midbrain dopamine neurons. Associations between the single nucleotide polymorphisms rs12744386 and rs2501432, which impair the function of the CNR2 gene encoding CB2R, and an enhanced risk of schizophrenia have been reported.

Additionally, reduced reflex responses in the pre-pulse inhibition test, where a sub-threshold stimulus precedes a startle stimulus, have been established in both schizophrenic patients and in mice lacking CB2R.This warrants future experiments with adult zebrafsh lacking CB2R and structurally dissimilar CB2R antagonists to further examine the CB2R’s potential action in the phenotype of interest and psychosis. Promising support for the circular swimming mimicking schizophrenia-like symptoms was obtained in the sulpiride tests . Sulpiride is an atypical antipsychotic that inhibits central DA D2 receptors and acts to dampen the disorder’s DA hyperactivity. Both 10 μM and 100 μM sulpiride with 1 μM THC lowered the mean RI of 1 μM THC alone to a RI not significantly different from the controls . Importantly, sulpiride alone and with THC did not significantly influence the overall velocity of the fish . Atypical antipsychotics have been successful in reversing additional aspects of schizophrenia-like behavior, such as cognitive impairment and social withdrawal, induced by NMDAR antagonist MK-801 in zebrafsh and rats . One of the downstream effects of their serotonergic and dopaminergic antagonism is NMDAR activation via d-serine release in the PFC. Te polypharmacology of atypical antipsychotics may therefore explain their efficacy, by simultaneously targeting the DA hypothesis and the glutamate hypothesis of schizophrenia. Similarly, THC’s discussed mechanisms of action are also intertwined with both hypotheses, making it difficult to pinpoint a direct cause-effect relationship . Future co-treatments of THC with other atypical antipsychotics, such as clozapine, will further strengthen these notions. With any animal model of complex disorders and diseases there is always the question of face validity and construct validity, i.e., how well the model resembles and measures the illness. One approach to address the complexity issues in gene-behavior interactions is to focus on endophenotypes, which concentrate on a specific heritable characteristic and its circuitry such as the PPI deficit in schizophrenia. Future experiments to further strengthen the THC-induced behavioral stereotypy as an endophenotype of psychosis include tests in zebrafsh lacking CB2R or carrying mutations linked to psychosis or addiction. Another limitation of using a newly established analytical method is that it lacks validation across different data sets. Further optimization of our newly developed algorithm and machine learning would allow better detection and extraction of repetitive patterns and bridge the gap between distinct behavior detected by the human eye and patterns detected by the computer. Tailored RI measures for abnormal repetitive behaviors can greatly improve assays such as the current one and lay a foundation for an automated analysis with standardized behavioral endpoints. This in turn can assist in further validating the behavioral stereotypy as an endophenotype for THC-induced psychosis. From there, the search for its genetic underpinnings and pharmacological interventions can be pursued. In conclusion, zebrafsh engage in intriguing concentration-dependent swimming patterns when immersed in THC, which share characteristics with other animal models of drug induced psychosis- and schizophrenia-like behaviors.

The lack of HCV clustering or transmission pairs is likely due to the smaller sample size than in other studies, as well as may relate uniquely to the geographically wide sexual networks in LAC compared to other urban areas. The lack of evidence of HIV-HCV co-transmission may reflect the low prevalence of HCV infection in the cohort, but may also suggest that co-transmission occurs infrequently, and that HCV infection is more often acquired following HIV infection, instead of simultaneously or preceding HIV infection, particularly in non-IDU settings. The lack of HCV DRMs is likely due to the few observed HCV infections.Methamphetamine is a central nervous system stimulant and is the second most commonly used illicit drug after cannabis.The effects of methamphetamine include euphoria, arousal, increased sexual pleasure, and psychomotor agitation. In particular, methamphetamine use is reported to prolong sexual performance and to delay and enhance orgasm. Worldwide, it is estimated that around 51 million individuals have used methamphetamine at least once in the last 12 months. The usage of methamphetamine is becoming increasingly popular in urban areas among gay and bisexual men with HIV. In San Francisco and Los Angeles, 11–13% of gay and bisexual men reported using methamphetamine in the past 6 months. Methamphetamine use for sexual pleasure is well documented. In addition to enhanced sexual pleasure, homosexual men have reported using methamphetamine to self-medicate the negative effects associated with HIV serostatus and may engage in hyper sexual behaviors without sexual protection. Concomitant illicit drug use occurs frequently with methamphetamine users and is associated with high-risk sexual behaviors. As methamphetamine is commonly used with other drugs, such as cocaine and rohypnol, container for growing weed it has been shown to promote high-risk sexual behavior, such as sex without condoms, anonymous sex, and receptive anal sex.

In contrast to its use for sexual enhancement, methamphetamine use has also been associated with genital self-mutilation. Methamphetamine is commonly administered via the following routes: intranasal, oral ingestion, pulmonary inhalation, and IV injection. In this case report, we describe two cases presenting to our urban county hospital associated with complications related to penile injection of methamphetamine. Both patients developed penile abscesses and required urgent surgical incision and drainage.A 47-year-old man with a history of methamphetamine use, prior penile abscesses, urethral foreign body insertions, HIV, hepatitis C, and diabetes mellitus presented to the emergency department with severe penile pain, fevers, and scrotal swelling. Several days prior to admission, the patient reported injecting methamphetamine into his corpus cavernosum. He denied any fever or difficulty emptying his bladder. He reported having sex with men without prophylactic condoms. He denied other active substance abuse and/or suicidal ideation. On exam, needle fragments were identified around the abscess cavity.Initial laboratory evaluation demonstrated a white blood cell count of 14,000/L, hematocrit of 40%, platelets of 316,000/L, creatinine of 1.01 mg/dL, and lactic acid of 0.8 mg/dL. Urinalysis was nitrate negative, positive for leukocyte esterase and had 10–20 white blood cells, 0–2 red blood cells, and squamous epithelial cells. Bedside ultrasound performed in the emergency room showed no apparent fluid collections in the penis. A contrast CT scan of the pelvis is shown in Figure 1. The patient was taken to the operating room on the day of admission for incision and drainage of complex penile abscesses.The abscess cavity was opened whereby 100 cc of purulent foul-smelling fluid drained spontaneously.The cavity was interrogated with a clamp and washed out with normal saline and packed wet to dry with gauze. An ultrasound of the right corporal base was performed which also demonstrated a 2 cm fluid collection, which was also drained similarly. There was no obvious involvement of the urethra. The patient’s postoperative hospital course was uneventful. He was placed on IV vancomycin and ertapenem .The patient was discharged two weeks following initial presentation.

His intraoperative wound cultures speciated with Streptococcus viridans spp.A 33-year-old male with no significant past medical history presented to the emergency department for evaluation of fevers, chills, and sharp penile pain, which began the day following a self-administered injection of methamphetamine into his penis. He denied any other significant past medical or surgical history. His family history was noncontributory. The patient endorsed a history of depression and reported having sex with only women. Laboratory studies showed a white blood cell count of 22,000/L, hematocrit of 37%, a platelet count of 374,000/L, creatinine of 1.11 mg/dL, and lactic acid of 3.9 mg/dL. CT scan of the pelvis with contrast is shown in Figure 2. Despite negative CT imaging, the patient was immediately taken to the operating room for incision and drainage after progressively worsening in the emergency department. A 17-French flexible cystoscopy confirmed no evidence of urethral erosion, injury, or stricture. After placement of a Foley catheter, a 7 cm incision along the right lateral aspect of the penis was performed whereby pus was drained. The abscess cavity was copiously irrigated and packed wet to dry. There was no involvement of the corpora or urethra. His postoperative course was complicated by pulmonary edema managed conservatively with diuresis. Initially, he was started on vancomycin and ertapenem antibiotics until his intraoperative wound culture grew sensitive Group A Streptococcusspp. He was discharged home with amoxicillin/clavulanate 875 mg/125 mg twice daily for 14 days based off antibiotic sensitivities.Here we discuss two case reports of penile abscesses following intracorporal injection of methamphetamine from an urban, county hospital. Both patients underwent surgical incision and drainage in conjunction with IV antibiotics. Prior literature has reported on the penile veins, specifically the dorsal vein of the penis, being used for IV drug administration and is associated with necrotizing ulcers. Prolonged IV drug users suffer from venous sclerosis and thus may resort to more dangerous sites of injection that is femoral, axillary, jugular, or penile veins. As a result from penile injections, penile gangrene has been reported.In both cases, the patients had a previous history of psychiatric disorders. The psychological reasons for penile injections are unknown. The first patient identified as a man who has sex with men . The second patient identified as a man who has sex with women . The use of methamphetamine has been reported to be up to 11– 13% among MSM from urban US cities. Although methamphetamine is often used to enhance sexual pleasure, no prior data suggests an association between penile injection drug use and sexual orientation. However, it has been documented that MSM who inject methamphetamine are more objectively impulsive. Treatment for methamphetamine addiction is limited with no approved medication for dependence. The route of drug abuse of methamphetamine does seem to impact treatment outcomes, as injectors have the poorest treatment prognosis as compared to intranasal users and smokers.

Although the exact psychological motivation for penile injection is unclear, more research is required, as this may become a growing trend among methamphetamine users. The diagnosis of a penile abscess is usually clinical along with supportive imaging studies, such as ultrasound or CT scans. More recent data suggest the use of magnetic resonance imaging to determine the extent of infection or inflammation, which can aid in surgical drainage of scrotal or penile pathology. For diagnosing other soft tissue abscesses, ultrasound is more sensitive than CT, but CT is more specific for superficial soft tissue abscesses. However, Case 2 in our report did not have radiological evidence of a penile abscess, yet pus was clearly identified in the operating room. Thus, clinicians must have a high index of suspicion for penile abscess with a patient who has a history of penile injection, along with penile pain and other signs of infection, such as fevers or a leukocytosis. MR imaging could be used if clinical symptomology is less clear. Although penile abscesses are relatively uncommon, a few case reports have been reported in the literature. Common etiologies of penile abscesses include trauma, injections, iatrogenic, or idiopathic. In the cases presented, we suspect the abscesses formed as a result of direct contamination from repeated intracorporal injections. Most penile abscesses are treated with surgical incision and drainage along with antibiotic therapy. Incision and drainage of abscesses, especially in patients with a history of IVDU, carry some risk of needle stick injuries to healthcare providers as a result of needle breakage.Therefore, healthcare providers should avoid blunt manual dissection at the time of surgical exploration. The most common complication following penile abscesses is penile curvature from fibrosis.Cannabis elicits in humans a complex subjective experience, a combination of mood elevation, heightened sensitivity to external stimuli, and relaxation ,cannabis square pot which results from the interaction of its main psychoactive constituent,9-tetrahydrocannabinol , with CB1 cannabinoid receptors in the brain . Functional imaging studies have shown that this drug-induced state is associated with changes in cerebral blood flow and glucose metabolism in limbic and paralimbic areas of the cortex that are involved both in the control of normal emotional behavior and the pathogenesis of depression . The idea that the mood-elevating properties of cannabis might be harnessed to treat depression was proposed first in the mid-19th century, but soon was disputed on account of the multiple side effects and inconsistent efficacy of the drug . Surprisingly, this controversy is still unsettled. Indeed, although clinical trials of cannabis in affective disorders have yielded mixed results , many patients continue to report benefits from its use in primary or secondary depressive syndromes . One likely explanation for these contrasting data is suggested by the diversity of functions served by CB1 receptors in the brain , which makes it difficult to separate the mood-elevating actions of 9-THC from its unwanted psychotropic effects. Synthetic cannabinoid agonists target the same receptors engaged by  9-THC and are limited, therefore, by equally narrow therapeutic indexes. An alternative way of enhancing cannabinoid function might be to use drugs that interfere with the deactivation of the endocannabinoids, anandamide and 2-arachidonoylglycerol . We have recently described a class of such drugs, which act by blocking the intracellular hydrolysis of anandamide by fatty-acid amide hydrolase . The index compound of this class, URB597, inhibits FAAH activity with nanomolar potency and has no affinity for CB1 receptors or other cannabinoid-related targets . This high degree of selectivity is paralleled by a lack of overt cannabinoid-like actions: For example, even when administered at doses that completely inhibit brain FAAH activity, URB597 does not cause catalepsy, hypothermia, or hyperphagia, three key signs of cannabinoid intoxication in the rodent . Notably, however, URB597 elicits profound anxiolytic-like effects in rats, which are prevented by the CB1 antagonist rimonabant . These findings suggest that FAAH inhibitors such as URB597 may selectively modulate mood states by enhancing anandamide’s interaction with a subset of brain CB1 receptors that are normally engaged in the processing of emotional information.

Here, we further tested this hypothesis, first, by examining the impact of URB597 on emotional and hedonic behavior and, second, by determining whether URB597 influences brain monoamine pathways that participate in the control of mood and reward.We have used the selective FAAH inhibitor URB597 to examine whether anandamide signaling modulates brain circuits involved in the control of mood and emotion. Our results show that administration of URB597, at doses that inhibit FAAH activity and elevate brain anandamide levels, enhances stress-coping behaviors and increases spontaneous firing of serotonergic and noradrenergic neurons in the midbrain. These actions are blocked by the CB1 antagonist rimonabant and are not accompanied by overt rewarding effects. We interpret these findings to indicate that endogenous anandamide interacts with a subset of brain CB1 receptors that concertedly regulate monoaminergic neurotransmission and stress responses. This interaction can be magnified, and consequently unmasked, by blocking intracellular anandamide degradation with URB597. Three lines of evidence suggest that anandamide modulates the emotional response to stress. First, stressful stimuli affect anandamide mobilization in brain regions that are involved in the control of emotions. In rats, for example, an electric shock to the paw elevates anandamide levels in the midbrain , whereas in mice, physical restraint decreases anandamide levels in the amygdala . Second, pharmacological blockade or genetic ablation of CB1 receptors exacerbates normal reactions to acute stress, presumably by disabling an endocannabinoid modulation of these reactions . Third, URB597 prolongs the time spent by rats in the open quadrants of an elevated maze , reduces the number of ultrasonic vocalizations emitted by rat pups after parental separation , lowers restraint stress-induced corticosterone release in mice , and prolongs nonopioid stress-induced analgesia in rats .

SAGE is one of the genome-wide association studies funded as part of the Gene Environment Association Studies under GEI. Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center . Assistance with data cleaning was provided by the National Center for Biotechnology Information. Support for collection of datasets and samples was provided by the Collaborative Study on the Genetics of Alcoholism , the Collaborative Genetic Study of Nicotine Dependence and the Family Study of Cocaine Dependence . Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI , the National Institute onAlcohol Abuse and Alcoholism, the National Institute on Drug Abuse, and the NIH contract ‘High throughput genotyping for studying the genetic contributions to human disease’ .Although pain perception is thought to be controlled mainly by neurotransmitter systems that operate within the CNS10 , antinociceptive mechanisms also occur in peripheral tissues. For example, endogenous opioid peptides released from activated immune cells during inflammation inhibit pain transmission by interacting with opioid receptors on peripheral sensory nerve endings11 . To determine whether endogenous cannabinoids have an analogous function to that of opioids, we used the formalin test, a behavioural model of injury-induced acute and tonic pain12 . Injection of dilute formalin into the hind paws of freely moving rodents evokes a pain behaviour consisting of two temporally distinct phases of licking and flexing o f t he injected limb12 . An early phase involving acute activation of pain-sensing C fifibres13 begins immediately after formalin administration, reaches a peak within 5 min, and then rapidly declines. After an interval of 10–15 min, a second phase of sustained pain behaviour appears, in which sensory fibre activity is accompanied by inflammation14 and central sensitization15 .In mice, vertical grow rack the early phase of pain behaviour was blocked when anandamide was injected into the paw together with formalin, whereas both phases were blocked by the synthetic cannabinoid agonists WIN-55212-2 and HU-210 .

These analgesic effectswere prevented by systemic administration of the CB1 antagonist SR141716A , but not of the CB2 antagonist SR144528 16 or of the opioid antagonist naloxone . The lack of effect of anandamide on late-phase pain behaviour may be explained by the short lifespan of this compound, which undergoes rapid biological inactivation in tissues17,18 . In support of this suggestion, the inactivation-resistant analogue methanandamide inhibited pain behaviour during the entire test . Local anandamide injections were not accompanied by central signs of cannabimimetic activity, indicating a peripheral site of action. To test this possibility, we measured the antinociceptive potency of anandamide following local , intravenous or intraperitoneal administrations. Anandamide was 100 times more potent in preventing formalin-evoked pain behaviour when injected locally rather than intravenously, with half-maximal inhibitory doses of 0.1 mg per kg and 10 mg per kg, respectively . Anandamide had no significant effect when injected intraperitoneally . As a further test, we determined the bio-distribution of 3H-labelled anandamide 10 min after i.pl. injection in rats. In three experiments, we found that 94% of recovered 3H-labelled anandamide remained associated with the injected paw , whereas little or no radioactivity above background was detected in forebrain, cerebellum and spinal cord . These results indicate that anandamide inhibits nociception after formalin injection by activating CB1-like receptors, which may be located on peripheral endings of sensory neurons involved in pain transmission. Anandamide is the ethanolamide of arachidonic acid and is thought to be produced by phosphodiesterase-mediated cleavage of N-arachidonyl phosphatidylethanolamine9,19 . Enzymatic cleavage of other N-acyl phosphatidylethanolamines may give rise to additional fatty acylethanolamides, the physiological roles of which are still poorly understood20 . PEA, an acylethanolamide found in neural and non-neural tissues, inhibits mast-cell activation and reduces inflammatory r esponses21,22 b y a m echanism t hat may involve binding to CB2-like receptors23 . The molecular identity of these receptors is unknown, although they are likely to be distinct from the CB2 receptors whose encoding genes have been cloned, as PEA shows little or no affinity for these receptors24 . We found that PEA, but not two closely related analogues, inhibited both early and late phases of formalin-evoked pain behaviour after i.pl. injection in mice . This effect may not be explained by the anti-inflammatory properties of PEA; 30 min after injection, the analgesic effects of PEA were not accompanied by a reduction in inflammatory oedema , which became apparent only 1 h after formalin administration.

The analgesia produced by PEA was reversed by administration of the CB2 antagonist SR144528 , whereas the CB1 antagonist SR141716A and the opioid antagonist naloxone were ineffective . In addition, PEA was more potent when administered locally than systemically . Together, these results indicate that PEA exerts antinociceptive effects that are mediated by peripheral CB2-like receptors. The cellular localization of such receptors and their possible structural relationship with the CB2 receptor whose gene has been cloned, which is primarily expressed in immune cells25, are unknown. The fact that anandamide and PEA activate pharmacologically distinct receptors and that these two substances can be produced simultaneously in tissues9 prompted us to examine their possible interactions in vivo. When injected together in equal amounts, anandamide and PEA inhibited the early phase of formalin-evoked pain behaviour with a potency that was approximately 100-fold greater than each of the compounds separately . A similar synergistic potentiation occurred in the late phase, on which anandamide had no effect when given alone . Earlier administration of either CB1 or CB2 antagonists entirely blocked the response . This interaction did not appear to involve pain-processing structures within the brain: injection of PEA in the cerebral ventricles did not affect the behavioural responses to acute thermal stimuli, assessed in the hot-plate test, and did not enhance the inhibitory activity of anandamide administered by the same route . These results indicate that the parallel activation of peripheral CB1- and CB2-like receptors by anandamide and PEA results in a synergistic inhibition of peripheral pain initiation. To test this idea further, we determined the intrinsic effects of CB1 and CB2 antagonists on formalin-evoked pain behaviour . Blockade of CB1 receptors with SR141716A produced significant hyperalgesia. This effectwas particularly pronounced after local injection of the drug, which resulted in a 10-min prolongation of the early nociceptive phase and in a two- to threefold increase in pain behaviour during the entire testing period . In contrast, systemic administration of the CB2 antagonist SR144528 caused a selective enhancement of early-phase, but not of latephase, responses . The selectivity of this effect may not result from a rapid elimination of SR144528 after early phase, as the drug reversed PEA-induced antinociception during both early- and late-phase pain behaviour . SR144528 could not be administered locally because of its limited solubility in the injection vehicle. Although the hyperalgesic effects of CB1 and CB2 antagonists may be accounted for by their inverse agonist properties16,26 , two lines of evidence suggest that these drugs acted by removing an endogenous cannabinoid tone. First, gas-chromatography/massspectrometry analysesshowed that anandamide and PEAare present in at paw skin . By comparison with internal deuterated standards, we measured 49 6 9 pmol of anandamide and 692 6 119 pmol of PEA per g of tissue . These amounts are five- to tenfold higher than those measured by the same method in rat brain and plasma27,28 , and are probably sufficient to activate cannabinoid receptors7,23 . Second, the CB2 antagonist SR144528 enhanced nociception selectively during the early phase of the formalin response , a result inconsistent with an inverse agonist effect. Thus, a parsimonious interpretation of our findings is that endogenous PEA acting at CB2-like receptors may participate in attenuating the early stages of nociception, whereas endogenous anandamide acting at CB1-like receptors may have a more sustained modulatory effect on both acute and tonic pain. Our results show that the tonic activation of local CB1-like and CB2-like receptors may regulate pain initiation in cutaneous tissue. These findings s upport t he p ossibility t hat e ndogenous cannabinoids, in addition to their spinal and supraspinal sites of action8 ,cannabis grow racks may participate in buffering emerging pain signals at sites of tissue injury. The results also indicate that selective agonists for the CB2-like receptor activated by PEA, or peripherally administered CB1-like/CB2-like agonists, may reduce pain without the dysphoric side effects and perceived abuse potential typical of centrally acting cannabimimetic or opiate drugs. Note added in proof: After submission of this paper, Jaggar et al. 29 have observed an analgesic effect of systemically administered PEA in formalin-induced pain.The District of Columbia and 15 US states – Alaska, Arizona, California, Colorado, Illinois, Maine, Massachusetts, Michigan, Montana, Nevada, New Jersey, Oregon, South Dakota, Vermont, and Washington – have legalized recreational marijuana sales, but few research studies have measured exposure to secondhand marijuana smoke in everyday settings.

On January 1, 2018, California legalized the sale of recreational cannabis to adults, and the state currently has 358 state-licensed stores selling recreational cannabis products . Many studies have measured the psychoactive compound delta-9- tetrahydrocannabinol and other related cannabinoids produced by marijuana use . Berthet et al. identified 958 papers on passive exposure to cannabis, and they selected 21 papers for review. These passive exposure studies generally employed biomarkers of exposure such as urine, blood, oral fluid, hair, and sebum to determine for forensic purposes whether an individual had recently used cannabis. For example, Moore et al. asked 10 healthy volunteers who were not marijuana smokers to spend up to 3 h in a Dutch coffee shop with heavy marijuana smoking. THC exceeding 4 ng/ml was detected in the oral fluid of half the volunteers but not the metabolite 11-nor-9-carboxy-THC , so the authors recommended measuring this metabolite as an indicator to avoid falsely concluding a person was an active cannabis smoker. We reviewed 729 papers on exposure to marijuana in the scientific literature, and we found almost no published papers measuring fine particle mass concentrations from secondhand cannabis smoke in homes. Both marijuana and tobacco cigarettes produce fine particle mass concentrations consisting of airborne particles less than 2.5 μm in diameter. Klepeis et al. and Posis et al. reported results from one of the few studies that measured indoor particles, a randomized clinical survey in San Diego of 298 predominantly low-income homes with an adult smoker and a child less than 14 years old. In each participating residence, a Dylos™ DC1700 monitor was set up for a week to measure indoor particle counts. Homes without indoor smoking had 7-day average particle levels lower than homes with only cannabis smoking or homes with both cigarette and cannabis smoking, and 33 homes reported that marijuana smoking took place from 1 to 7 times per week.The Dylos monitor provides an indication of particle levels, but it does not measure particle mass concentrations with the same accuracy as the gravimetric filter-and-pump “gold standard,” or a research-grade air monitor with its calibration factor based on gravimetric filter measurements. The common methods of smoking marijuana include a pre-rolled joint, which is similar to a cigarette or a cigar, a pipe or bong containing marijuana buds, and a vaping pen that vaporizes cannabis liquid from a commercially available cartridge. A nationwide survey of 4269 adults in 2014 found that 7.2% had used marijuana over the past 30 days . Among current users, 10.5% reported medicinal use only, 53.4% reported recreational use only, and 36.1% reported both. More than half of current users reported only one method of use ; 22.4% reported two methods; and 18.8% reported three methods. For these users, the two most popular methods of smoking marijuana were the joint and the pipe , with less popular use of the bong, water pipe, and hookah . In 2014, 7.6% of the respondents reported using marijuana vaporizers, but more recently battery-powered pens using liquid cannabis cartridges have become increasingly popular for cannabis vaping. In 2015, 5.3–8.0 million children in the US lived with a parent who was a cannabis user, and both current cannabis use and daily cannabis use have been increasing among parents .

The American Civil Liberties Union report data from the NSDUH and Uniform Crime Reporting Data showing that Black males were no more likely to report marijuana use, but 4-times more likely to be incarcerated for marijuana possession compared to their non-Hispanic White male counterparts . Epidemiologic data have shown a linear increase in cigarette and marijuana co-use in Whites, Blacks/ African-Americans, and Hispanics with the fastest rate of increase among Blacks/ African-Americans . Among Blacks/ African-Americans, it is possible that statewide legalization of medical marijuana could help to reduce marijuana-related incarcerations, and at the same time, influence the rate of couse. We are cognizant of the many layers that add to the complexities around the issue of marijuana legalization that are well beyond the scope of our study. We recommend future research will assess potential and actual benefits/ costs of marijuana legalization to society at large, and in states where marijuana is legal, identify issues that can be addressed with specific regulatory measures . Study limitations include the cross sectional nature of these analyses which limits our ability to infer causality. Interpretation of our findings is limited to cigarette smokers which is distinct from those who reported other tobacco products . We were unable to examine statewide legalization of medical marijuana by the number of years the policy went into effect using the NSDUH to account for time lags from adoption to full implementation. The NSDUH public dataset only provides a binary categorization of states that were legal vs. illegal that lumps states that just passed the law with long-term legalization states limits our ability to detect long-term effects and may have attenuated our findings. Further study is needed to examine the effect of combusted vs. non-combusted marijuana use on nicotine given increasing prevalence of edible and aerosolized delivery of marijuana with vaporizers . At present, the NSDUH does not ask respondents to indicate whether use was combusted and/ or non-combusted and we recommend that future surveys collect information on marijuana modality to elucidate the relationship between various forms of marijuana intake and nicotine and/ or THC dependence. Data on combusted vs. non-combusted THC intake can also help to identify if there might be differences in health effects across marijuana use modality. In addition, the present study did not examine population density which might be a potential covariate for marijuana use.

Strengths of the study were use of a large national dataset representative of the U.S. population and internal validity of nicotine dependence comparisons across age categories using the same dataset,indoor cannabis grow system which eliminates methodological variations from one study to another. Medical marijuana legalization was positively associated with cigarette and marijuana couse and co-users were at greater risk for nicotine dependence. Long-term longitudinal data across age groups are needed to elucidate these results. In the meantime, it is recommended that stakeholders in tobacco control participate in policy discussions involving marijuana legalization including regulatory measures to prevent further co-use and develop novel cessation treatments to help co-users who may have a harder time with quitting. Substance use disorders, hazardous drinking and mental illness all peak in prevalence in early adulthood, yet few young adults receive appropriate services. For example, the 2011 National Household Survey on Drug Use and Health found that the 1-year prevalence of illicit drug or alcohol abuse or dependence increased from 7 % among 12–17 year olds to 19 % for 18–25 year olds, decreasing to 6 % for individuals over 25. The same report found that adults ages 18–25 had higher rates of mental illness and were less likely to receive treatment in the prior year than older adults. Alcohol use can adversely impact symptom severity and treatment of co-occurring mental illness. Reduced response to antidepressants and increased risk of side effects have been reported with even moderate levels of alcohol use. In the STAR*D depression treatment cohort, individuals with major depressive disorder and co-occurring substance use disorders had earlier onset of depression, greater severity and functional impairment, and higher rates of suicide attempts and completed suicide. Similarly, while many individuals with anxiety disorders use alcohol for short-term symptom relief, drinking can ultimately make anxiety more severe. These associations highlight the need to assess alcohol and drug use patterns among young adults with mental health problems, in order to understand potential symptom exacerbation and medication interaction risks. Assessment could also help to identify which individuals may benefit from psychiatry-based brief interventions to reduce harmful drinking patterns, and who should be referred to specialty care addiction treatment. Apart from the potential value of brief interventions, screening provides benchmark medical record data at intake to help providers track potential changes in drinking over time. Some studies suggest that screening alone could help to reduce drinking. In the clinician’s guide to identifying and treating drinking problems in health care settings, the National Institutes on Alcohol Abuse and Alcoholism recommends asking how many times in the past year individuals have had 5 or more drinks for men and 4 or more for women. In 2009 Smith et al., reported a sensitivity of 88 % and specificity 67 % of this cutoff in detecting a current in a primary care setting. Using the Alcohol Use Disorders Identification Test as reference, Massey et al. reported 96 % sensitivity and 82 % specificity of screening question to detect harmful drinking in an alert non-psychotic consult-liaison population.

In the present study we used a similar cutoff drawn from electronic health record intake data in a psychiatry clinic setting to examine prevalence and correlates of hazardous drinking in young adults. The same cutoff was used for both sexes as this was the information available from the data, which was based on a graduated frequency measure that did not adjust quantities based on sex. Although young adults are at high risk for alcohol related problems, studies evaluating drinking patterns and their association with clinical characteristics are lacking. This study evaluated self-reported alcohol use patterns and the association between prior-year hazardous drinking and potentially relevant patient characteristics, including gender, age, clinician-assigned psychiatric diagnosis, and other substance use in a sample of young adults presenting for initial mental health treatment. We hypothesized that prior-year hazardous drinking would be associated with an AUD diagnosis, with other common psychiatric diagnoses, in particular, anxiety and depression, and with other types of substance use prevalent in this population such as tobacco and marijuana.Study participants were adults ages 18–25 seeking psychiatric services in an outpatient clinic in a university medical center. This clinic provides a range of assessment and treatment services, including medication management and individual and group psychotherapy. The clinic has no formal services for patients primarily seeking alcohol or drug treatment. Individuals seeking such services are pre-screened by telephone by clinic staff and referred to local specialty care programs. The sample included all individuals who presented to the clinic for initial evaluation between September 14th, 2005 and June 29th, 2011, were between the ages of 18 and 25 at intake, and completed routine computerized questionnaires, including a self-administered Electronic Health Inventory, Beck Depression InventoryII and a clinical interview. Other than age range and intake dates, there were no exclusion criteria. The EHI was completed on private computers in the clinic waiting area. It included questions about demographic characteristics, current and past medical history, and patterns of substance use for alcohol, cannabis and tobacco. For each substance, participants were asked if they had ever used that substance during their lifetime. Positive responses prompted questions on duration and frequently of use. Providers received a printed copy of the EHI questionnaire results for use in evaluation of new patients at intake. The University of California, San Francisco Committee on Human Research approved the study, including the examination of de-identified records of patients who had an initial clinic visit during the study time period. Participants who endorsed any lifetime alcohol or cannabis/marijuana use were asked the timing of most recent use prior to intake. Alcohol use questions included usual quantity consumed per occasion , frequency of use in the past 30 days and number of days in the past year when 1–2, 3–4, 5–7, and ≥8 drinks were consumed on one occasion.

Combining the responses of any consumption of 5–7 or ≥8 drinks consumed on one occasion in the past year, hazardous drinking was defined for this analysis as any past-year consumption of 5 or more drinks on one occasion, consistent with the definition used by the NHIS during the same time period. While NIAAA currently recommends a different cut-off for hazardous drinking in men and women , data were not available to assess this distinction.By chart review, we obtained all assigned Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition Text Revision diagnoses listed on each participants’ standardized initial intake evaluation form, as assigned and documented by the clinician. Blinded to responses on the EHI, a study research assistant reviewed and coded all listed diagnoses. We coded only definite diagnoses, excluding “rule out” diagnoses.We coded drug use disorder positive if abuse or dependence was diagnosed for the following drugs: amphetamine, cannabis, opiates, methamphetamine, mushrooms, benzodiazepines, cocaine, stimulants, or if poly substance abuse was diagnosed. Given the young age of the sample, disorders in remission would still be temporally relatively recent. Therefore,cannabis grow setup no distinction was made between diagnoses in remission or active. We coded alcohol use disorder positive if alcohol abuse or dependence was diagnosed. Likewise, no distinction was made between diagnoses in remission or still active. We coded depressive disorder positive if major depressive disorder, dysthymia, or depression not otherwise specified was diagnosed. Similarly, we coded an anxiety disorder if anxiety disorder NOS, generalized anxiety disorder, social anxiety disorder, panic disorder, specific phobia, post-traumatic stress disorder or obsessive compulsive disorder was diagnosed. We coded bipolar disorder positive if bipolar affective disorder type I, II or NOS was diagnosed. We coded psychotic disorder positive if schizophrenia, schizo affective disorder, delusional disorder or psychosis NOS was diagnosed. We coded attention deficit hyperactivity disorder positive if ADHD or ADHD NOS was diagnosed. We coded eating disorder positive if anorexia, bulimia or eating disorder NOS was diagnosed.We linked self-reported demographic and substance use data from the EHI to diagnostic data from the chart review to create a single dataset for analysis. We compared differences in alcohol use rates between men and women using the χ2 test, and differences in BDI-II score and mean quantity of alcohol consumed between women and men using t tests. Similarly, using χ2 tests for categorical variables and t tests for continuous variable, rates of alcohol, tobacco and marijuana use, as well as rates of specific psychiatric diagnoses at intake were examined by prior-year hazardous drinking. Underage alcohol use was also examined . Given that participants could be assigned several diagnoses at intake, individual diagnoses were not included in regression models . Instead, we assessed diagnostic burden as indicated by the number of diagnoses assigned at intake. We used a single logistic regression model to test the association between number of psychiatric diagnoses, any lifetime use of tobacco and cannabis, age, race/ethnicity and gender as potential predictors of participants reporting any hazardous drinking in the prior year. We used STATA version 13 for all analyses.Overall, rates and frequency of alcohol, tobacco and marijuana use were significantly greater in those who endorsed hazardous drinking in the prior 12 months compared to those who didn’t . Rates of AUDs were four times greater among those who endorsed hazardous drinking in the prior 12 months, compared to those who didn’t . Rate of psychotic disorders among those who endorsed prior 12-month hazardous drinking were less frequent compared to those who denied hazardous drinking in the prior 12 months. There were no significant differences in the rates of other psychiatric disorders among those who did and those who did not endorse hazardous drinking in the prior 12 months.The single model included number of diagnoses at intake, age, gender, race, and any lifetime marijuana or tobacco use. Variables positively associated with prior-year hazardous drinking included lifetime marijuana use , lifetime tobacco use and older age .

The consequence is that California is effectively experiencing a water crisis resulting in agricultural drought, economic and natural devastation, and limiting water availability for California residents. Water diversion practices for marijuana cultivation serves only to further exacerbate the issue during the most critical drought months. Water flow assessments estimate that an average of 650,000 gallons of water goes unaccounted for in California every day throughout the year.Estimates of unaccounted water during the summer months can reach numbers as high as 3.6 million gallons per day.This over consumption depletes groundwater resources causing lowlands to subside below sea level, rivers to dry up, and salt water from the ocean to intrude and contaminate California’s primary fresh water source the Sacramento San-Joaquin River Delta. Changes in water quantity cause the temperatures, pH, and salinity of lakes, rivers, and canals to increase. These decreases in water flow and reductions in water quality reduce the amount of viable breeding habitat for the sustenance and restoration of aquatic species. The direct correlation between water consumption and marijuana bud production creates a large incentive for marijuana cultivators to heavily irrigate their crops. Remote cultivators extract water in mass quantities, blatantly “degrading the public water trust because they are divorced from the foundation of [American] laws.”Due to the illegal status of marijuana cultivation, growers experience limited liability for their diversion practices within the state of California, because they are outside of the realm of institutional oversight. Their access to water is difficult to obstruct because they extract water from the top of watersheds. Thus, they act in disregard for human communities, flora, and fauna that depend on reliable sources of fresh water. When Cannabis cultivators exploit over-extended water supplies, California is forced to extract increasing amounts of water from the Colorado River and other sources, for which the citizens of California and other areas foot the bill. As in industrial agriculture,mobile grow systems chemicals are applied in order to create plants that are fast growing, develop specific desired traits, and have an optimized yield. For the Cannabis plant, this means maximizing bud production, increasing THC levels and preventing any damages from deer, rodents, mites or mold.

An average cultivation site of about 5 acres and 7,000 plants can contain 20 pounds of rat poison, 30 bags of fertilizer, plant growth hormones, insecticides, herbicides, fungicides, and a variety of other chemical inputs.60 The key difference between industrial agriculture and marijuana cultivation is that Cannabis cultivators are not subject to government or industry regulations. DTO’s import banned chemicals from Mexico which they apply in unrestricted amounts, causing extensive harm to the laborers and to the ecosystems exposed. It is estimated that 1.5 pounds of fertilizer is used for every 10 plants. Excess nutrients not taken up by plants are washed into lakes, rivers, streams and the ocean during periods of precipitation. These fertilizers cause nutrient imbalances with varying effects. Residual toxic compounds “enter and contaminate groundwater, pollute watersheds, kill fish and other wildlife, and eventually enter residential water supplies.”The marijuana mono-cultures that Mexican DTOs create are especially susceptible to damage and infestation, causing cultivators to take preemptive measures to protect their plants. Four of the foremost threats to Cannabis plants are mold, mites, rats and Deer. Cultivators spray sulfur dioxide and pesticides directly onto Cannabis plants in order to combat mold and mite problems. Excess sulfur gas and sulfate particles diffuse into the atmosphere, high exposure to which can cause respiratory effects in humans and animals ranging from shortness of breath to respiratory diseases and premature death. In the environment, sulfur dioxide is the leading source of haze in national parks. More importantly, sulfur dioxide in the atmosphere leads to acid rain that “damages forests and crops, changes the makeup of soil, and turns lakes and streams acidic which causes unsuitable” conditions for aquatic life.Acidic precipitation occurs in the form of rain, fog, snow, and particulates that can travel in winds for hundreds of miles, causing damage to plants, buildings, and monuments along the way. One of the most notable chemicals that is used to combat mite infestations is Dichloro-Diphenyl-Trichloroethane . DDT was banned in the United States in 1973 after scientific research led to public outcry over its adverse effects on human health and the environment. DDT can persist in the environment for up to fifteen years because it binds to soil and bioaccumulates in plant materials and the fatty tissues of animals such as fish and birds.DDT is a carcinogen that damages the nervous system , reduces reproductive success, and causes cancer to the liver. Despite the known health hazards posed by DDT, people throughout the world have been subjected to acute exposures through food consumption and inhalation. Another commonly used pesticide is Malathion, which is a synthesized organophosphate insecticide.When Malathion enters the environment it has little harmful effects because it is broken down rapidly by bacteria in soil and water, and by UV radiation when it enters the atmosphere.

However, direct “exposure to high amounts of Malathion can cause difficulty breathing, tightness in the chest, vomiting, cramps, diarrhea, blurred vision, sweating, headaches, dizziness, loss of consciousness, and possibly death,” all symptoms which are most likely to be experienced by on-site laborers who do not wear proper respiratory protection.The methods that cultivators use to apply chemicals are especially hazardous. At best, cultivators wear long sleeves, pants, and thin polypropylene masks as protection, all of which are inadequate for preventing significant exposure to chemical toxins.They are subjected to concentrated chemicals for prolonged periods, causing high rates of exposure through inhalation and contact with clothing and exposed body parts. However, cultivators are not the only group risking exposure through direct contact. Chemical residues can persist on marijuana buds, resulting in exposure when buds are consumed. Another threat to marijuana plantations is that “marijuana stalks are very appetizing to deer and rodents that chew the stalks of the plants.”To combat this problem, growers use rat poison pellets to kill rodents, and rifles to kill large mammals. Chemical repellents and poisons are applied at or near the base of the Cannabis plants and around the perimeter of plantations to kill rats, deer, and other animals that could cause crop damage. “The poison kills the animals close by, and when the bodies decompose,” these poisons enter into the water table and contaminate soil and wildlife that come into contact with the polluted water.Contaminants accumulate in small biotic creatures, which are then eaten by larger animals causing progressively concentrated levels of toxins within the tissue of large predators. Ultimately, this can lead to the death of large animals and the consumption of toxins by humans. Sustained inhabitance at remote locations is one of the crucial distinctions between outdoor marijuana cultivation sites operated by Mexican DTOs and those operated by other groups. Mexican nationals inhabit sites over a period of three to five months in order to prepare the landscapes, maintain plants, and aggressively protect their plantations. On average, two to five people live on the site throughout the season while a total of ten to fifteen actively aid in supplying materials and preparing grow systems. These men ensure that the site is properly equipped, concealed by camouflage, and guarded against detection and seizure. ustained inhabitance at remote locations is one of the crucial distinctions between outdoor marijuana cultivation sites operated by Mexican DTOs and those operated by other groups. Mexican nationals inhabit sites over a period of three to five months in order to prepare the landscapes, maintain plants,cannabis grow supplies and aggressively protect their plantations. On average, two to five people live on the site throughout the season while a total of ten to fifteen actively aid in supplying materials and preparing grow systems. These men ensure that the site is properly equipped, concealed by camouflage, and guarded against detection and seizure. Cultivators rely on sufficient tree canopy as the primary camouflage for Cannabis plantations. They plant marijuana in areas where the sunlight reaches through the holes in the trees, but the tree cover is sufficient to obstruct the view of plants from an aerial perspective. Cultivators cut down trees strategically in order to let in more sunlight while maintaining obstruction to aerial detection. They then spray green spray paint and other colorings on stumps to mask the reflectivity of freshly cut wood.

In more exposed areas, marijuana is sometimes interspersed with legitimate commercial agriculture to prevent visual detection. In addition, inhabitants paint camouflage patterns and netting to hide camp equipment and tents that do not blend in with the natural environment. Cultivator concern for concealing their activity is limited to arboreal camouflage. Inhabitants contaminate sites by littering the ground with garbage including cook ware, stoves, empty propane tanks, extendable pruning saws, excess plastic irrigation hose, tarps, beer cans, plastic wrappers and many other forms of refuse. Dug out latrines contain months worth of excrement and excess chemicals. In Sequoia National Park in 2007, the California Army National Guard and the California Air National Guard cleaned up resident-camp infrastructure from 11 grow sites and 9 camps that were occupied by growers. In this effort they removed 5,600 pounds of garbage, including 75 propane canisters and 5.8 miles of irrigation hose.68 In addition to leaving trash, some cultivators construct and leave fences around cultivation plots. They build deer fences that are 6-10 feet tall around planted areas with standard chicken wire, cattle fence, plastic netting, or livestock wire. These fences act as barriers to faunal migratory pathways and tangle animals in the netting or micro-filaments. Wildlife is also impacted directly through cultivators’ use of high powered weaponry. Many sites have scattered carcasses of deer and bears that were poached by laborers, who shoot almost anything that comes near their site. This aggressive behavior protects the plants and provides supplemental protein in the laborers diet. However, the vast majority of these carcasses are left to rot and to be eaten by vultures because growers cannot viably consume or preserve all of the meat from large mammals before it rots. The scavengers that successfully feed on carcasses have an increased risk of developing lead poisoning because they begin eating at the point of bullet entry where inner flesh is the most exposed and easily accessible. By eating from a gunshot wound, scavengers consume bullets containing lead. Over time, lead can accumulate in their bodies and cause lead poisoning. Lead poisoning caused by hunting is cited as the number one killer of the California condor, an endangered species, and poses one of the most significant threats to wild scavengers in California.69 Sustained inhabitance poses a significant hazard to fire prone areas throughout California. Cultivator activity can cause wildfires and the presence of a marijuana garden obstructs firefighting efforts due to safety issues. “On the Hume Lake Ranger District of the Sequoia National Forest, a wildfire in 1999 was started by a campfire in a marijuana garden. Firefighters found the garden and had to stop fire suppression activities in the area until law enforcement secured the area. This problem occurs several times every year.”Cultivators use campfires and burn volatile gases for cooking during the dry season in areas vulnerable to fire. Under prime fire conditions, a stray spark, improperly connected tank, or overturned stove can initiate an out of control fire with drastic and widespread consequences. A crucial function of sustained inhabitance is to perform counter-surveillance efforts. Cultivators are trained by cartel employees, often veterans of the Mexican army, and equipped with weapons ranging from shotguns to assault rifles. A station is setup at a vantage point above the grow site so a watchman can detect and alert his colleagues to approaching scouts or the presence of pedestrians. While entering sites, laborers sweep trails of any prints so they can patrol for signs of entry by others. One positive development is that the use of booby-traps has drastically declined. However, the protective behavior of inhabiting guards has become increasingly aggressive year to year as a result of escalating grower competition, law enforcement pressure, high crop value, and DTOs’ demand for harvest delivery.Men on patrol have been known to threaten anybody they encounter, and even harass law enforcement and forest service employees at their homes.

When heroin and heroin-cocaine abusers have been compared, a direct relationship has been found between cocaine abuse and the rate of psychiatric disorders, together with correlation with the severity of self-rated psychopathology. We do not know if this lack of awareness of psychopathological symptoms is due to the use of cocaine or to the underlying excitement that sustains cocaine use. Moreover, if cocaine use represents self-enhancement of one’s level of hypomania, cyclothymia or hyperthymia, the craving for hypomania is likely to be particularly strong in heroin addicts, whose level of excitement is lowered by heroin use. In addition, cocaine has been reported to induce a higher frequency of mixed states when abused by bipolar patients. This evidence suggests that some bipolar patients, after deciding to use cocaine instead of being excited, may have shifted from a manic or hypomanic to a mixed episode. During a manic episode, patients show a high level of consumption of stimulants and cannabinoids. In the literature, the abuse of cannabinoids in bipolar patients has been found to induce manic symptoms, so it is possible that, in our manic patients, as with cocaine use, they may use cannabinoids to optimize their level of excitement. To date, cannabis use is also considered to be one of the most important risk factors for schizophrenia, thanks to its ability to precipitate or exacerbate psychotic symptoms. In line with this assumption, in our sample, cannabis is mainly abused in manic and mixed states that, unlike depressive and hypomanic episodes, are often characterized by the presence of psychotic symptoms. Whatever the causes of the use of cannabis grow system, Khantzian’s hypothesis is not supported in its application to cannabis use. For many subjects, ending cannabis use is difficult to achieve, not only because of prior habits of use, but also because of the attendant psychotic symptoms, including poor insight and judgment, lack of impulse control and cognitive impairment.One widely debated issue is whether Khantzian’s hypothesis is a suitable instrument for interpreting alcohol dependence. In examining patients with a mixed episode, we found that, besides their abuse of cocaineamphetamines and cannabinoids, and in contrast with the other three clinical presentation groups, they often resort to alcohol use.

Patients experience their mixed mood as something undesirable and unpleasant, but they still continue to consume substances that tend to preserve their mixed, dysphoric state. Craving for substances and dependence create a loop, a senseless vicious circle in which patients obtain neither satisfaction nor physical benefit . In line with this observation, a past or current alcohol use disorder has proved to raise the likelihood of a switch from depressive to manic, mixed or hypomanic states in patients with bipolar disorder. Nervousness in alcoholic patients has been hypothesized to be the only negative mood state to predict increases in alcohol consumption later in the course of the day. Further examination of this within-person relationship has demonstrated that men were more likely to consume alcohol when nervous than were women, but this association is unrelated to family history of alcoholism, problem drinking patterns, or traits of anxiety and depression. Consistently with the self-medication hypothesis, alcohol consumption has been associated with lower levels of nervousness, but this effect varies in a way dependent on several demographic and clinical variables. Almost one quarter of individuals with mood disorders use alcohol or drugs to relieve symptoms, with the highest prevalence of self-medication in bipolar I disorder. After checking the effects of substance use disorders, self-medication has been associated with higher rates of comorbid anxiety and personality disorders than those found in individuals who do not self-medicate. On the basis of these data we believe that, in the case of alcohol, Khantzian’s hypothesis accounts for anxiety disorders more satisfactorily than mood disorders, although it must be added that it actually explains controlled rather than addictive use. In fact, enduring use, despite the worsening, or the inadequate balance, of symptoms, is inconsistent with a current self-medicating explanation, although that explanation may have been appropriate in a previous stage of controlled use. It should also be remembered that patients were assessed for mood during current drug use, thus ruling out the ambiguity between spontaneous mood swings and substance-induced intoxication. In fact, our patients had been displaying affective dys regulation for some time before being diagnosed, and had been engaged in substance use, which was bound to worsen the affective core of their clinical pictures .

The hypothesis of symptomatological overlap between temporary substance-related intoxication and mood states is superseded in this way. After reviewing our data we speculate that, setting aside depressive and mixed episodes, the abuse of substances in hypomanic and manic episodes of bipolar disorder is more probably due to patients’ desire to maintain their current affective state rather than to resolve depressed mood. These considerations also provide a possible explanation for the fact that bipolar patients tend not to comply with therapy during hypomanic, manic and mixed states. In the literature, patients’ lack of compliance with prescribed therapy has been principally associated with their lack of insight into their mental illness. We go beyond that in suggesting that, during hypomanic and manic phases, bipolar patients do not comply with prescribed therapies and tend to exacerbate their mental status by means of substances, not only because they are unaware of their mental illness, but also because they somehow live the current episode as a pleasurable and rewarding experience . The obvious limitations of this study are due to the fact that this is a retrospective analysis carried out on a small cohort of patients, rather than a study specifically designed to elucidate this issue. Assessments of the same subject in various different clinical presentations of the natural history of this illness would have provided a better level of information. In addition we must consider the difficulty in determining whether the substance use modifies the mood or the mood state determines the substance used. It is possible that stimulants are seen in those with mania or hypomania because the stimulant produced the mood state. They could have been depressed without it. Lastly, we have no information about the temperament of our subjects. So we cannot exclude the presence of a depressive temperament that is able to moderate the nature of patients’ substance abuse; that would set up the need to modify our hypothesis. One of our earlier findings, however, was that heroin users mainly have a cyclothymic temperament.Cannabis is an adaptive and highly successful annual with the ability to grow in most climates across the globe. Cannabis belongs to the Cannabaceae family, “has a life cycle of only three to five months and germinates within six days.”Cannabis can occur in a wild, reproducing state throughout the California floristic provinces, and is cultivated even outside of areas where it may naturally reproduce.Cannabis planting, growing, and harvesting seasons are similar throughout California and typically take place April through October. “Exposed river banks, meadows, and agricultural lands are ideal habitats for Cannabis” since these ecosystems provide “an open sunny environment, light well-drained composted soil, and ample irrigation.”

The Cannabis plant has been utilized to produce a diverse set of products with various applications. Today, Cannabis is most commonly produced for its psychoactive properties, though historically it has been used for agricultural production, nutritional value, and industrial purposes. The two species of Cannabis cultivated for psychoactive and physiological effects are Cannabis sativa and Cannabis indica.Marijuana is the most common name referring to varieties of Cannabis produced for mind altering affects. Marijuana contains high levels of chemical cannabinoid compounds including delta-9 tetrahydracannabinol, or THC, the primary psychoactive component of Cannabis. Cannabis has a long history of use in the United States. During the 17th century, the government encouraged hemp production, a fibrous form of Cannabis, for use as rope, clothing, and sails. In the early 20th century after the Mexican Revolution, the recreational use of marijuana grow system was introduced by Mexican immigrants. In 1937, the Marijuana Tax Act was enacted to effectively criminalize marijuana consumption as a result of an anti-marijuana propaganda campaign led by the commissioner of the Federal Bureau of Narcotics, Harry J. Anslinger. During World War II the U.S. Department of Agriculture provided incentives, including draft deferment, for farmers to grow hemp to meet wartime fiber needs. In the 1950s, a series of federal laws were enacted to create mandatory sentencing for people convicted of using drugs classified as illegal, including marijuana. Despite stricter regulation, marijuana was embraced by popular counter-culture movements in the 1960s. This act classified marijuana as a Schedule I controlled substance, the most restrictive schedule of illegal drugs “found by the government to have a high abuse potential, a lack of accepted safety under medical supervision, and no currently accepted medical use.”In fact, the whole Cannabis plant was classified as Schedule I, which means that possession of any portion of the Cannabis plant became illegal under federal law. Petitions to reclassify Cannabis have been proposed since the 1970s based on an ever increasing literature of clinical studies and scientific research that disputes the vague classifications of “high abuse potential, a lack of accepted safety under medical supervision and no currently accepted medical use.”This article of the Comprehensive Drug Abuse Prevention and Control Act was brought to the forefront of legal and political debate in 1996 when the Compassionate Use Act, or Proposition 215, passed in California, followed by 13 other states, to legalize the medical use of marijuana.Criteria for the legal possession of medical marijuana vary from the state to county levels, but Cannabis possession and consumption remain illegal at the federal level. In the pivotal Supreme Court decision of Gonzales v. Raich, the court ruled that the federal ban on cannabis may be enforced at all levels of jurisdiction based on the Commerce Clause of the United States Constitution. Their basis was that “incidents of the traffic which are not an integral part of the interstate or foreign flow, such as manufacture, local distribution, and possession, nonetheless have a substantial and direct effect upon interstate commerce.”

Despite the precedent set by this case, the development of legalized medical marijuana has led to significant changes in domestic Cannabis cultivation. In California, marijuana is cultivated in various amounts ranging from a single plant grown for personal consumption to thousands of plants per plot cultivated for commercial distribution. Law enforcement and US Forest Service reports indicate that Drug Trafficking Organizations control a significant portion of Cannabis cultivation in the United States and are establishing an increasing number of both indoor and outdoor growing sites. The primary DTOs operating in California are of Mexican origin and consist of the most powerful cartels in Mexico. The outdoor cultivation sites developed by DTOs are of special concern because they mainly occur on public lands. Remote areas used by cultivators include land holdings managed by the US Forest Service, the Bureau of Land Management, the National Park Service, the Fish and Wildlife Service, the Bureau of Indian Affairs, and the Bureau of Reclamation.However, DTOs also cultivate marijuana plots on private lands including conservation reserves, game lands, and large private land holdings. Marijuana cultivation on public lands is entrenched in California structurally, institutionally, economically, and culturally. The issues that surround marijuana cultivation and prevention efforts are both complex and large in scale. The systems and processes employed by both cultivators and law enforcement agencies are long established and the product of a dynamic progression. However, the scale of marijuana production and the adverse effects of cultivation have reached unprecedented proportions. Black market revenues have increased with the demand for marijuana, giving rise to criminal enterprises that go to any lengths necessary to maximize profits. The result is an oligopolistic market control, continued natural resource damage and sustained infringement on public safety. Marijuana is California’s largest cash crop, estimated to be worth between 10 and 14 billion dollars annually.This immense profit incentive is the main cause for continual marijuana cultivation on public lands, and is based on high demand and inflated market prices. In the most highly concentrated cultivation counties in California, the economies of which are based on the marijuana industry, only a handful of cultivators are arrested each year.

As is true of all studies, it is important to keep the findings in perspective. The original sample was limited to non– alcohol-dependent European American and White Hispanic male college students or nonacademic staff, and additional studies are needed to demonstrate if the current results generalize to women and to other samples. Also, although the SDPS began with a relatively large population for such intense every-5-year evaluations, the current analyses focused on outcomes for men who developed AUDs, which, despite the greater than 90% 35-year overall follow-up, produced a modest 156 subjects. Furthermore, the analyses were dependent on the existing baseline data gathered four decades ago that included information from multiple domains but offered a limited number of specific variables in each category. In addition, although data from additional informants were used for evaluations at ages 30, 35, 40, and 45, financial restrictions contributed to the decision to gather data only from probands at the two most recent assessments, with a potential for under reporting of heavy drinking and alcohol problems. Finally, it is important to remember that Table 4 presents four separate binary regression analyses, and although Bonferroni corrections for multiple testing would still be significant for the R2 values and for specific predictors with p values less than .01, predictors in Table 4 with p values less than .05 are more tenuous. In summary, these data described the age 50–55 outcomes for 156 higher educated and accomplished men who developed an AUD during the prior 30 years. For most, their AUDs were persistent and severe, despite which their accomplishments did not fit the public stereotype of the “average alcoholic.” Their achievements and public persona in their 50s underscore the importance of clinicians screening all patients for possible AUDs,cannabis grow system including those with high levels of life achievements. The robust predictions of alcohol problems from their LR in this and other studies offer potential promise in instituting earlier intervention programs based on tailored feedback about their vulnerability .

With the legalization of “medical” marijuana and recreational cannabis use in some states of the U.S , the high rates and earlier onset of cannabis use , the increasing potency of cannabis , the recreational use of highly potent synthetic cannabinoids , and the high rates of emergency department visits related to cannabis there is a need to understand the basic mechanisms underlying the behavioral effects of cannabinoids such as delta- 9-tetrahydrocanabinol , the primary psychoactive constituent in cannabis. Δ 9 -THC, via activation of brain cannabinoid 1 receptors , induces a range of acute alterations in perceptual, emotional, and cognitive functions that are relevant to psychotic states and psychotic disorders such as schizophrenia . Neural oscillations in the gamma -band are thought to play a key role in the operation of these functions by participating in sensory registration and integration, associative learning, and conscious awareness among other processes . Therefore, it is expected that alterations in these processes will be associated with abnormalities in γ-band oscillations. Consistent with this view, a number of studies in schizophrenia patients have confirmed the existence of an association between functional and γ-band abnormalities as measured by electroencephalography . This raises the intriguing possibility that some of the acute psychosis-relevant functional abnormalities induced by Δ9 -THC may be associated with γ-band alterations . paradigm , which is associated with some of the characteristic abnormalities of the disorder . In view of this, we selected the ASSR paradigm to study the relationship between the acute 9 -THC-induced alterations in γ-band oscillations and psychosis relevant effects. This study was part of a larger project that aimed to assess the dose-related effects of 9 -THC on several electrophysiological indices of information processing relevant to psychosis and to determine the relationship between the electrophysiological and behavioral effects of 9 -THC. In this study we examined the acute, dose-related effects of intravenous 9 -THC on the ASSR in a number of frequency bands, and the relationship between these effects and the psychosis-relevant effects induced by 9 -THC. We hypothesized that 9 -THC would specifically reduce the γ-band ASSR, and that γ-band ASSRs measures would be inversely correlated with the psychosis-relevant effects of 9 -THC.

This randomized, double-blind, placebo-controlled, counterbalanced, cross-over study was conducted at the Neurobiological Studies Unit . Subjects were recruited by advertisements and by word of mouth, and were paid for their participation. The study was approved by the institutional review boards of the VACHS and Yale University School of Medicine and was carried out in accordance with the Helsinki Declaration of 1975. Subjects were informed about the potential for adverse effects of Δ9 -THC including psychosis, anxiety, panic and abuse liability. For assessment of ASSRs, subjects sat in an acoustically shielded booth in front of a computer monitor with eyes open, while passively listening to click trains presented through Etymotic insert ER-1 earphones . Stimuli consisted of standard, unattended auditory click trains from a three-stimulus oddball task as reported previously . The auditory click trains were presented at 3 different frequencies . Each block contained 150 trials of a single frequency presented for 500ms each . Each trial lasted 1250ms, and each block lasted 4 minutes. Across subjects, the order of blocks was counterbalanced and the order of conditions was randomized. A detailed account of EEG methods is provided in the supplementary text 1. Continuous EEG data were band-pass filtered , line noise was removed using a multi-tapering technique , muscle artifacts were removed using a blind source separation algorithm, and eye movement and blink artifacts were removed with an adaptive filter algorithm . Data were segmented in 1200ms epochs time locked to stimulus onset, with a 300ms pre-stimulus baseline. A ±95 μV voltage criterion was used to reject bad epochs. EEG data from three midline electrodes were used for ASSR analyses, given that the ASSR is typically maximal at the midline electrodes . All analyses were done in Matlab using either custom-made scripts or the EEGLAB toolbox‟ scripts and plugins . Demographic and cannabis use data are listed in table 1. Of 56 subjects who were initially consented for the study, 10 failed the screening process and 8 chose not to initiate the study. Of the remaining 38 subjects, 30 completed all three test days of which 5 had to be dropped due to technical difficulties during EEG acquisition. There were no obvious differences between dropouts and completers . Of the remaining 25 subjects, 2 were dropped during the EEG preprocessing due to artifactual contamination , and 3 were categorized as outliers and dropped during the statistical inspection of the EEG measures. Thus, EEG data from 20 subjects who completed all test days were used for statistical analyses. The inspection of the behavioral measures of these 20 subjects, revealed 1 outlier for the PANSS general and total scores during the 0.015mg/kg condition. This data point was excluded from the regression analyses . Alcohol and drug use among women of childbearing age represents an increasing burden to society and healthcare providers across the United States. Substance use during pregnancy is associated with increased rates of obstetric University of North Dakota School of Medicine and Health Sciences, North Dakota Fetal Alcohol Syndrome Center, Department of Pediatrics, Grand Forks, North Dakota complications, fewer prenatal visits, and poor perinatal outcomes.Fetal alcohol spectrum disorder , a serious consequence of prenatal alcohol exposure, is the leading preventable cause of birth defects and neurodevelopmental disability in the U.S.

It often reoccurs within sibships and themortality among birth mothers of children diagnosed with an FASD is increased by nearly 39-fold.Recent data demonstrate that 11.9% of non-pregnant women and 5.3% of pregnant women age 15-44 reported illicit drug use in November, 2016.1 Alcohol use at levels meeting criteria for binge or heavy drinking was reported by 23.7% of non-pregnant women and 2.8% of pregnant women.1 According to the National Institute on Drug Abuse, of the more than 130 million visits to emergency departments in 2009, 2.1 million were for drug abuse.From 2004 to 2009 ED visits for non-medical use of drugs increased 98% , with 32% of patients reporting concurrent alcohol use.7 In 2005 the National Alcohol Survey found that 24% of individuals presenting to the ED reported high-risk drinking behaviors.Approximately 50% of pregnancies in the U.S. are unplanned, with fetal first trimester exposure rates of 56% for all women and 78.9% for women with recent alcohol dependence.While the majority of women cease or reduce alcohol consumption during pregnancy, in the U.S. alone every year around 80,000 women report drinking during all three trimesters.11Women meeting criteria for a substance use disorder used ED services 57% more frequently than women who did not have a substance use disorder and were hospitalized 67 % more frequently.Given the high prevalence of substance use in the patient population most using ED services, this setting presents a unique opportunity to screen a high-risk population for substance use. However,marijuana grow system limited data exist to examine the nuances of the screening process in the ED for substance use. In this study, we compared rates of screening for substance use among pregnant and non-pregnant women seeking care at an ED facility. The project was approved by the Altru Health System Institutional Review Board and the University of North Dakota Institutional Review Board. We captured all ED records of women from a single community hospital for the years 2010 to 2016 . A woman was considered pregnant if her pregnancy status was recorded as “pregnant.” All other women were classified as not pregnant. Demographic data included age in years, race/ethnicity , marital status , and body mass index .We created a dependent binary variable based on whether the woman was tested for alcohol or drugs during her ED visit or not tested. We examined the electronic medical record and the lab record for any test for substance use that was ordered or completed by the lab. Testing modalities included blood, urine, hair, or breathalyzer readings. We included testing for amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, opioids, and alcohol. The 399 unique chief complaint ICD-9 codes were then further grouped into 20 categories . The last department used by the woman was categorized as ED, urgent care, or other . Their dispositions were combined into two groups, internal or external .We compared the association between pregnancy status and drug/alcohol testing using the chi-square statistic with relative risk and 95% confidence intervals . This association was assessed for the demographic covariates. The risk of drug/alcohol testing for pregnant woman relative to non-pregnant women was produced for levels of other variables using relative risk and 95% CIs. We tested interactions between pregnancy status and the demographic variables using the Breslow-Day test for homogeneity in odds ratios. Logistic regression was then used to test for interactions between pregnancy status and demographics or ED visit characteristics. We used SAS version 9.4 for analyses.

Our study found that pregnant women presenting to the ED were 75% less likely to be tested for substance use than non-pregnant women. Even among the most-tested presenting complaints for all women ,pregnant women were still 37%-54% less likely to be tested. These data may suggest a relatively lower index of suspicion for substance use among pregnant women seeking care in the ED. This difference by pregnancy status was present even for women with similar presenting complaints and demographics in the ED. While no prophylactic treatment exists at this time, early screening and counseling is the best practice to support women in decreasing the risk of the serious consequences associated with prenatal substance exposure.12 Identification of prenatal alcohol exposure is of particular importance as the long-term implications of alcohol exposure for the fetus have shown significant consequences in comparison to other substance exposures.3,13-15 With fetal first-trimester alcohol exposure rates of 56% for all women and 78.9% for women with recent alcohol dependence,10 the ED presents a unique opportunity to address a population of women with a greater than average incidence of alcohol and drug use. The opportunity to provide education and intervention at this stage is especially compelling among women of low socioeconomic status who are seen in the ED more frequently than in primary practice.16 Women who received treatment based on positive drug/alcohol screening results have been shown to subsequently have fewer future ED visits, injuries and hospitalization.