Hemp Growing

More research is needed to understand the socioeconomic impacts of legalization, which likely extend beyond those accounted for in the state’s economic impact analysis, which primarily focuses on economic contributions that a legalized market will bring to the state.Bodwitch et al.report that surveyed growers characterized legalization as a process that has excluded small farmers, altered local economies and given rise to illicit markets.The environmental impacts of cannabis production have received attention because of expansion into remote areas near sensitive natural habitats.The negative impacts are likely not because cannabis production is inherently detrimental to the environment, but rather due to siting decisions and cultivation practices.In the absence of regulation and best management practices based on research, it is no surprise that there have been instances of negative impacts on the environment.At the same time, many growers appear to have adopted an environmentally proactive approach to production and created networks to share and promote best management practices.Organizations that we approached to recruit survey participants had a fairly large base membership , which is on a par with other major commodity groups, like the Almond Board of California and California Association of Wine grape Growers.Membership included cannabis growers, distributors and processors as well as interested members of the public, and some people were members of more than one organization, suggesting a large, engaged community.Most of the organizations we contacted enthusiastically agreed to help us recruit growers for our survey, and we received excellent feedback on our initial survey questions.Growers who completed the survey were also clearly knowledgeable about cannabis cultivation.Some potential future research topics include the development of pest and disease monitoring programs; quantifying economic treatment thresholds; evaluating the efficacy of different biological, cultural and chemical controls; developing strategies to improve water use and irrigation efficiency; understanding grower motivations for regulatory compliance; understanding the impacts of regulation; and characterizing the competition between labor in cannabis and other agricultural crops — to name just a few.

As cannabis research and extension programs are developed, it will be critical to ensure that future surveys capture a representative sample of cannabis growers operating inside and outside the legal market, to identify additional areas for research and develop best practices for the various cultivation settings in which California cannabis grow equipment is grown.Approximately, 35% of high school seniors and young adults ages 19–28 reported using cannabis in the past year.Cannabis use during youth has been a recent focus in public health research, as it may influence one’s risk for reporting symptoms of anxiety and depression.A potential mechanism underlying cannabis’ influence on mood and affective symptoms may involve frontolimbic functioning [see ].Understanding differences in frontolimbic connectivity among young adults with frequent cannabis use may provide insight into the etiology of associated mood or affective risk.Cannabinoids in cannabis, such as 1 9-tetrahydrocanabidiol and cannabidiol , are chemicals that mimic endogenous neurotransmitters anandamide and 2AG by binding to endocannabinoid receptors CB1 and CB2.THC is the main psychoactive component of cannabis and is responsible for the subjective “high” individuals experience [see ].CB1 activity modulates the release of the neurotransmitters GABA and glutatmate [see ].The eCB system modulates several functions related to physical and mental health, including regulation of emotional and stress responses [see ].More specifically, the eCB system plays a role in mood and affect , integrating reward feedback , and threat related signals.Brain regions primarily involved in the affective processing system include several interacting cortical and subcortical regions.This system is highly innervated with CB1 receptors and animal models demonstrate developmental changes in CB1 expression within the mPFC, ACC and insula , suggesting the system demonstrates plasticity during adolescence.Therefore, repeated THC exposure during development may impact naturally occurring changes in eCB functioning within mesocorticolimbic regions.Indeed, daily cannabis users have shown decreased CB1 receptor density within frontolimbic regions , ACC, and insula compared to non-users which recovered after a month of abstinence.Further, acute THC administration has resulted in abnormal performance on behavioral measures of emotional processing , amygdala reactivity , and altered functional connectivity and signaling in PFC regions.

However, additional research is needed to confirm the influence of repeated THC exposure on affective outcomes in adolescents and young adults.Due to the neuromodulatory role of the eCB system, examining brain functional connectivity is an important outcome to study in regular cannabis users.These relationships can be examined during tasks and also at rest, when individuals are not actively engaging in any specific cognitive tasks, called resting state, or intrinsic functional connectivity.Connectivity patterns in frontolimbic regions continue to develop into late adolescence and emerging adulthood; prefrontal maturation purports enhanced emotion regulation and behavior inhibition capabilities [see ], giving rise to a functional coupling between frontal and limbic regions.Collectively, the developmental changes in frontolimbic connectivity are thought to enhance socioemotional regulation [see ], specifically via functioning within the amygdala, medial PFC, vmPFC, ACC, insula, and inferior frontal gyrus.A particular region within the PFC, the ACC, also undergoes significant age-related changes in intrinsic functional connectivity, particularly in rostral ACC subregions involved in social cognition and emotion regulation.Therefore, this system may be particularly vulnerable to repeated THC exposure during development.Thus far, studies have found slower response times in users when identifying emotional faces and more liberal criterion for selecting sadness , poorer facial recognition and emotion matching , and emotion identification and discrimination impairments compared to non-users; though accuracy in emotion identification may not display a dosedependent relationship.fMRI studies have found aberrant amygdala and ACC activity in young cannabis users during affective processing tasks, including blunted ACC and amygdala activation during sub-conscious facial viewing , blunted amygdala response among youth with comorbid cannabis dependence and depression , and greater amygdala reactivity to angry faces in young adolescents.However, to date very few studies have examined intrinsic functional connectivity in adolescents and emerging adults.Studies to date in adolescent and young adult cannabis users have demonstrated increased intrinsic connectivity in frontal -temporal gyrus-cerebellar regions , frontal-parietalcerebellar network , increased middle-frontal and cingulate gyrus connectivity , and increased frontal gyrus activity along with reduced middle temporal activity.Increased connectivity patterns were linked with increased symptoms of cannabis dependence and recent cannabis use frequency.In young adult males, cannabis use was linked with increased connectivity in insula and decreased connectivity in the anterior cingulate and midbrain, even after a month of abstinence.

Thus, overall, young cannabis users appear to demonstrate increased intrinsic connectivity patterns, especially in frontal-limbic regions.Still, these studies were primarily in men , thus findings may not generalize to female users.Further, two studies did not control for comorbid alcohol use and despite the aforementioned link between cannabis use and affective processing, no studies to date have specifically examined affective processing networks in cannabis users.Therefore, additional research is needed to examine intrinsic connectivity in affective processing networks in larger samples that include both males and females, controlling for comorbid alcohol use.The purpose of the current study was to explore whether regular cannabis use in adolescents and young adults was associated with aberrant ifcMRI frontolimbic connectivity at rest.We employed a priori region of interest analysis focusing on regions with reported cortical differences between young cannabis users and controls, including: vmPFC , ACC , insula , and amygdala.This project utilized ifcMRI data from three collection sites from the Imaging Data in Emerging Adults with Addiction Consortium.The strength of utilizing multi-site data sets include excellent reliability and validity when combining multi-site ifcMRI data , increased generalizability of more heterogenous groups , and larger sample sizes.It was hypothesized that cannabis users would demonstrate increased intrinsic connectivity patterns in regions subserving emotional expression [amygdala, insula, and caudal and rostral ACC ].Lastly, in order to interpret the findings, a secondary aim examined if group differences in connectivity were associated with cannabis users’ self-reported anxiety and depressive symptoms.The current study examined whether cannabis use was associated with frontolimbic intrinsic connectivity using a cross-sectional design in a sample devoid of independent Axis I anxiety FIGURE 2 | Scatter plot between total depression symptoms and bilateral rAcc connectivity in cannabis users.or mood disorders.After controlling for MRI collection site, recent alcohol, and nicotine use, and abstinence from cannabis use, cannabis users demonstrated increased intrinsic connectivity between the left rACC and the following: left insula, left amygdala, and right rACC in comparison to controls, though only group differences between bilateral rACC survived after correcting for multiple comparisons.Further, we found that increased bilateral rACC connectivity was associated with greater sub-clinical depressive symptoms in cannabis users.Current findings parallel previous intrinsic functional studies indicating frequent cannabis use among youth is associated with greater connectivity between frontal and temporal regions , and increased ACC connectivity in males.Resting state connectivity increases in comparison to controls was also reported within the medial frontal gyrus among a high-risk mostly male adolescent group.The present study adds to existing literature by including more females, controlling for other substance use and cannabis abstinence period, and relating the observed connectivity differences to mood-related symptoms.

Task-based studies also report altered medial PFC activity associated with cannabis use among emerging adults ,vertical grow system suggesting chronic cannabis use is associated with region-specific changes in brain activity and connectivity among regions implicated in emotion regulation, identification, and modulation.The current findings of abnormal functional connectivity in the rACC and limbic regions, which is consistent with our previous structural findings.Our team recently reported that greater cannabis use was related to reduced left rACC volume among young cannabis users, and smaller rACC volumes were also significantly associated with lower performance in an emotional discrimination task.Further, we also found reduced right ACC cortical thickness in a sample of young cannabis users, including a subset of cannabis users with a history of childhood attention deficit hyperactivity disorder, compared to non-using controls.The ACC undergoes significant developmental shifts in functional connectivity during young adulthood , has been implicated in ones’ ability to detect and monitor self-produced errors whether one is conscious/aware of the error or not.The ACC may be less engaged in cannabis users compared to controls during tasks requiring inhibitory control and error monitoring.The rostral subdivision of the ACC is functionally connected with the amygdala , forming a network for processing affective facets of behavior.In concert with the insula, the ACC also serves to incorporate perceptual information with autonomic and emotional information.More specifically, the rACC has been posited to have top down control influence, serving as a gatekeeper, between regions processing negative affective information and those integrating environmental stimuli [see ], and demonstrates protracted development during young adulthood.The rACC is involved in implicit or automatic emotion regulation that occurs at a subconscious level.Indeed, lesions in the rACC are posited to impair ones’ sensitivity to adjustments in personal performance during a cognitive control task.For example, cannabis users have demonstrated reduced P300 during implicit and empathic emotional processing paradigms, particularly for the highest using cannabis users that also demonstrated deficits in explicit processing of negative emotions.Thus, abnormalities in rACC structure and function may impact various behavioral aspects, including cognitive control and emotional regulation.The current study suggests that chronic cannabis use may increase intrinsic connectivity between emotion regulation regions, which was opposite of our original hypothesis.A potential interpretation may include the inefficiency of prefrontal top-down regulation, as hypothesized by Behan et al., suggesting reduced intrinsic amygdala responsiveness.Further, Pujol et al.found reduced ACC and insula connectivity; however, the study did not examine sub-components of the ACC and used seed-based rather than region of interest approaches.Thus, disruptions in rACC function may lead to challenges in modulating ones’ mood, consistent with the current study findings, or adjusting to emotionally salient internal and external information.Indeed, we also found that increased depressive symptoms among cannabis users were associated with greater connectivity between the bilateral rACC.Alterations in rACC structure and function [see ] have been previously linked with depressive and affective symptoms and antidepressant response.Though the current sample did not meet criteria for an Axis I mood or anxiety disorder, cannabis use may impact regions implicated in symptom manifestation.Although cannabis users reported significantly greater sub-clinical levels of depression, we are unable to determine whether the endorsed symptoms predated the initiation of cannabis use or whether the endorsed symptoms occurred during the course of regular cannabis use among users.Indeed, cross-sectional and longitudinal studies among cannabis using youth have found increased risk of mood and affective symptoms.Even casual cannabis using young adults report greater depressive symptomatology.Thus, structural and functional abnormalities within the rACC observed in cannabis users may result in mood dysregulation.

The Court stated that the possession of cannabis is protected by Article 19 of Argentina’s Constitution, which states that “private actions that in no way offend public order or morality, nor are detrimental to a third party, are reserved for God and are beyond the authority of legislators.” Recent developments in Canada and nine US states signify the growing momentum of the trend toward the legalization of recreational uses of cannabis and the development of more complex regulatory models to govern legal cannabis markets.In different ways, these jurisdictions grant licenses to professional farmers and pharmacies to produce and to sell cannabis commercially and exempt individuals from criminal responsibility for noncommercial uses. The trend toward liberalizing cannabis prohibitions illustrates the recursive nature of transnational processes of legal change. The networks of actors participating in these processes—comprised of grassroots activists, legislatures, bureaucratic elites, criminal justice actors, scientists, journalists, and public health officials—created new regulatory models that gradually transformed the application of cannabis prohibition norms in various jurisdictions. These actors invoked the indeterminacy of treaty provisions, contested the framing of cannabis use as indicative of a moral malaise, and highlighted the diverse ways in which the enforcement of cannabis prohibitions produces social harms that are severer than those generated by cannabis use. They also utilized the space for norm-making provided by the mismatch between the institutions and actors that formulate global norms and those assigned with the actual implementation of these norms in national and sub-national settings. The success of these campaigns warrants a reflection on the conditions under which local and national acts of contesting TLOs can reshape the agenda of global actors invested in preserving the current normative settlements. The following section focuses on this question. The rapid and widespread transnational diffusion of new models of decriminalizing, depenalizing or legalizing the use of marijuana serves as a product and a catalyst of the declining capacity of the cannabis grow system prohibition TLO to shape the policy choices of criminal lawmakers and the routine practices of enforcement officials.

However, to what extent do these reforms change the agendas of the global actors that play key roles in shaping and maintaining the normative and institutional structures of this TLO? Faced with the global spread of cannabis liberalization reforms, the INCB has positioned itself as the most steadfast defender of the normative expectancies of the cannabis prohibition TLO.In its annual reports, the Board contested the legitimacy of the legal interpretations underpinning states’ engagement with decriminalization, depenalization, and legalization initiatives. The Board repeatedly expressed its concern that the introduction of civil sanctions for possession offenses was sending the wrong signal, downplaying the health risks of marijuana use.Most recently, the Board condemned Uruguay and Canada for adopting legalization schemes, stating that such reforms constituted clear breaches of the international conventions. The literature examining the roles of naming and shaming mechanisms in international politics observes that most countries are inclined to bring their laws into formal compliance with international standards to avoid being stigmatized as “deviant states.”The efforts of the INCB to achieve such influence by condemning countries deviating from the prohibitionist expectancies of the international drug conventions failed to generate such adaptive responses.Some countries have practically ignored the Board’s proposed interpretation of the international obligations set by the conventions. Others have argued that the Board’s interpretive approach was too narrow and relied on selective use of the available evidence-base concerning the medical uses of cannabis. Still others contended that the Board was exceeding its mandate when it adopted a hostile stance toward legitimate policy choices of sovereign states.The limited impact of the Board’s attempts to delegitimize the adoption of non-punitive models of cannabis regulation provides important insights into the conditions under which naming and shaming strategies can succeed.One reason for this limited impact is that some of the central countries pioneering the experimentation with decriminalization and legalization schemes are not particularly vulnerable to economic and reputational pressures.Supporters of cannabis liberalization reforms across Europe and North America justify these policies on the grounds that they are needed to reconcile drug policies with fundamental human rights values as well as with human development concerns.In this polemical context, it is unsurprising that the INCB, which has long failed to restrain the human rights abuses inflicted in the name of the war on drugs, has not succeeded in harnessing transnational civil society actors to support its line of attack on the perceived departures from the settled interpretations of the international drug conventions. Whereas the INCB has remained unambiguously committed to the task of defending the normative settlements of the cannabis prohibition TLO, the approach taken by the US has been marked by ambivalence.

President Barack Obama’s administration adopted the ambiguous position of respecting the decisions of US states legalizing the medical and recreational use of marijuana while continuing to condemn steps toward legalization in Latin American and Caribbean countries. Responding to shifts in national public opinion, the administration set out lenient guidelines for the federal prosecution of marijuana users in states that had legalized its medical and recreational uses.It thereby allowed legalized drug markets to take roots in Colorado and Washington, and subsequently in other states. Like other national governments, the US federal government invoked its domestic constitutional principles to argue that its policies are in compliance with the international standards. However, during the same period, the US continued to apply its strict punitive approach to evaluating the compliance of other countries with the UN drug conventions. The annual certification process continues to include assessments of the extent to which the seventeen countries currently identified as “drug majors” are willing to eradicate the cultivation of cannabis and to penalize its growers and sellers. With a majority of Americans supporting the legalization of marijuana and a majority of US states already implementing decriminalization schemes for medical marijuana, lawmakers in the House and Senate are facing increasing pressure to end the federal ban on cannabis. Despite efforts by Attorney General Jeff Sessions to revive the zero-tolerance approach of the federal government, President Donald J. Trump has recently expressed his intention to support such reforms. It is too early to predict whether and when such a change will take place or how it will impact the federal government’s foreign policy stance on the issue of cannabis legalization. However, as long as the US adheres to this “do as I say, not as I do” message, its ambivalent posture enables further steps toward the unsettling of cannabis prohibition norms. Nevertheless, it is important to note that despite its declining regulatory effectiveness, the cannabis prohibition TLO continues to exert considerable influence on the development of drug policies at the international, regional, national, and local levels. In this context, it is notable that countries that have liberalized their cannabis laws emphasize their commitment to remain bound by the confines of the current treaty regimes of the international drug control system. Remarkably, the extensive recognition of the severe failures and counterproductive effects of the cannabis prohibition TLO has not generated viable political efforts to amend the international treaties underpinning its operation. To a considerable extent, the reluctance to renegotiate the treaty norms governing cannabis policies stems from the notion that the cannabis prohibition TLO is embedded within the mega-TLO of the international narcotic control system.This serves as a powerful mechanism of issue linkage, leading countries that support cannabis liberalization reforms to avoid initiating formal treaty amendments out of concern that such actions might destabilize the settled norms prevailing in other issue-areas of narcotic control.

The fact that the UN drug conventions regulate the global trade of both the illicit and licit uses of drugs, including substances on the World Health Organization’s list of essential medicines, further escalates the stakes in renegotiating the terms of these treaties. In addition, the reputational costs of defecting from UN crime suppression treaties might be higher than those suffered by persistent objectors in other areas of public international law. The branding of countries as pariah states, or “narco-states,” as it were, carries a stigma that resonates with the censuring functions performed by criminal labels in domestic contexts.These factors help explain why current efforts to restructure the regulatory frameworks governing cannabis markets are contained within the narrow space of policy experimentalism created by the textual ambiguity of the current treaties. Under these circumstances, many of the inherent weaknesses of the prohibitionist approach resurface in the new regulatory landscapes created by the decriminalization and depenalization of possession offenses. The involvement of criminal organizations in illicit drug markets remains of intermediate sanctions has a net-widening effect, which expands the use of control measures against low-risk drug offenders.Most fundamentally, the insistence on promoting drug liberalization reforms within the confines of the current system constrains the capacity of individual states and of the international community to imagine more effective and humane alternatives, such as those offered by harm-reduction and development-centered approaches.With the majority of U.S.states having adopted legislation to medically and/or recreationally legalize cannabis, the already high prevalence of cannabis use is expected to further increase nationwide, especially among existing users.States that allow the legal use of cannabis grow lights for medicinal purposes have higher rates of cannabis use and cannabis use disorder in national survey data and specifically within the Veterans Health Administration.Veteran advocacy groups have been created to further veterans’ rights to access cannabis for medical purposes and discuss its use with their VHA providers.There are also published reports that veterans perceive cannabis to be a low-risk or safe substance unlike other drugs of abuse and expect cannabis to provide relief from symptoms of combat-related trauma.However, there has been little research on the patterns and correlates of MC use specifically among veterans.Growing research indicates that rates of cannabis use and CUD are particularly elevated among veterans with post traumatic stress disorder and major depressive disorder.These individuals are particularly likely to use cannabis as a means of coping with negative affect and with sleep disturbances.Nonveter an research also identifies cannabis use as an emotion-regulatory strategy to reduce or manage perceived aversive psychological and mood states.However, although such sleep and emotion regulation motives are commonly endorsed reasons for non-MC use among veterans in general, little is known about potential differences in motives among veterans using MC relative to those using cannabis recreationally for non-medical reasons.Motivation for MC use has been examined in non-veteran populations , with the most commonly endorsed reasons for use being pain, anxiety, and sleep problems.

Besides pain management, relief of anxiety, especially PTSD, appears to be a prevalent motive for MC use in community samples and among veterans.Indeed, PTSD is now recognized as a qualifying condition by the majority of states permitting legal access to medicinal cannabis.Sleep disturbance, particularly in conjunction with PTSD, is associated with more frequent and more problematic use of cannabis in non-veteran samples and with frequent cannabis use and CUD among veterans.Thus, MC use may be driven by specific motives for use that are inter-related with certain comorbid conditions that are particularly prevalent in veteran populations.Medical dispensary patients also report using cannabis as a substitute for prescription medication and for alcohol , with the most common motives for using cannabis instead of alcohol or illicit or prescription drugs being fewer perceived side effects, better symptom management , and decreased severity of withdrawal with cannabis.Indeed, the vast majority of MC patients self-report at least moderate symptom relief across all conditions.Preliminary prospective research found a 42% reduction in use of prescribed opiates over 3 months following the initiation of MC treatment.Yet, cannabis used specifically for pain management among MC users is significantly associated with past history of more severe substance use patterns including use of alcohol, illicit drugs, and non-prescribed pain relievers.In contrast to the growing literature on MC use, only a few non-veteran studies explicitly compared MC and RC users on cannabis-related behaviors and motives.MC users were found to have poorer health but lower levels of alcohol and drug use disorders relative to RC users.Compared with RC users, MC users have reported lower frequency of alcohol and drug problems during a visit to the emergency department and primary care clinic.Among MC users, patients with state legal access to cannabis had lower rates of other substance use relative to cannabis users without access to MC who might have used cannabis recreationally.To date, there has been little research on MC use in veteran populations, with only one study differentiating between MC and RC use in veterans.

All but the small pipe calibration factor are higher than typical cigarette smoke calibration factors. By calibrating our instruments to machine-smoked cigarette smoke, we may have underestimated the true PM2.5 concentration in the dispensary. Our findings show that allowing customers to smoke cannabis indoors can create conditions that are known to be hazardous. Improvements to the ventilation system during the experiment had no effect on the PM2.5 concentrations. Exposure to PM2.5 from cannabis consumption is likely to have negative effects on the respiratory andcardiovascular health of the employees and may have negative effects of the respiratory and cardiovascular health of vulnerable patrons. Cannabis is the most commonly used illicit psychoactive drug in the United States with an estimated 9.6% of the population aged 12 and older reporting use in the past month.The majority of new users are under 18 years of age, and cannabis use has increased among youth and teens since 2007. In addition, pregnant women are increasingly using it to mitigate morning sickness. In the U.S., between 2002–2003 and 2016–2017, the adjusted prevalence of past-month cannabis use increased from 3.4 to 7.0% among pregnant women overall and from 5.7 to 12.1% among pregnant women during the first trimester. A recent national survey suggested that the public perception of “great risk” from weekly cannabis use has dropped from 50.4% in 2002 to 33.3% in 2014. Another recent survey found that 81% of U.S. adults believe that cannabis has at least one health benefit, such as use in pain management, disease treatment, or relief of anxiety, stress, or depression. While 91% of U.S. adults also believe cannabis use has at least one risk, including those associated with legal issues, 9% believe it has no risks, and the American public has an overall favorable view of cannabis drying racks. Cannabis is composed of over 400 chemicals, of which over 60 are cannabinoid compounds. The four major compounds include Δ9 -tetrahydrocannabinol , cannabidiol , Δ8 -tetrahydrocannabinol, and cannabinol. The major psychoactive cannabinoid in cannabis, THC, targets the endocannabinoid system, which regulates biological processes involved in development and neuroplasticity. It mimics eCB action, exerting most of its effects via cannabinoid receptors s 1 and 2.

CBR1 is one of the most abundant G protein-coupled receptors in the adult brain, and it is localized inregions important in movement, cognition, attention, emotion, and memory. In animals, expression begins early in the central nervous system during embryonic development. One study found CBR1 expressed in the human fetal brain at 20 weeks, with high expression in the hippocampus and amygdala. In contrast, CBR2 is mainly expressed in immune cells. Male mitotic germ cells also express a high level of CBR2, whose activation promotes their differentiation and progresses spermatogenesis.During adolescence, the eCB system continues to facilitate neurodevelopment through its involvement in neuroplasticity and synaptic function. Levels of CBRs fluctuate during adolescence and depend on the brain region. For instance, there is a rapid, sustained increase in CBR binding sites in the striatum that is reduced by half in early adulthood, as well as high levels in limbic related regions that gradually decrease by adulthood. Tightly regulated biosynthetic pathways ensure proper signaling throughout development, and correct brain function depends heavily on the temporal and spatial layout of the eCB system. Thus, exposure to THC, especially during critical windows of brain development, has the potential to disrupt the tightly regulated system. Parallel to the increase in adolescent cannabis use, the percentage of adolescents and young adults experiencing certain types of psychiatric disorders has risen in the United States over the past decade, despite the lack of increase in adults.In human studies, THC has been shown to disrupt the development and function of the brain, and in animals, THC has been experimentally shown to lead to molecular impairments that are heritable and extend into subsequent generations, thus increasing the risk of offspring developing a psychiatric disease. Three different routes of multi-generational transmission have been summarized in a prior review; they include fetal programming , germline transmission , and behavioral or social transfer . The first route is typical for prenatal exposure, the second route is typical for pregestational exposure, while the third route is typical for both. In a recent commentary, which was published in response to a study examining the epigenetic impact of cannabis use on rat and human sperm, the authors highlighted that the epigenomic toxicology of cannabinoids should have priority on the research agenda, especially considering the potential transgenerational health implications.

A review published in 2016 focused on the epigenetic effects of cannabis exposure. The authors noted that the majority of addiction-related epigenetic neurobiological studies had targeted the adult brain, while there was a dearth of literature on the potential intergenerational impacts of cannabis. Another article published in 2018 provided an overview of the current data regarding vulnerabilities of the developing brain to cannabinoid exposure during sensitive windows of development, especially with regard to epigenetic changes associated with cannabis use. Since that time, additional studies were published that address research gaps and have the potential to better inform clinical guidelines, preventative policy, and public opinion related to cannabis use during specific time points of the life course. Heritable molecular impairments include epigenetic modifications, such as DNA methylation, histone modifications, and changes in non-coding RNA , which regulate patterns of gene expression by altering DNA accessibility and chromatin structure. DNA methylation occurs when a methyl group is added at a cytosine nucleotide that precede guanines , influencing DNA function by activating or repressing transcriptional activity of a gene and by altering chromatin accessibility and remodeling. DNA methylation in the promoter region of a gene usually downregulates its expression, while higher DNA methylation in a gene body may promote expression of a gene. In most instances, DNA methylation represses gene expression by preventing the binding of transcription factors, or recruiting proteins that bind to methylated DNA. Histones are large groups of protein complexes that help DNA condense into chromatin. Histone modifications include methylation and acetylation of lysine residues on histone tails, which affect gene expression by altering chromatin structure and accessibility. In addition, ncRNA, such as micro RNA and long non-coding RNA, control DNA availability and transcription, regulate RNA processing and splicing, and form a scaffold upon which layers of DNA regulation are built. Some epigenetic modifications are passed down to offspring through genomic imprinting , in which offspring only inherit one working copy of a gene. Imprinted genes are silenced via DNA methylation in either the egg or sperm. Other modifications are passed down when genes escape epigenetic reprogramming, a process that occurs during the formation of primordial germ cells and in the early embryo soon after fertilization, in which genomic potential resets and epigenetic memory is erased. In this review, we provide an analysis of the recent literature relating to pre-gestational and prenatal cannabinoid exposure and its effect on genes and molecular pathways. Along with the studies discussed in the review, additional animal studies are summarized in Tables 1 and 2, in which molecular changes are observed in the F0 generation of adolescent brain tissue.

Since 2002, there has been an increase in pregnant women in the U.S. reporting daily cannabis use, use in the past-month, as well as an increase in the number of days during pregnancy that they report using cannabis. Pregnant women report using cannabis most frequently during the first trimester, in order to mitigate morning sickness. Studies have confirmed that THC readily crosses the placenta, distributes into the fetal compartment, and crosses the fetal blood-brain barrier. A handful of studies in both human subjects and animal models have indicated that the embryonic nervous system patterning is particularly susceptible to maternal cannabis use. Its use during pregnancy has been associated with an increased risk of various cognitive, behavioral, and neuropsychiatric defects. Use during pregnancy has also been associated with an increased risk of preterm birth in some studies, as well as decreased birth weight. This section highlights recent studies that have examined the epigenetic mechanisms by which prenatal cannabis exposure increases the risk of postnatal psychiatric disease.Considering that maternal cannabis grow tray use during pregnancy is associated with long-term adverse behavioral outcomes and addiction vulnerability in offspring, it is possible that epigenetic changes established in utero that affect dopaminergic reward signaling are involved. The striatal dopamine system, composed of medium spiny neurons enriched in cannabinoid receptors, is implicated in the pathogenesis of neuropsychiatric disorders. One study tested the neurobiology underlying the risk of addiction vulnerability in humans by examining mRNA expression in fetal brain specimens of the putamen and nucleus accumbens , from mothers who underwent elective abortions between 18 and 22 weeks of gestation. Half of the fetal brain specimens were those from mothers who had positive maternal self-report and/ or maternal urine that tested positive for THC and/or fetal meconium positive for THC, while the other half had no cannabis exposure. Not only did fetuses exposed prenatally to cannabis have decreased dopamine receptor D2 mRNA levels in the NAc, compared to controls, but there was also a dose response observed in which greater maternal use was correlated with decreased DRD2 mRNA levels. In contrast, there was no difference in DRD2 mRNA levels in the putamen. There was also no difference in DRD1 mRNA levels, or mRNA levels of the opioid neuropeptides proenkephalin and prodynorphin in the putamen or NAc, between the exposed and unexposed groups. The NAc core and shell are important components of motor and reward circuits, respectively, and disruptions in these signaling pathways could lead to adverse psychiatric outcomes. Additional studies were conducted on the same fetal brain specimens used in the study discussed above. In these analyses, decreased DRD2 mRNA levels were observed in the amygdala basal nucleus of fetuses exposed prenatally to cannabis compared to controls, which was consistent with the reduced levels observed in the NAc.In addition, fetal brain specimens with maternal cannabis exposure had reduced PENK expression in the caudal putamen, and PENK mRNA levels were inversely correlated with amount of maternal cannabis intake during pregnancy.

Disruptions in the opioid system during development contribute to the development of psychiatric disorders and persist into adulthood, increasing vulnerability to opiate-seeking behavior. Dysregulation of DRD2 is implicated in addiction risk and other psychiatric disorders, and its alteration was a consistent finding in the animal studies, as well as the human studies. Another recent study evaluated whether prenatal cannabis exposure is associated with DNA methylation of dopamine receptor D4 promoter in buccal cells from the neonates of maternal subjects with either cannabis or no cannabis use anytime during pregnancy.Buccal epithelial cells have the same developmental origins as neuronal cells, and prior studies provide support for buccal cells as a proxy for neurodevelopmental phenotypes. There was no association between DNA methylation at individual CpG sites in DRD4 after correction for multiple testing. It is unclear if the null findings were due to the relatively small sample size , the tissue specificity, or a lack of biological relevance. Certain genetic polymorphisms of DRD4 increase risk of drug use and severity of ADHD symptoms in children, both of which have been associated with cannabis exposure. Future candidate gene studies should examine the association between prenatal cannabis exposure and epigenetic changes in DRD4 in brain or other target cells, instead of the buccal cell proxy, as well as account for genetic polymorphisms.A recent study evaluated the association between male rat exposure to synthetic CBR1 agonist WIN 55212-2 during adolescence and global DNA methylation in the prefrontal cortex of their offspring. The offspring were also subjected to unpredictable stress, variable stress, or no stress, in order to examine the interaction between pre-gestational WIN exposure and stress response. Increased global DNA methylation was observed in offspring with pregestational WIN exposure, compared to controls, regardless of presence or absence of stress exposure. In addition, increased DNA methyltransferase 1 mRNA levels were observed in offspring with pre-gestational WIN exposure, compared to unexposed controls in non-stressed animals only, while increased Dnmt3 mRNA levels were observed in offspring with pre-gestational WIN exposure, compared to unexposed controls, regardless of presence or absence of stress exposure. It is plausible that the increased global PFC DNA methylation observed in animals with pre-gestational WIN exposure, as well as in stressed animals, was mediated by the upregulation of DNMT enzymes, since these are responsible for epigenetic maintenance.

Even though PRS were correlated with conduct disorder, associations between the PRS and trajectory membership persisted even after controlling for conduct disorder. Thus, general deviance does not appear to fully account for these associations. Our study had several limitations, including a modest target sample size . Further replication studies in larger, independent samples are warranted. Also, the current analyses were restricted to individuals of European ancestry, so we cannot confidently extrapolate our conclusions to other populations. Thirdly, COGA is ascertained for genetic liability to addiction, which may have influenced findings. Our ‘high’ group is somewhat larger than those noted in two prior general-population longitudinal studies, but similar to one study that over sampled for tobacco smoking and lower than a study with over-representation of individuals from high crime neighborhoods. Thus, similar classes have been noted, although there is much variability in their class size. Fourthly, while self-report of perceived peer use is commonly studied and does not significantly differ from actual peer use, it is possible that it is less objective than reports by peer nominees. Furthermore, as we did not have reports of concurrent peer cannabis use at older ages , we cannot speculate whether trajectory membership was associated with subsequent affiliations with cannabis-using peers. Fifthly, we binned frequency of use data into 20-unit intervals and this may have obscured the identification of smaller classes. For instance, our method combined those using one to two times in the past year with those who may have used cannabis 15–20 times. However, sensitivity analyses with 10-unit intervals provided similar results. It is also possible that reported frequency at the upper end of use was imprecise . It is hoped that with larger discovery efforts of both cannabis use and of cannabis use disorders the predictive quality of PRS, not merely in terms of what they predict, but also when and how they do so, will be elucidated more clearly. However, this study highlights that even as discovery GWAS sample sizes grow and PRS begin to attain a greater level of precision, it will be of paramount importance to consider not only how genetic liability shapes health and behavior, but also the environmental context within which such behavior unfolds .According to the Center for Disease Control data , falls are the leading cause of fatal and nonfatal injuries among adults aged ≥ 65 years . For older adults, falls and associated injuries threaten their health, independence, and quality of life. More than a third of people aged 65 and older living independently fall each year , representing a major public health problem.

Aging HIV+ individuals have an increased prevalence of many fall-related risk factors, and a study has previously shown that the fall rate among middle-aged HIV+ individuals on effective antiretroviral therapy mirrors that of uninfected adults aged 65 or older . In addition to their high risk of falls, HIV+ individuals may be at a greater risk of sustaining an injurious fall or fracture due to underlying low bone density, low body weight, peripheral neuropathy, neurocognitive impairment, and frailty . Cannabis is used recreationally as well as for different medical indications among HIV+ individuals and studies have shown an improvement of neuropathic pain in HIV+ individuals using cannabis cultivation technology. According to a National Academies of Sciences, Engineering, and Medicine 2017 report, there is conclusive or substantial evidence for the use of cannabis for the treatment of chronic pain . Cannabis use is also legal for recreational purposes in many states in the USA, which has likely increased its use in the general population. The active components in cannabis are known as cannabinoids, and the main cannabinoids are tetrahydrocannabinol and cannabidiol . Cannabinoid receptors are expressed in the brain and are involved in its health and disease; CB1 receptors are found in the brain region that mediate the control of balance and CB2 receptors are found in immune cells in the brain, playing a role in neuroinflammation . THC and CBD interact with these receptors, thereby influencing balance and neuroinflammation. THC is the primary psychoactive component in cannabis, and it is associated with variable degrees of drowsiness , dizziness, and sedation , which alone or together could contribute to imbalance and consequently to falls during acute intoxication. By way of contrast, CBD is the major non-psychoactive component of cannabis and has been shown to be anti-inflammatory in models . Despite the potential health benefits of cannabis use for HIV infection, the relationship between long-term cannabis use and balance disturbances remains unknown. In this study, we compared the prevalence of balance disturbances among HIV+ and HIV− cannabis users, controlling for relevant covariates. We hypothesized that long-term cannabis use in HIV+ individuals might be associated with more severe balance disturbances than in HIV− individuals due to potential neurotoxic interactions between HIV infection and cannabis.The study comprised 3664 ambulatory HIV+ and HIV− individuals enrolled in multiple NIH-funded research studies at the University of California, San Diego HIV Neurobehavioral Research Program . Participants were enrolled between September 2003 and June 2017, and the most recent evaluation was used for each participant. At the time of enrollment, all participants provided written, informed consent. Secondary data analysis was performed. Inclusion criteria for this analysis included completion of a structured clinical interview which provided details regarding the occurrence of cannabis use and balance disturbances and completion of a neurological examination.

The clinical interview and the physical examination were performed on all participants. Exclusion criteria included blindness, being a wheelchair user and experiencing falls as a consequence of sustaining a violent blow, loss of consciousness or sudden onset of paralysis as in stroke or epilepsy. We excluded individuals with other neurologic conditions such as motor neuron disease, Parkinson disease, and multiple sclerosis. Individuals with stroke were excluded only if they had persistent neurological deficits after their stroke. Recognizing that peripheral neuropathy and vestibular disease are common in HIV+ individuals, we did not exclude these conditions. Additionally, urine samples were collected at screening and participants with a positive toxicology report were excluded.Cannabis and other substance use data were collected using the interviewer-administered timeline follow-back assessment , a gold-standard measure for retrospectively assessing detailed alcohol and drug use characteristics. The TLFB uses a calendar method to evaluate daily patterns and frequency of substance use over a specified period. It has high retest reliability, convergent and discriminant validity with other measures, agreement with collateral informants’ reports of participants’ substance use, and agreement with urine toxicology assays .Other cannabis variables assessed self-reported frequency, density, cumulative dose, and total years of cannabis use. For the present analysis, we used the total quantity of cannabis use as the predictor variable. The main study aim was to assess interactions between HIV infection and long-term cannabis use on balance disturbance; therefore, total quantity of cannabis use as predictor provides an estimate of potential cumulative toxicity. We used the Composite International Diagnostic Interview version 2.1. to reliably assess substance use disorder.A structured clinical interview was administered to participants by trained interviewers to collect any history of balance disturbance. Inter-examiner reliability was ensured through systematic training. Participants were asked about balance problems in the past few days up to the previous 10 years. Balance disturbances were self-reported and classified according to their severity into the following categories: normal; occasionally unsteady, and no falls; frequently unsteady, some near falls, and rare falls; and must use a cane, walker, or other prop.

We recoded balance disturbances into no or minimal balance disturbances and moderate-severe balance disturbances.This method has been previously used in a study of the influence of distal sensory polyneuropathy on balance disturbances in HIV+ individuals . The presence or absence of ataxia was assessed during the gait examination .We collected data on HIV disease characteristics including current and nadir CD4 count, plasma viral load < 50 copies/mL , duration of HIV infection, historical AIDS status, and current use of ART. We asked about the use of medications commonly associated with balance problems: antihypertensives, sedatives, and opioids. We also collected data on age, gender, race/ethnicity, and education. History of long term alcohol abuse and diabetes were also reported. Height and weight were measured in order to calculate the body mass index . Chronic distal sensory polyneuropathy was diagnosed based on the presence of any of the following abnormal findings in a distal , symmetrical distribution during physical examination: reduced sharp sensation, vibration sense, or reflexes.Comparisons between HIV+ vs. HIV− groups and moderate-severe vs. no or minimal imbalance in participant characteristics were performed using Student t tests for continuous variables and Fisher’s exact test for binary and categorical variables. Using similar methods, HIV disease characteristics were compared in HIV+ individuals with moderate severe vs. no or minimal imbalances. Prior to statistical analyses, current and nadir CD4 counts were square root transformed to better fit a normal distribution. Multivariate logistic regression was applied to determine the interaction effect of total quantity of indoor grow cannabis use with HIV status on balance disturbance. Age, gender, cDSPN symptoms, gait ataxia, opioid medications, and sedatives were included as covariates in the adjusted model after variable selection. The effect sizes are presented as Cohen’s d or odds ratios; Cohen’s d was calculated by dividing the difference of means by the root-mean-standard-error and the odds ratios were used to quantify effect sizes for nominal variables. Statistical analyses were completed with JMP Pro 14. Alpha was set at 0.05.Controlling for age, gender, cDSPN symptoms, gait ataxia, opioid medication, and sedatives, we evaluated the relationship between self-reported balance disturbances and cannabis use by HIV status. We observed a statistically significant interaction between HIV status and total quantity of cannabis use as regards balance disturbances such as while total quantity of cannabis use was associated with more severe balance disturbances in HIV−individuals, it was unrelated to balance disturbances in HIV+ individuals . In a sensitivity analysis, we found similar results after excluding participants with more severe balance disturbances.

Contrary to our hypothesis, this study provides evidence that more extensive, long-term cannabis use among HIV+ individuals is not associated with a higher likelihood of balance disturbances. While we did not find any research study in the literature to compare with our findings, one prior report found that the occurrence of balance disturbances was associated with a 13-fold higher odds of recurrent falls among HIV+ individuals . It is not clear why the more frequent use of cannabis was not associated with a higher likelihood of balance disturbances in the HIV+ group, but a plausible explanation is that any deleterious effects of cannabis are counteracted by its effect of reducing inflammation . Yet, the difference between HIV+ and HIV− individuals in cannabis-associated balance disturbances as both acute effect and chronic effect suggest that neuroinflammatory differences alone may not explain these results. In the brain, CB2 receptor expression is associated with inflammation and it is primarily localized to microglia . This selective localization together with the modulatory effect of the CB2 receptor on microglia function is particularly relevant since microglial cells have a significant role in neuroinflammation in HIV infection. In fact, HIV-infected monocytes not only infect brain resident cells upon migration into the CNS but also produce proinflammatory cytokines, which in turn, further activate microglia. These activated microglia, along with perivascular macrophages, are the main contributors to neuroinflammation in HIV infection, resulting in neuronal dysfunction and death . In contrast, more prolonged chronic cannabis use was related to more severe imbalance among the HIV− individuals. One potential mechanism for this is adverse effects on the cerebellum and basal ganglia, both of which express high levels of CB1 receptors. Prior research found that chronic cannabis use in HIV− individuals was associated with increased postural sway in individuals who were not acutely intoxicated. Our results are similar to those of Bidwell et al. who found that balance function was impaired after immediate cannabis use and different from those of Pearson-Dennett et al. who found that the effect of long-term cannabis use was associated with long-lasting changes in open-chain elements of walking gait, but the magnitude of change was not clinically detectable. Those studies assessed balance impairment after immediate cannabis use in small samples. In contrast, our study focused on prolonged use of cannabis and had more power due to the large population size.