Cannabis Grow

A log-rank test was used to determine the significance of difference between two survival curves. All analyses were conducted using JMP staThistical softwar.Survivorship of adults reared from wild-caught larvae and pupae was examined in three different environments: indoor, plantation, and forest . Female mosquitoes placed indoors survived significantly longer than those in banana plantation and forest for both An. minimus and An. sinensis . The mean survival duration of female An. minimus mosquitoes were 21.6, 18.8 and 14.8 days in indoor, banana plantation and forest, respectively . A similar result was found in female An. sinensis mosquitoes in different land use and land cover settings. Male mosquitoes lived for a significantly shorter period of time than females for both An. minimus and An. sinensis, but the pattern of survivorship in indoor, banana plantation, and forest environment was the same as the females . The daily survival rate ranged from 0.88 to 0.91 for females and 0.84 to 0.89 for males .The present study identified a significant effect of land use and land cover on vector survivorship. Mosquitoes placed under indoor environment exhibited significantly higher survivorship and longevity than banana plantation and forested environment. When mosquitoes were placed indoors in two sites differing in elevation, cannabis grow setup mosquitoes exhibited higher survivorship in sites with lower elevation. The effects of land use and land cover on mosquito survivorship likely resulted from differing microclimatic conditions among the habitats where adult mosquitoes were placed.

Significantly higher mosquito survivorship was found in an indoor environment where mean daily temperature was 2°C higher than in the forested environment. This result on the impact of land use and land cover on mosquito survivorship was consistent with other studies on An. arabiensis and An. gambiae in African highlands , and An. darlingi in the Peruvian Amazon. The findings from this study have important implications for understanding malaria transmission and vector control in changing ecosystem. The developing world has been experiencing rapid land use and land cover changes. Deforestation is a major component of land use and land cover changes. Increased survivorship of adult mosquitoes in the indoor environment indeforested areas, as demonstrated in the present study, suggests that Indoor Residual Spraying and Insecticide-Treated Nets should be used for vector control to prevent indoor malaria transmission. In addition, deforestation could alter the microclimatic conditions of aquatic habitats and subsequently enhanced survival and development of larval mosquitoes as demonstrated in An. gambiae and An. arabiensis in Africa. Because vector survivorship and vector density are important components of vectorial capacity, deforested agricultural areas could exhibit dramatically higher vectorial capacity than forested areas. Therefore, deforested agricultural area can increase the risk of malaria transmission. There are several limitations in our study. First, although it is a conventional method, microcosm rearing of mosquitoes in cages for determination of vector survivorship was in a confined condition. In field conditions, mosquitoes could hide and rest in moisture and dry habitats with microclimate conditions that are different from our cage condition.

Because it is not feasible to track the mosquitoes under field conditions, determination of vector survivorship under field conditions has been indirect based on biomarkers such as ovarian structural evaluation, fluorescent pigment pteridine concentration, cuticular hydrocarbon, and gene expression. These methods have significant limitation in estimation reliability such as the age of mosquitoes beyond certain period cannot be identified, and sensitive to blood feeding and other physiological changes. Our microcosm rearing of mosquitoes is the most direct measurement of mosquito survivorship. Second, we fed mouse blood and sucrose sugar in our experiments. The food source to adult mosquitoes may affect survivorship as An. minimus prefers biting human. Because all mosquitoes were reared under the same food condition, the results on the impact of land use and land cover should be valid. It is important to assess the impact of land use and land cover on vector-borne disease transmission when an economic development plan that significantly alters land use and land cover is being formulated. This study suggested that deforestation is the worst scenario, re-cultivation with banana plantation or other economically valuable trees such as rubber trees could boost incomes and reduce malaria transmission risk at the same time. Therefore, government policy should encourage local farmers to re-cultivate on deforested land. The estimated daily survival rate for An. sinensis and An. minimus under different land use and land covers provides a valuable parameter in modeling vector population dynamics and malaria transmission risk.When California voters approved Proposition 64 in 2016, legalizing recreational cannabis for adults, they fundamentally altered the state’s cannabis landscape. They also, albeit unintentionally, furnished UC researchers with intriguing new avenues of potential inquiry — many of which are blocked by federal law and pursuant UC policy. For example, researchers interested in the cannabis-derived sprays and beverages readily available at California’s retail cannabis establishments cannot obtain those products for research purposes by any permissible means. Licensed cannabis businesses dot the state today, but cannabis research still operates within the same strict constraints that have hindered it since legalization was a futile sentiment on a bumper sticker. Because state law is subordinate to federal law, Proposition 64 is subordinate to the 1970 Controlled Substances Act. Associated with that act is a “scheduling” apparatus, overseen by the Drug Enforcement Administration , that identifies cannabis as ripe for abuse and devoid of medical merit. Thus, along with heroin and other Schedule I substances, the psychoactive variety of cannabis cannot under federal law be cultivated, processed, sold, consumed — or, for the most part, researched. 

The University of California, as a law-abiding institution, complies with the Controlled Substances Act and its nearly total cannabis prohibition. As an institution that receives federal funding, UC complies with the Drug-Free Workplace Act and the Safe and DrugFree Schools and Communities Act — which require universities, if they wish to receive federal funding, to implement policies prohibiting on-campus activities such as possession or use of controlled substances. UC personnel, including staff, faculty and UC Cooperative Extension specialists and advisors, are therefore prohibited, in their professional capacities, from direct contact with the cannabis plant or its extracts, and also from certain types of indirect contact. They cannot, for example, visit cannabis cultivation sites or advise cannabis growers on topics such as yield increases. Researchers can’t even use cannabis or cannabis-derived products in medical studies — unless they fulfill a rather daunting set of federal requirements. Those requirements for medical studies include obtaining a Schedule I license from the DEA; submitting research protocols for Food and Drug Administration approval; submitting to the FDA an investigational new drug application ; and, as a non-federal matter, gaining the approval of a state entity, the Research Advisory Panel of California . If all goes well, researchers can then obtain cannabis or cannabis-derived substances from a DEA-licensed cultivator, a DEA registered bulk manufacturer or, with a DEA import license, a foreign exporter. The only DEA-licensed cannabis cultivator is the University of Mississippi, which grows the plant under a contract funded by the National Institute on Drug Abuse . Bulk manufacturers of cannabis products such as tetrahydrocannabinol — the psychoactive component in cannabis — include, for example, vertical grow system the Massachusetts based life science company MilliporeSigma . Providers of imported cannabis products — such as Tilray, a Canadian firm — must be based in jurisdictions where such products are legal. No matter which path researchers choose, the process isn’t fast or easy. “You need a patient, dedicated team willing to jump through extra hoops at the institutional, state and federal levels,” says Jeffrey Chen, Executive Director of UCLA’s Cannabis Research Initiative. Even so, Chen reports, federal restrictions on types and sources of cannabis products can prevent researchers from conducting cannabis studies at all. And again, only medical researchers are eligible to obtain cannabis for research. Those who wish to perform agronomic studies, for example, are simply out of luck. For all that, opportunities to research cannabis are not scarce around the UC system. Observational studies of cannabis users are permissible, though the cannabis in question cannot be provided by the university and must be consumed off campus. Researchers interested in the legal or economic dimensions of cannabis, or in cannabis policy, will discover few obstacles in the Controlled Substances Act. Several UC researchers are vigorously investigating the environmental consequences of cannabis cultivation — and in fact Proposition 64 has effectively expanded the scope for such research. According to Ted Grantham, a UCCE specialist at UC Berkeley and co-director of the UCB Cannabis Research Center, researchers can now interact with cannabis growers — to learn, for example, about their cultivation practices — in a way that grower reluctance previously precluded. Today, Grantham reports, “a subset of growers is very interested in day lighting the cannabis industry to establish its legitimacy as an agricultural crop rather than an illicit substance.” In years to come, UC investigators will likely perform extensive research on industrial hemp.

This form of cannabis, which contains extremely small amounts of THC, is useless for producing a “high” — but very useful for making fabrics, insulation, paper and more. Until recently, however, federal law did not distinguish between low-THC hemp and high-THC cannabis — nor between THC and cannabidiol , a nonpsychoactive cannabis compound purported to relieve medical conditions ranging from arthriThis to anxiety. The legal landscape for hemp and CBD began to change on the federal level in 2014, when that year’s Farm Bill allowed universities to cultivate industrial hemp for research purposes . In June of last year, the FDA approved a CBD-based medicine for treatment of epilepsy-related seizures. With last December’s passage of the 2018 Farm Bill, industrial hemp became a legal crop — pending establishment of a regulatory framework to govern it. Hemp-derived CBD now appears on course for complete de-scheduling by the DEA, and the FDA is wrestling with how to regulate the CBD-based consumer products already hitting the market in many states. Amid this liberalization of federal law on hemp and CBD, it becomes easy to envision UC academics and UCCE personnel performing agronomic studies with hemp — and providing California hemp growers with the same sort of research-based knowledge that has long been available to cultivators of almonds, grapes and lettuce. Federal laws identify cannabis as one of the most dangerous drugs with no medical use, and its cultivation, possession, and distribution are criminally prosecuted. At the same time, many states adopt a different view admitting the medical benefits of cannabis and advancing decriminalization and legalization policies. As of 2019, 14 states and the District of Columbia have legalized cannabis for recreational use, and 35 states and the District of Columbia have legalized it for medical use. California’s cannabis policy makes for a special case. Owing to its large population and gross domestic product, California is the most prominent market of legal cannabis in the US . In 1996, California voters made history by passing Proposition, which legalized the medical use of cannabis. Twenty years later, in 2016, the state adopted Proposition 64, which permitted cannabis for recreational use with record rates of public support . Los Angeles and San Francisco lead by example in creating a supportive environment for the legal cannabis market. Their governments adopted social programs designed to lower the barriers for individuals with past cannabis convictions 1 and expedite the expungement of cannabis-related records.2 Nevertheless, it would be erroneous to assume that acceptance of cannabis arose with the same intensity across California counties and cities. Local jurisdictions have discretion over deciding whether to allow or forbid cannabis companies within their borders. At the moment, only one-third of California cities permit the distribution, cultivation, testing, manufacturing, or sale of cannabis, while the rest have passed ordinances forbidding any cannabis-related economic activities within city borders. This project is the first and the most comprehensive study of the unfolding process of cannabis legalization, which empirically addresses a set of interrelated questions. First, how is the legalization of cannabis for recreational use spreading across California cities? Second, what accounts for the uneven legalization of cannabis across California cities? And third, what does the case of cannabis legalization reveal about the relationship between legitimacy and legality more generally?

The AUMA initiative appropriately prohibits sales of marijuana to minors and prohibits anyone under the minimum age be allowed in any store that sells marijuana and marijuana products, including staff. This provision is stronger than regulations for retail alcohol stores, which explicitly allow underage people in convenience stores. However, AUMA fails to include other important provisions that will prevent underage access and appeal including vending machine, internet and mail order sales, coupons, promotional discounts, and sales of flavored products, including THC-containing e-liquid. The AUMA initiative also prohibits marijuana businesses within a 600-foot radius of “a school providing instruction in kindergarten or any grades 1 through 12, day care center, or youth center that is in existence at the time the license is issued, unless a licensing authority or a local jurisdiction specifies a different radius.” AUMA establishes a series of discretionary criteria for determining whether a license should be issued, including “excessive concentration.” However, this term is not adequately defined and is applicable if such limitation did not impede development of the legal market or perpetuate the illicit market. The effectiveness of these licensing criteria is severely hampered because they are discretionary and lack specificity. An important provision in AUMA is that local governments will be permitted to adopt retail licensing restrictions stronger than the state law. Good public health practice, cannabis grow equipment based on provisions for tobacco retailers, would prohibit marijuana retail stores within 1,000 feet of schools and parks. There would be requirements against issuing new licenses in areas that already have a significant number of retail outlets, which would not be contingent upon whether or not such limitation impeded market growth.

Retail marijuana businesses would be prohibited from selling marijuana through vending machines or self-service displays, using coupons including digital coupons, promotions, discounts, sale of flavored products , and other offers that would encourage underage initiation and frequent use, as well as impulse buys. In addition to these prohibitions, the law would also mandate that retailers be required to verify government-issued identification cards through age-verification systems for face-to-face sales. Electronic commerce such as internet, mail order, text messaging, and social media sales would be prohibited because these forms of nontraditional sales are difficult to regulate, ageverification is impossible, and they can easily avoid taxation. The state would establish a minimum set of restrictions for marijuana retailers that local governments could not weaken and local governments would be permitted to adopt stronger regulations than the state law, including additional annual licensing fees and penalties for noncompliance . The stated goal of the AUMA initiative is to simultaneously “legalize marijuana for those over 21 years old [and] protect children.” However, there are no provisions that will prevent marijuana retail stores from being located within 1,000 feet of a college or university property, recreational center or facility, public park, library, or a game arcade, malls, movie theaters, churches, substance abuse treatment facilities, or hospitals, where underage people are likely to congregate. Furthermore, it will be legal to sell marijuana in ways that will increase underage persons’ access and appeal, through vending machines, self-service displays, and coupons, and through nontraditional sales, such as the internet, mail order, text messaging, and social media. Under the AUMA initiative it is likely that marijuana legalization will have a negative impact on the health of young people and communities of color.

Experience from tobacco and alcohol control shows that retailer density is positively associated with youth and young adult smoking and alcohol use. It is likely that marijuana retail density will have the same impact. There are also no provisions that will require new marijuana retailers be located a minimum distance from other retail stores or that will limit the number of marijuana retailers in a specific geographic unit . This is a key problem with tobacco retailers and alcohol outlets in poor communities, and is an emerging issue in Colorado’s minority, mostly Latino, neighborhoods with retail marijuana. Similar to tobacco and alcohol, it is likely that marijuana retail stores and marijuana cultivation sites will be over-concentrated in low-income communities and communities of color. In order to uphold the social justice goals on which the initiative stands, it is important that clustering and over-concentration of licensed marijuana facilities is prevented. While an age-restriction for marijuana and compliance checks to deter sales to underage persons are included in the initiative, it severely limits the capacity to use the licensing system to enforce this restriction on retailers by suspending or revoking licenses for businesses that sell to underage persons. In particular, the initiative states that retailers will be penalized if they “intended” or “knowingly” sold to underage persons. Experience from tobacco and alcohol control demonstrates that requiring knowledge makes enforcement difficult, if not impossible, and compliance much less likely. Further, the initiative’s language requiring licensees see documentation prior to selling or transferring marijuana is weak and at risk of being violated by marijuana retailers. The initiative states a licensee shall not sell marijuana unless presented with “documentation which reasonably appears to be a valid government-issued identification card showing that the person is 21 years of age or older [emphasis added].” Rather than creating a duplicative system, a public health framework would model the marijuana retail licensing system on existing inspection systems or the Target Responsibility for Alcohol Connected Emergencies programs in California.

As with tobacco and alcohol enforcement programs,marijuana retailers would be required to ask for identification from anyone that looks under the age of forty. Marijuana retailers would be required to enter government-issued identification cards into age-verification system for face-to-face sales or the transaction would be cancelled. Violations would be for cases in which retailers do not ask for identification before selling marijuana to consumers and for cases in which the retailer asked for identification but still sold marijuana to an underage person without the state having to prove intent. The AUMA initiative maintains separate medical and retail marijuana markets, complicating policy efforts to prevent initiation and reduce marijuana use. The experience in Colorado, where the separate medical and retail marijuana markets are being maintained provides strong support for a unitary market. In Colorado, although legalization advocates claimed that retail marijuana legalization would reduce the number of medical marijuana users, the medical marijuana industry has continued to grow. Regulatory in consistences between the medical and retail markets are likely driving medical marijuana market growth. For example, marijuana possession and cultivation limits are higher for medical marijuana than retail marijuana, medical is more affordable because it is exempt from state and local excise taxes, and persons under age twenty-one can purchase marijuana through the medical marijuana program but not through the retail market. It is important to avoid complexity in the marijuana regulatory environment because complexity favors large corporations with the financial resources to hire powerful lawyers and lobbyists. A public health framework for marijuana legalization would create a unitary market, in which all legal sales are regulated as retail marijuana and marijuana products, and the medical market is eliminated. A unitary market would simplify regulatory efforts, including licensing enforcement, vertical grow rack implementation of underage access laws, prevention education programs, and taxation. A unitary market would also avoid sending mixed messages to the general public about the safety of marijuana, particularly as more research accumulates on the adverse health effects. Without a unitary market, it is likely that California, which has a stronger medical marijuana advocacy community and industry than Colorado, will experience similar regulatory distortions. It is important to note that in 2015 the State of Washington merged its medical and retail marijuana markets. Licensed marijuana retailers that want to also sell medical marijuana are required to obtain a medical marijuana endorsement that meets the Department of Health’s requirements. The AUMA initiative focuses funding on youth-centered substance abuse treatment programs without a specific mandate dedicated to the primary purpose of preventing and reducing marijuana use and protecting the public from secondhand smoke exposure. The experience from tobacco control is that dedicating taxes solely to youth-based and school programs is not the best way to prevent initiation or minimize use, and may have counteractive effects. Evidence-based tobacco prevention and control programs aimed at the general population are the most effective way to prevent youth initiation. AUMA assigns the Department of Health Care Services , an agency that provides information to the public on how to improve access to health care services, such as Medi-Cal and Family Planning, responsibility to educate on and prevent substance use disorders in youth. The initiative allocates $5 million from the General Fund to the DHCS to develop and run a public information campaign on the provisions of AUMA, penalties for sales to minors, dangers of driving while intoxicated by marijuana, potential harms of using while pregnant or breastfeeding, and potential harms of over consumption. In contrast, the California Department of Public Health’s media budget for tobacco control was $43 million when it first aired in fiscal year 1989/90. There are no funds earmarked to provide for the continued public information program or for an ongoing statewide media campaign aimed at the general population informing the public on the harms of marijuana use, production , driving under the influence, secondhand smoke, industry manipulation, or offering cessation services for users.

The Legislature will have to appropriate these funds from the General Fund to continue such a public information campaign. Beginning in Fiscal Year 2018-2019, AUMA would require sixty percent of the left over marijuana tax revenue to be allocated to youth programs “designed to” educate and prevent substance use disorders. These programs may include prevention and treatment services for youth and caregivers, early intervention services, grants to schools to develop school-based intervention programs , grants to programs to address substance abuse for homeless youth, family-based interventions, and workforce training to increase the number of available behavioral health staff with substance use disorder prevention and treatment experThise. The DHCS is given broad latitude to determine where the funding is allocated and how much a particular program will receive. For example, the DHCS may dedicate most of the funding toward prevention and early outreach or it may dedicate most of the funding toward workforce training. If funding exceeds demand for youth substance abuse prevention and treatment services, then funds may be dedicated to treatment for adults with substance use disorders. Because these programs will not impact market growth, it is likely that the marijuana industry will either not oppose or may lobby to continue their funding. As is the case in tobacco and alcohol control, dedicating taxes to programs other than marijuana prevention and control may be popular among policymakers and likely will be promoted by marijuana companies to displace effective denormalization campaigns. Often these programs are not controversial and fund important causes like early childhood education, college scholarships, or to fund state school projects , or focus prevention programs on pregnant women and children, or provide funding to healthcare services unrelated to preventing tobacco or alcohol use. Without a specific legal requirement, the emphasis on substance abuse prevention and treatment programs suggests that funding will not go towards preventing and reducing marijuana consumption. For the same reasons as the tobacco and alcohol companies, marijuana companies may endorse these programs to boost their public image and strengthen relationships with policymakers. Marijuana companies may also launch voluntary youth prevention programs or corporate social responsibility projects, to displace effective denormalization campaigns used to prevent and control marijuana use. Similar to the alcohol industry’s “drink responsibly” campaign, which is ineffective at informing the public on the actual harms of alcohol use, in 2014, the Marijuana Policy Project launched its own “Consume Responsibly” campaign, with the “goal to educate [consumers] about the substance, the laws surrounding it, and the importance of consuming it responsibly.” It is likely that marijuana responsibility messages on consumption will be used to promote marijuana and marijuana products rather than providing accurate public health information to deter and minimize use. As noted above in California use of tobacco, a legal product, has been dropping while use of marijuana, despite being illegal, is rising.

NIH cannabinoid research support increased from $111.3 million for 285 projects in 2015 to $189 million for 408 projects in 2019, with more than a doubling of funds dedicated toward cannabis and cannabinoid therapeutics from 2015 to 2019, from $21 million to $46.5 million , about 0.5% of the overall NIH research budget. Of the 27 NIH components, 20 supported some cannabinoid research in 2019. NIDA was the primary source of support, with $118.7 million for 258 projects. Noteworthy changes include the National Center for Complementary and Integrative Health research on the potential therapeutic benefits of minor cannabinoids and terpenes and the National Cancer Institute workshop and research funds dedicated to cannabinoids and cancer. In addition to NIH, additional sources for funding have become available for cannabis and cannabinoid research. For example, in 2000, $3 million per year for 3 years was appropriated to the California state-funded Center for Medicinal Cannabis Research based at the University of California, San Diego, through legislation calling for a research program to oversee medical research of cannabis and cannabinoids. This center, now funded by revenue from taxes on adult-use cannabis sales, was initially created to conduct and support clinical trials on the efficacy of cannabis. The research agenda expanded to include supporting clinical trials on the efficacy of cannabis and cannabinoids to determine optimal dosing, timing, and modes of administration; comparing the efficacy and safety of various delivery methods; assessing the safety and toxicity of cannabis in the medically ill; and conducting limited preclinical studies. Although funding is available only to investigators at institutions based in California, submissions are high, vertical growing weed with 55 applications received in the past 2 years. Yet, similar to NIH funding rates, the CMCR awards are very competitive, with a 12% funding rate . The volume of grants submitted demonstrates the eagerness of researchers to do work in the field, and the limited success rate exemplifies the difficulty in obtaining funds. In addition to state-funded research, private philanthropy and foundation support are other sources for supporting cannabis and cannabinoid research for specific conditions.

Without funding, it is impossible to cover the expenses associated with the study, among which are personnel, participant expenses, study medication, and the costs to maintain regulatory approvals and drug storage security . With limited funding opportunities and the highly competitive nature of those that exist, a proposal’s impact and novelty are weighed alongside the study’s feasibility and potential for success in trial initiation and completion. A key component of study feasibility for cannabis and cannabinoid studies is the existing infrastructure needed for this type of research, including institutional support for this research, investigator expertise, and a schedule I license, if required for the study medication proposed in the grant application. As such, to obtain funding, it is optimal for the researcher to demonstrate experience in the field and have the support necessary to have successfully applied for and obtained a schedule I license. This is nearly impossible for most new investigators given that obtaining a schedule I license requires funding to support 1) the secure drug storage space and 2) a study that is submitted for IRB, FDA, and state regulatory approvals. These mutually dependent conditions create a situation that shuts out new investigators, especially those based at institutions that do not have infrastructure in place to support clinical studies with schedule I substances.Until recently, NIH did not have pathways specifically dedicated to provide funds to study the therapeutic effects of cannabis; however, funds were set aside to investigate the potential adverse effects of the plant. Hence, 25 years ago, to assess whether cannabis could be useful in patients with AIDS wasting, Donald I. Abrams and colleagues in the Department of Medicine at San Francisco General Hospital, California, proposed a clinical trial that was funded to primarily determine the safety of adding cannabis to HIV protease inhibitors, which also allowed for the potential study of the therapeutic effects of cannabis in this population .

A second study funded by the CMCR 20 years ago sought to determine the effects of inhaled cannabis on neuropathic pain in patients with HIV-related peripheral neuropathy. This trial was designed to enroll 16 participants in a pilot phase to assess the activity of inhaled cannabis and calculate the sample size needed for a follow-up randomized controlled trial if the initial results were encouraging. The study involved 9-day inpatient stays in the San Francisco General Hospital Clinical Research Center. Inpatient studies were favored for research involving this schedule I substance to ensure that the participants were using cannabis as described in the study protocol and not diverting it to family or friends. Participants were not allowed to have visitors or leave the Clinical Research Center ward. To standardize the inhaled dosing, the Foltin uniform puff procedure was employed . To anchor the participants’ subjective description of their pain, the heat and capsaicin experimental pain model was performed to provide a more objective measurement. This method involved heating an area of the forearm to 40 C and then applying capsaicin cream, creating an area of allodynia and hypesthesia that was mapped with a brush and a piece of foam while the subject looked off in another direction. These areas were measured before and after exposure to the study drug. The trial was successfully completed with 50 participants enrolled in the randomized trial .Simultaneous with funding awarded to assess the effects of cannabis on HIV neuropathy, the Abrams team was awarded a CMCR grant to study cannabis in combination with opioids inpatients with breast and prostate cancer with painful bone metastases. This study also involved 9-day inpatient stays in the San Francisco General Hospital Clinical Research Center, and most of the study procedures were identical to those used in the HIV neuropathy study. However, in the time that it took to complete the neuropathy study, only 3 participants enrolled in the cancer pain study. In an effort to increase accrual, eligibility was expanded to include any cancer patient with any pain. Ultimately, the funding for the cancer pain study was withdrawn. Barriers to enrollment of cancer patients in this trial were considered. It was suggested that cancer patients may not be interested in spending unnecessary inpatient time . The IRB expressed concern about inflicting experimental pain models on cancer patients. In addition, patients in San Francisco have long had access to cannabis without having to consent to a trial and risk getting randomly assigned to receive a placebo. In an effort to bypass the need for inpatient Clinical Research Center admission, an outpatient study to examine the effects of cannabinoids on delayed chemotherapy-induced nausea and/or vomiting was designed and favorably reviewed for funding by the CMCR nearly 2 decades ago. Patients who had experienced delayed nausea after the first cycle of chemotherapy were then randomly assigned to receive true cannabis cigarettes and placebo dronabinol, placebo cigarettes and active dronabinol, pipp shelving or placebo cigarettes and placebo dronabinol. The target sample size was 81. After enrolling the first 8 patients in this study, aprepitant was licensed and improved for this precise indication. Local oncologists lost interest in referring patients to a trial where a placebo was possible in view of the new available effective treatment option. Having only enrolled 10% of the accrual target, trial funding was withdrawn. The question of possible synergy between cannabinoids and opioids still loomed as a compelling area of investigation despite the failure of the initial attempt to study it. In an effort to be sensitive to the potential concerns of cancer patients regarding the smoked method of cannabis administration, use of the Volcano vaporizer as a smokeless delivery system for cannabis was explored. In healthy volunteers, the dose-dependent subjective effects and pharmacokinetics of smoked and vaporized cannabis were compared.

Findings demonstrated that vaporization was a safe and effective delivery system and likely had reduced respiratory risk compared with smoked cannabis . The Abrams team then submitted a proposal to NIDA to do a pharmacokinetic interaction study in patients with cancer on sustained-release morphine or sustained-released oxycodone to determine whether it was safe to add vaporized cannabis to the regimen. After screening 218 cancer patients who expressed interest, only 1 had met the eligibility criteria and enrolled in the trial. The most frequent reasons that potential participants were deemed ineligible were because they were not taking the correct opioid analgesic, or more commonly, they were taking the sustained-release morphine or oxycodone preparations 3 or 4 times a day, which would not allow for the 12-hour opioid kinetics curve desired. Rather than forfeit funding because of lack of accrual, the protocol was modified after several months to eliminate cancer-related pain as an entry criterion and included any participants with any pain as long as they took the sustained-release opioid twice a day. With the expansion of the eligibility criteria beyond cancer patients, the study was successfully completed .More recently, a colleague of Dr Abrams, Kalpna Gupta, PhD, works with transgenic mice with the human sickle hemoglobin gene that experience pain. In her laboratory, she found that cannabinoids ameliorate the chronic hypoxia-reoxygenation – evoked acute pain in the mice. Approximately 8 years ago , she was seeking a collaborator interested in doing a human proof of principle study to accompany a grant that she was submitting to the National Heart, Lung, and Blood Institute. Having completed the opioid-cannabinoid pharmacokinetic interaction study, the Abrams team felt that a trial in sickle cell pain would be easily designed using a similar protocol as most of the participants would be on opioid analgesics. By this time, CBD had come bursting onto the scene as the most favored cannabinoid. A 4-arm trial was envisioned comparing THC-dominant cannabis, CBD-dominant cannabis, a balanced blend, and a placebo. However, funding was only available to support 2 arms, and 1 had to be a placebo. Eager to evaluate a CBD-containing product, the team requested that NIDA provide a balanced strain, and they received a 4.4%THC to 4.9% CBD chemovar. The goal of this inpatient randomized, double-blind, placebo-controlled crossover trial was to determine the analgesic and subjective effects of cannabis in sickle cell patients maintained on opioid analgesics. This study required approvals from multiple regulatory bodies as described in Section General Challenges for the Clinical Researcher, and more than 1 year elapsed from the time the protocol was submitted to the IRB for approval when enrollment began. Nearly 3 years later, only 23 of the target 35 patients had completed both arms of the crossover trial; similar to cancer patients, patients with sickle cell disease also found the inpatient component difficult .In the early fall of 2018, a minor media storm described a seafood restaurant in Maine that was proposing to expose lobsters to marijuana smoke prior to cooking . At least three testable assertions were made including 1) that some psychoactive constituent of cannabis would be transferred to the lobster via open air respiration , 2) that this would have specific behavioral effects similar to those produced in vertebrates and 3) that the cooking process would remove intoxicating psychoactive constituents from the meat thereby rendering it safe for human consumption. This latter assertion was related to a claim that “a steam as well as a heat process” would bring the lobster to 420 °F , which would presumably require broiling or oven baking in preference to the more typical boiling or steaming cooking method. These assertions lead to at least two key questions. Can air exposure to Δ9-tetrahydrocannabinol , the primary psychoactive constituent of cannabis, produce significant tissue levels of the drug in lobsters? If so, does it have any discernible behavioral effects? Lobsters are aquatic species that respirate via gills located inside their carapace. Lobsters can survive in air for many hours up to a few days, if they are able to keep their gills wet enough to function, but they do go into oxygen debt, e.g. across a 24 h emersion from water . It is unclear if the gill structures would support the uptake of THC that is rendered airborne via smoke particulate or Electronic Drug Delivery System device vapor.

To discover an answer, we will look at medical marijuana, crime, arrest, unemployment, and mortality rates in California counties from 2005-2014. The arrest and mortality rates will be used specifically to examine the possibility of marijuana being a substitute drug. Today, there are approximately 572,762 medical marijuana patients in California, which is equivalent to 1.49% of California’s population. While recreational use of marijuana has not been legalized in California, it is estimated that 9% of Californians use marijuana.3 If recreational marijuana use is legalized in California, it is possible that the percentage of marijuana users will increase. Given that California already has numerous marijuana farms and is predicted to provide 60-70% of the United States’ crop if legalized within the state, according to the International Business Times, it is pertinent to analyze the outcomes marijuana has on California’s society today. In 2010, the number one cause of death among 25-64 year olds in California was drug overdose. Many individuals have grown up with the notion that marijuana is a gateway drug to other illicit “hard” drugs. These other substances could include cocaine, heroin, methamphetamines, and prescription drugs, all of which can be extremely addicting and fatal. Since 1999, deaths from painkiller drug overdoses have increased 400% for women and 237% for men.6 This causes us to think of potential solutions for fatal substance abuse. If medical marijuana can be offered as a substitute drug, pipp racks will it decrease drug-poisoning deaths? According to a survey implemented by the U.S.

Department of Health and Human Services from 2005 to 2011, illegal drug use percentages were much higher in unemployed individuals than individuals with some sort of employment.7 Specifically, it was shown that 18% of the unemployed were involved in illegal drug use, compared to 10% of part-time workers and 8% of full-time workers. This causes us to question whether or not there’s a relationship between drug use and unemployment. When California passed Proposition 215, referred to as the California Compassion Use Act, it allowed patients, along with their primary physicians, to possess and grow marijuana for medical use, once given a referral from a California-licensed doctor. In 2004, California passed SB 420 to supplement Prop 215. The SB 420 specified the amount of marijuana each patient could possess and cultivate and created a voluntary, statewide, ID database through California health departments. This database is run by the California Department of Public Health and will be used to estimate marijuana use for this report. While both Prop 215 and SB420 protect patients and physicians from arrest in California, marijuana continues to be a federal crime, where there is no differentiation between medical and recreational marijuana use. Currently, the Drug Enforcement Administration has marijuana listed as a Schedule I drug, defined as a drug with the highest potential for danger and abuse and is listed along with heroin, LSD, and ecstasy. Schedule I drugs are assumed worse in comparison to Schedule II drugs, which are recognized to be less abusive. Schedule II drugs include cocaine, methamphetamines, and other highly addictive prescriptions. According to the Office of National Drug Control Policy, the reason marijuana legalization is refused at the national level, is because marijuana use is believed to increase the use in other illicit drugs. This brings us back to the question of whether or not marijuana can act as a substitute, rather than a “gateway”, to other hard drugs. While there has been little to no research done in the area of recreational marijuana, there have been many articles published on the effects of medical marijuana legalization. In 2013, Anderson et al. published a paper that studied the effects of MMLs on traffic fatalities across the nation by using alcohol consumption as an instrument. The authors first used price data to observe the effects on the marijuana market after the MML took effect.

They found that the supply of high-grade marijuana dramatically increased, while the lower quality cannabis was moderately impacted. Getting to the basis of their main goal, they used data on traffic fatalities within a 20-year period, across 14 states, to determine if marijuana was a substitute for alcohol. It was discovered that there was an 8-11% decrease in traffic fatalities within the first year of legalization with an even larger effect on traffic fatalities involving alcohol consumption. The authors then used individual behavioral data to examine the probability of consuming alcohol in the past month, binge drinking, and the number of drinks consumed after the MML took place. They found that these probabilities drastically decreased after the legalization occurred. When looking at alcohol sales, it was also discovered that there was a decline of 5% on beer consumption in the age range of 18-29. The MMLs were then used as an instrument of beer consumption to establish the amount of traffic fatalities. It was deduced that for every 10% increase in beer sales per capita, alcohol related traffic fatalities increased by 24%. The article goes on to conclude that marijuana does have a substitution effect on alcohol, especially among young adults, which inherently declined traffic fatalities.There is currently a working paper called “The Effect of Medical Marijuana Laws on Marijuana, Alcohol, and Hard Drug Use,” where Hefei Wen studied these effects using geographic identifiers and by estimating a state-specific time trend model that included two-way fixed effects. It was discovered that the relative probability of marijuana use among individuals over 21 increased by 16%, the frequency of marijuana use increased by 12-17%, and marijuana abuse and dependency increased by 15-27%. While there was an overall increase in marijuana use after MMLs went into effect, there was no strong evidence that showed marijuana use increased in youth.

While the authors predicted that there could be a spillover effect of marijuana on other substances, there was no significant evidence that marijuana caused increases in alcohol and other drug use. A more recent study done through the Drug and Alcohol Review examined medical marijuana as a substitute for alcohol, prescription drugs, and other illicit substances. The data was taken from a cross-sectional survey, completed online by 473 Canadian medical marijuana patients. The analysis found that 87% of patients substituted cannabis for one or more substances. This included an 80.3% substitution rate for prescription drugs, a 51.7% substitution rate for alcohol, and a 32.6% substitution rate for other illicit substances. These rates serve as evidence that marijuana can “play a harm reduction role in the context of use of these substances, and may have implications for abstinence-based substance use treatment approaches.” While these results show significant effects for marijuana substitution, there are an estimated 2.3 million users of cannabis in Canada alone, pipp rack making it difficult to assume a survey of only medical marijuana patients represents the entire population of all marijuana users. An additional study was done through the University of Virginia in 2014 that examined how MMLs affect crime rates. The author, Catherine Alford, decided to use difference-in-differences estimations where she controlled for state specific crime trends by collecting data across states over time from 1995-2012. It was discovered that after the implementation of MMLs, overall property crime and robbery rates increased. However, if the MMLs allowed for home cultivation, robbery rates actually decreased by about 10%. While these results show a positive relationship between MMLs and the previously mentioned crime rates, there was no statistically significant effect on violent crime rates. However, a study done in 2012, by the Center on Juvenile and Criminal Justice, showed that after California passed the SB 1449 for the decriminalization of marijuana, youth crime rates were at an all-time low. The SB 1449 allowed for a small possession of marijuana to count as an infraction, instead of a misdemeanor. Within a one-year period from 2010-2011, youth arrests declined by 16% for violent crime, 26% for homicide, and 50% for drug arrests. The author, Mike Males, concluded that the only significant explanations for a dramatic decline in juvenile crime rates would be the passing of SB 1449 and the improvement of socio-economic programs in California’s poor neighborhoods. In the previous reports examined, crime rates, drug and alcohol use, and traffic fatalities were all studied after the passing of MMLs among multiple states to discover any significant effects. While my proposed project would like to examine both crime rates and drug use affected by marijuana, it will look purely at California county data across a 10-year period and will not focus on age-specific crimes. The following report will also include an analysis of how the issuance of medical marijuana identification cards affects other drug and alcohol use, controlling for unemployment. The methodology used to answer the research questions above will be a series of multiple regressions with county and year fixed effects. To begin the analysis, we will determine how MMIC issuance affects crime rates. This regression will include unemployment as a right hand side variable to control for variations in the workforce.

A regression will be run for every type of crime rate, as well as for total crime, in order to discover if marijuana has individual effects on different types of crime. In addition to regressing crime rates on MMICs, drug and alcohol arrest rates will be regressed on MMICs to examine if there’s a substitution effect between marijuana and other drugs and alcohol. Because arrest and crime rates do not depend solely on MMICs, we will also include unemployment rates as a right hand variable. After analyzing the number of MMICs on crime and arrest rates, drug, alcohol, and other mortality rates will be regressed on the number of MMICs issued per county. The point of this is to observe whether or not marijuana has a negative effect on drug and alcohol related deaths, implying that marijuana is a substitute for other drugs. Because cross-sectional data will be used, there are unobservable events that could affect the analysis within that time period. For example, the Great Recession occurred from 2007-2009, which could have possibly increased crime rates. In order to combat time trend errors in the model, I will add annual fixed effects. This will allow the model to absorb any overlooked effects dependent on time. Because California counties are diverse and not all of them implement laws to the same extent, county fixed effects are also necessary for all regressions. By using these fixed effects, we will control for county-specific omitted variables that are time invariant. Relevant county-controlled variables may include the number of police stations or type of legislation implemented within a single county. The main data set we will use is the number of MMICs issued each fiscal year per county. This data was collected by the California Department of Public Health when SB 420 was implemented in 2005. The count of MMICs is updated through September 2015, but we will only use the number of cards issued from 2005-2014 since all other data is given annually. The cards issued each year range from zero to 1475. Because each card is only valid for one year, we assume that these annual numbers include renewed cards. There is a variation in these numbers between counties and time due to the fact that some patients may not have renewed their cards and every county implemented this system at different times. Because it is a voluntary identification system, any significant results would be under estimated. The MMIC data has been converted into number of MMICs issued per 100,000 people, as shown in 7.1.1 of the Appendix, in order for an easier interpretation between variables. It should be noted that some counties did not participate in some years and many others had zero medical marijuana cards issued at the beginning of 2006. Sutter and Colusa counties still have not applied this system and thus have no observations. Because there is no data on medical marijuana cards issued, Sutter and Colusa counties were omitted from all data sets. Table 4.1 below offers summary statistics for the MMICs issued per 100,000. In order to use unemployment as a right-hand side variable in the models, data from the California Employment Development Department was collected and offers per county unemployment rates from 1990-2014. This data will allow us to have a stronger model when examining the given research questions.

Los Angeles was the first county to industrialize dairy production ; the number and size of milk cow herds expanded to supply the rapidly expanding demand for dairy products. By 1925, Los Angeles County was the leading producer of milk in the state, driven by population growth after World War I. The high cost of hauling fresh milk long distances meant dairies were located near the demand for the milk. Scientific advancements in breeding, urbanization squeezing available land for grazing, and the introduction of drylot feeding by Dutch immigrant dairymen also drove the industrialization. Drylot feeding, also known as corral feeding or zero-grazing –essentially the practice of concentrating cows into a small acreage and bringing their food to them – was revolutionary for California dairy production . This practice succeeded in California because the abundance of local agricultural by-products like sugar beets and citrus and the availability of cheap hay made drylot feeding affordable, actually increasing milk production per cow compared to grazing . A quote from the 1946 book California Agriculture written by the University of California College of Agriculture faculty exemplifies this well.The Great Depression almost sank the dairy industry in California; surplus production, price cuts, and unregulated competition between processors, retailers, and farmers became known as the Milk Wars of the 1930s. The government stepped in with a Federal Milk Marketing Order to help regulate national milk prices, but Californians, both farmers and distributors, argued it was a local issue, pushing instead for state legislation.

The Young Act of 1935 set minimum prices for fluid milk in California, stabilizing the industry and increasing profits for farmers . California would maintain its own price regulations under a state MMO, indoor grow rack resulting in less aggregate milk produced , until 2018 when the dairy industry voted to move to the federal MMO . The new stability from the state MMO allowed farmers to invest in new technologies. This included upgrading facilities to have stainless steel and tile for sanitary improvement and, more importantly, introducing machines that milked cows with a vacuum pump connected to a cooler for immediate processing. These upgrades reduced the labor required for milking and enabled herd sizes to grow significantly in number . As urban expansion in Los Angeles increased land values, farmers were able to sell their dairies at high returns and move east towards the Valley, often choosing to buy more land, build new dairy structures, and expand their herds. This cycle of urban encroachment, farm relocation, and herd expansion reoccurred several times during the 1930s and 40s in Los Angeles County, until eventually most of the dairy had moved to San Bernardino . For the same reason 40 years later, dairy farmers in Marin established the first agricultural land trust to protect family farms from urban development pressures in the Bay Area . Between the 1970s and 2000s, California production rates accelerated, surpassing Wisconsin as the leading producer of milk in the 1990s with almost 20% of the U.S. total production . This acceleration is attributed to unique geographic features of California that created ideal conditions for growth, despite several setbacks related to land prices, water availability, and the relatively late start for the industry . The warm climate allowed for large herd sizes without the need to house them indoors during the winters; the nearby crop production of high quality alfalfa and fruit or vegetable by-products, especially almonds-hulls, that helped minimize costs of feed; the geographic isolation of the state requiring sufficient in-state processing facilities; the large and diverse population creating demand and labor for the industry; and the early adoption, or rather invention, of dairy science technology, have all helped bolster and accelerate dairy industry expansion .

Throughout the past two decades, California remained the leading dairy producer in the country and became known for its “megadairies” of more than a thousand cows in a herd . The technological developments and huge herds established a new mode of production for dairies, unlike anything attempted by the traditional dairying states in the Midwest and Northeast. Yet the industry in California is still heterogenous. Organic dairy production is heavily concentrated along the coasts, in Marin, Sonoma and Humboldt, while conventional dairies and concentrated animal feeding operations dominate the Central Valley. Despite the large size of the farms, 99% of dairies are considered family farms1 . The environmental impacts of dairy production are primarily methane emissions from enteric fermentation and manure storage, water quality impacts due to nitrogen and phosphorus excretion from manure lagoons, and water and land use for feed production . California has implemented mandates for reducing greenhouse gas emissions to 40% below 1990 levels by 2030. While California’s agriculture sector makes up a smaller share of GHG emission compared to transportation and energy, its emissions have more than tripled since 1990 . There are currently efforts to reduce methane emissions in dairy production; with state programs that incentivize anaerobic digesters for manure, or alternative manure management practices like composting or separating solids; as well as increasing the productivity per cow to reduce the GHG footprint per unit of milk produced; and research into feeding seaweed supplements to reduce methane gas from digestion . Water quality impacts are acutely felt in the San Joaquin Valley, as drinking water is contaminated with nitrates from agriculture, including manure from dairy concentrated animal feeding operations , which is associated with higher rates of disease and cancer . In Marin County, Conflict over land use for grazing is exemplified by tensions between conservation efforts to re-establish free-ranging tule elk in Point Reyes National Seashore and the long-term beef and dairy producers in the designated pastoral zone . The unique history and geography of California has both supported and challenged the expansion of the dairy industry into the modern day giant of milk production. The following literature review looks at structural changes in dairy production in California, the United States and globally through the lens of political economy.

Fundamentally, agriculture is the production of living things, relying on plants, animals, and life sustaining ecological elements like water, soil, air, and sunlight to grow food, fiber, and fuel. For the entire history of humanity, and even in a modern capitalist society, agriculture and access to food has been, is, and will continue to be essential to the function of society. The expansion of agricultural production and the planned food system has enabled the development of all other sectors of the economy and society. With fewer people producing food as their occupation, ebb and flow system producing more of it is both necessary and opportunistic. The study of food and agriculture is undertaken by many disciplines; biologists, chemists, economists, historians, sociologists, anthropologists, and geographers – this long list exemplifying its complexity and importance. Within the discipline of Geography, and sometimes overlapping with other social sciences, there are several sub-disciplines that attempt to capture and explain the relationships between environmental, economic, political, social, and cultural factors that converge in the production of food. These sub-disciplines include political economy of agriculture, political agroecology, rural agrarian sociology, black food geographies, and sustainable agriculture and food systems, etc. For understanding California’s milk production, I am interested specifically in literature related to: agricultural production, rather than supply chains or consumption; animal agriculture, although CAFOs rely wholly on feed from corn, soy, and hay growers, and benefits from crop production by-products; and industrialized operations, although there remains a small amount of small-holder dairy operations in the state. For understanding the realm of industrialized animal agriculture, that which California milk production lies within, the political economy of agriculture is the most appropriate sub-discipline to contextualize the structures that shape change in the dairy industry in recent history.The political economy of agriculture is a cross-disciplinary concept that deals with the relationship between agricultural production and structural forces. “The political economy of agriculture investigates how “structural changes” in agri-food systems shape the means of production, thereby constraining and/or enabling producers’ decision-making ”. Political economy of agriculture is rooted in liberal and Marxian traditions and the belief that capitalism is the organizing force for agriculture in the U.S. The clearest difference between political economy of agriculture and political ecology of agriculture is that the former focuses more on structures, while the latter leans more toward individual agency and also tends to emphasize topics of environmental conflict and ethics. The following subsections describe three themes of agrarian political economy related to structural changes that shape dairy industries: capitalist penetration of agriculture, productivism, and the treadmill of production.In the production of living things, agriculture presents natural barriers to capital penetration. The Mann-Dickson Thesis states that “[c]apitalist development appears to stop, as it were, at the farm gate” which is to say that the unique nature of agriculture and food production, such as the perishability of food or the long production time compared to labor time, hinder the accumulation of capital in agriculture.

In the pursuit of surplus value, capitalism must transform and subvert these natural processes into a source of productivity, a process known as the real subsumption of nature . In the United States, dairy operations have overcome natural barriers to capital such as perishability, long production time, and waste in the following ways. Fluid milk is highly perishable, which presents many risks to the producer. “The more perishable the commodity is and the greater the absolute restriction of its time in circulation as a commodity on account of its physical properties, the less it is suited to be an object of capitalist production” . Standards for sanitation and food safety, and the interest of prolonging the shelf life of milk, led to the invention of pasteurization and refrigeration. Too little time on the shelf is coupled with too much time for production. The long production time of has been shortened with concentrated feeding to increase weight gain and shorten time until puberty, and the use of hormones to increase the imminence and volume of milk production. That said, unlike most other agricultural products, milk production requires daily ‘harvesting,’ increasing the labor time. Finally, the production of milk inevitably coproduces manure and methane as waste. This becomes problematic under intensified conditions, requiring removal and creating sources of pollution. The generation and concentration of manure produced in large dairy operations is dealt with using flush systems to waste lagoons, resulting in water pollution and methane emissions. These three examples of agriculture’s unique properties that hinder capitalist penetration, but are still overcome with certain interventions, or sub-sumptions of nature, set the stage for the other transformations that have occurred in the dairy industry, detailed below. The concept of productivism, or the emphasis on increasing agricultural production above all else, appears frequently in the literature about dairy production in the Global North. In 1993, Lowe et al. defined productivism as “a commitment to an intensive, industrially driven and expansionist agriculture with state support based primarily on output and increased productivity”. Jay describes how productivist sentiments shaped the New Zealand dairy industry to expand rapidly in the 1980s, resulting in dual pressures to maintain its economic efficiency while reducing its environmental impact. In their summary of three different narratives about the preferred trajectory of milk production in the Global North, Clay and Yurco situate the growth of the US dairy industry in the 20th century as the result of productivism after World War II, couched in language about growing a nation through growing strong bodies with “more milk”. Attitudes of productivism manifesting as the intensification of milk production were, and continue to be, the catalysts for multiple other forms of transformation at the dairy farm and industry.The treadmill of production is a concept coined by Cochrane to explain how economic pressures to lower prices and competition with other producers keeps agribusiness in a constant state of the pursuit of growth. Schnaiberg built on this concept in 1980 by applying the treadmill of production to explain the increasing demand for natural resources resulting in increasing environmental degradation . The use of new technology or resources by early adopters eventually brings a boost in production, which allows that producer to eventually lower their prices, making their product more competitive on the market. To compete, other producers must also adopt the new technology or increase in resource use, until eventually most producers have either invested in the technology or gone out of business because they could not produce enough compete.

We included measures of employment indicating whether respondents were employed, temporarily unemployed or seeking work, or part of a residual category that included retirees, students, and stay-at-home spouses or partners. The study was approved as exempt by the UCSF institutional review board on July 16, 2016. The 2016 survey contained 3,058 respondents. Weighted probabilities of use in each category, by sociodemographic characteristics, are shown in Table 1. Overall prevalence rates were 14.5% for cigarette smoking, 5.6% for ENDS use, and 9.5% for cannabis use. Prevalence of separate use for tobacco and cannabis, for all modalities, was 6.1% and prevalence of simultaneous tobacco and cannabis use was 3.4%. As shown in Table 1, rates of cigarette smoking, ENDS use, and cannabis use were higher for men than women. Rates of cigarette smoking and combined cannabis and tobacco use decreased with higher levels of education, but were not associated with higher education levels for ENDS use, cannabis use, or combined use. Rates of cigarette smoking, ENDS use, cannabis use, and combined use were highest among those unemployed and seeking work and persons with disabilities, relative to those who were employed or retired. Over half of cigarette smokers who initiated smoking over the age of 18 reported smoking in the past 30 days.For cigarette smoking, there was a lower odds ratio among those with at least a bachelor’s degree and those with household incomes greater than $100,000, as shown in Table 2. There was a significantly greater odds ratio among persons with disabilities and those who had begun smoking at 15 or older. For ENDS use, grow tables 4×8 there was a significantly lower odds ratio among those aged 55 or older. For all cannabis use, women were approximately half as likely to use as men .

Additionally, those with household incomes from $25,000–$49,999 were half as likely to use cannabis as those who had incomes of less than $25,000 . For combined tobacco and cannabis use, there was a significantly lower odds ratio among some lower-income groups. There was a significantly greater odds ratio for those who were unemployed and seeking work. For using tobacco and cannabis simultaneously, there was a significantly lower odds ratio for those with incomes $25,000–$49,999 and greater than$75,000. There was a significantly higher odds ratio for those who were unemployed and seeking work or and persons with disabilities. Past research has identified the practice and consequences of simultaneous tobacco and cannabis use among adolescents, however there has been limited data on the prevalence of this practice in different population subgroups or relative to other consumption, such as use of individual substances or separate use . Existing research suggests that young adults may be more likely to engage in simultaneous use, particularly given the increase in new modalities of use , however surveillance data has not yet verified this expectation . Our findings suggest that in contrast to findings from previous research, rates of simultaneous use may be highest among those who were involuntarily unemployed and persons with disabilities rather than among youth. We also found that more people used either cannabis or ENDS than smoked cigarettes, despite the relative novelty of these products. These results suggest a transition toward modalities that allow simultaneous use, a trend that could continue or accelerate as these novel products become increasingly normalized. Research on simultaneous use suggests that such a transition would lead to more dependence and reduced quit attempts , a concern given that these sub-populations are likely to have lower income and co-occurring conditions . Our findings have limitations. The data are based solely on California residents and responses reflect a policy environment that for 20 years has focused on reducing tobacco use and increasing access to medical marijuana.

These policy changes preceded similar changes made in many other states, suggesting that these data , primarily provide insight into how use patterns may change over time in those states that also legalized medical marijuana prior to recreational cannabis. Survey responses were based on self-report and did not biochemically validate responses; previous research suggests that respondents may under report use . As a result, our findings may have failed to identify other groups at risk of simultaneous use. As states continue to legalize medical marijuana and recreational cannabis, it is critical to monitor shifts in patterns of tobacco and cannabis use. Adolescents and young adults have been a focus of prior research, particularly in light of their susceptibility to uptake of novel delivery devices such as JUUL . However our findings suggest that young adults are not necessarily the population with the highest prevalence or highest risk of simultaneous use. Simultaneous use is linked with more severe consequences than using tobacco or cannabis alone, or with separate use of these products. Our findings that simultaneous users in California were not disproportionately young adults are relevant for developing targeted prevention and cessation interventions for individuals at high risk. In addition to emphasizing risks faced by adolescents and young adults, our findings suggest that public health interventions should expand their focus to address other vulnerable populations, including persons who are involuntarily unemployed and those with disabilities. Disproportionately more rural veterans are enrolled in Department of Veterans Affairs healthcare than their urban counterparts . Most rural veterans receive care from smaller VA community based outpatient clinics established by VA expressly to improve access to care, including mental health care. Rural veterans who utilize VA community-based clinics are typically older, sicker and poorer, and experience significantly greater MH burden and poorer clinical outcomes than their urban counterparts receiving care at VA medical centers. 

VA mandates that all veterans, including those receiving care at VA community-based clinics, have access to evidence-based MH treatments. Minimally adequate MH treatment has been defined as ≥ 8 MH treatment sessions or receiving ≥ 2 months of psychiatric medication plus > 4 visits within 1 year. Nevertheless, despite access to VA community-based clinics, rurality remains one of the strongest predictors of poorMH treatment engagement. Roughly, only 20% of rural veterans with MH conditions initiate any MH treatment and even fewer complete a full course of evidence-based MH treatment. Rural veterans’ lack of engagement in MH treatment reflects a myriad of logistical barriers, paramount among them geographical distance, and lack of access to consistently available MH services. Other barriers are cultural norms in rural communities, including negative beliefs surrounding MH treatment, stigma against needing or seeking MH treatment, and stoicism, with rural veterans preferring to address MH and emotional problems within their own communities, families, and religious organizations. Motivational interviewing is an evidence-based approach to facilitating behavioral change, and multiple studies over decades have demonstrated MI’s effectiveness for MH treatment engagement among veterans. One pilot trial of 73 younger Iraq and Afghanistan veterans who screened positive for MH symptoms demonstrated that 4 brief sessions of telephone MI conducted by trained research staff resulted in 62% initiating MH treatment versus 26% assigned to receive 4 brief neutral telephone sessions . Of note, this trial was conducted in younger, urban veterans by research staff with backgrounds in psychology. However, none of these trials were conducted among rural veterans who might experience greater barriers to MH treatment engagement. In addition, ebb flow tray most prior trials have used MH clinicians to deliver MI. There is emerging evidence that peers who may have shared experiences and “speak the same language” as the populations they serve may encounter less resistance and be more effective in promoting positive change, including engagement in MH care, especially in rural populations. Here, we describe the results of a multisite pragmatic randomized controlled trial , “Motivational Coaching to Enhance Mental Health Engagement in Rural Veterans,” hereafter abbreviated as “COACH.” The trial tested a veteran peer-delivered telephone motivational coaching intervention for veterans receiving care atpredominantly rural VA community-based clinics in either Northern California or Louisiana who had screened positive for ≥1 MH symptoms but were not engaged in MH treatment. We hypothesized that veterans who received MI-consistent feedback about MH screen results and MH referrals plus several sessions of veteran peer delivered telephone motivational coaching would be more likely to engage in clinician-directed MH treatment than veterans who received MH screen results and a referral without motivational coaching . Secondarily, we hypothesized that veterans assigned to veteran peer-delivered telephone motivational coaching would experience improvements in MH symptoms, quality of life indicators, and self-care as a direct effect of peer coaching itself compared to those randomized to the control condition. Qualitative exit interviews of participants in the intervention arm were conducted to better understand trial results.VA administrative databases were used to identify veterans with the following criteria: had received primary care within 1 year of study enrollment at 1 of 8 participating VA community-based outpatient clinics: 4 facilities in Northern California and 4 in Louisiana ; and had screened positive on ≥ 1 VA MH screens or had received ≥ 1 MH diagnosis, but had never attended an MH visit , or had attended up to 2 MH visits , but without follow-up within 90 days of recruitment.

Veterans identified through VA administrative data were mailed a study information sheet and a postcard they could mail back to indicate interest in study participation. If participants indicated interest or if no postcard was received after 2 weeks, study staff attempted to contact veterans by phone. In addition, VA community-based outpatient clinic providers were encouraged to refer patients to the study and flyers were posted in their clinics. Veterans deemed eligible and interested on initial telephone screening underwent informed consent prior to enrollment. Participants were enrolled from October 29, 2015, to October 19, 2017, and the study concluded June 1, 2018. The study protocol was approved by the VA Central Institutional Review Board and the local Research and Development Committees at the participating VA enrollment sites.60-min baseline assessment by telephone to collect baseline data and verify trial eligibility. Information was collected on sociodemographics, VA service connection/disability status, and prior VA and non-VA mental health treatment experiences in the past 5 years and past 60 days. Psychometrically valid assessment instruments with published cut points were used to determine participants’ symptom status for 5 target MH disorders: posttraumatic stress disorder , depression , anxiety , panic disorder , and alcohol and illicit substance use . Additional instruments were used to assess: quality of life across 4 domains: physical health, psychological health, social relationships, and environment ; importance, confidence, and readiness for MH treatment; and logistical, stigma- and beliefs-related barriers to MH treatment . Results from the telephone baseline assessment were entered directly into a web-based data collection system and scored in real time to verify non-MH treatment-engaged participants who screened positive for ≥ 1 MH problems, thereby confirming trial eligibility. This was defined as: scoring in the “mild” range on at least 2 MH screening instruments ; or scoring in the “moderate” range on at least 1 MH screening; or scoring in the “mild” range for at least 1 substance and in the “mild” range on at least 1 MH screen.The study was a single-blind, 2-arm pragmatic effectiveness RCT comparing MI-styled veteran peer-delivered feedback on MH screen results and referrals plus 4 sessions of telephone motivation alcoaching versus veteran peer-delivered MH results and referrals without motivational coaching . The study was designed as a Hybrid Type 2 pragmatic implementation effectiveness study, in which the implementation of the trial intervention was tailored to meet the needs, resources, and preferences of stakeholders at each VA community-based clinic study site. Thus, prior to trial implementation, a formative evaluation was conducted at each of the 8 VA community-based clinic sites, beginning with qualitative interviews with study stakeholders—veterans and VA staff—to understand barriers and facilitators of MH treatment for veterans at the clinic and in the local communities. Subsequently, the study team convened lunchtime meetings with study stakeholders at each of the VA community-based clinics to review evidence for the motivational coaching intervention, provide feedback from the qualitative interviews, and to engage study stakeholders in decision making about flexible components of the trial. For instance, some clinic stakeholders preferred to be more involved with recruitment efforts than others. Also, in this formative stage, the study outcomes related to MH treatment engagement were broadened to reflect rural veterans’ preferences for self-care activities based on input from VA stakeholders at the 8 participating VA community-based outpatient clinic sites.

The ECP also helps the missions of other agencies like the National Institutes of Health , National Science Foundation , National Oceanic and Atmospheric Administration , and the National Aeronautics and Space Administration. Such large-scale systems require interconnections between thousands of computing nodes. Traditional networks offer fixed links where optical fibers connect electronic packet switches with high-speed point-to-point optical links. Standard topologies to interconnect computing nodes include 3D and 4D Torus and fat-trees. where the network architecture is hierarchical. At the bottom in the edge layer, hosts are connected to Top-of-rack switches. Spots in the network can be barely or heavily loaded, and throughput bottlenecks may occur. Hence, the necessity of reconfigurable networks for bandwidth steering arises, to allocate higher bandwidth resources in hotspots on demand. To enable these flexible networks, we combine traditional electronic packet switches with optical switching technologies. In that way, we get the benefits of both fabrics to develop a reconfigurable optical network. The topology can be dynamically modified with an optical switch. Finally, routing and forwarding is managed with flow updates, so we can orchestrate the traffic to go through the newly configured physical links. We do not use traditional routing protocols, but a Software Defined Networking control plane that allows more flexibility in the definition of the routing schemes and forwarding rules. In the following subsections we briefly introduce the related work and enabling technologies relevant to different modules of the test bed that was implemented in this research. Finally, we discuss the purpose and contribution of our investigation.All-optical switches, hydroponic flood table such as optical micro electro mechanical systems, MachZehnder switches, microresonator ring and wavelength routing are alternatives to electronic switches.

They offer lower power consumption, scalability, fast reconfiguration, low latency and cost savings with silicon photonics integration. However, optical switching technologies have not been commercially deployed in datacenters and HPC systems due to several challenges, including the lack of optical buffers, the scalability limitation posed by physical layer technology , and the design of a scalable control plane that can orchestrate fast reconfiguration operations at large scale to follow the bursty nature of the traffic. Therefore, it is necessary to investigate hybrid switching systems that combine the benefits of traditional electronic devices and optical technologies.Our test bed combines aMEMS optical switch and SDN-enabled electronic packet switches, as described later in Chapter 3.In the Software Defined Networking approach, the control plane is decoupled from the hardware. It leaves only the data plane in the chassis, while the controller is software-based and uses Application Programming Interfaces to send instructions to the hardware to handle network traffic. A centralized control plane is useful to manage complex networks. Google’s Software Defined Wide Area Network , B4, which connects their data centers globally, is an example of a successful deployment of a commercial Software Defined Network . B4 maximizes the average bandwidth, and gives complete management across all network. It also enables traffic engineering, which derives in other benefits. One is multi-path routing, that leverages resources based on application priority, and assigns bandwidth on demand. Google reports an improvement of 3× in link utilization efficiency compared to previous standard practices . On average, links run at 70% of their capacity in the long term.

In addition, Google adopted SDN in their data centers when they realized that traditional decentralized routing protocols were not the solution to challenges such as creating routes through a broad, fixed and multi-path network. Management in such systems is easier to achieve if the network is modeled as a single device with multiple ports instead of a collection of several individual switches running routing protocols. LIGHTNESS is one example of research project that explored and demonstrated the integration of SDN control plane, virtualization of network resources, and an all-optical dynamic data center network. With a modified version of OpenFlow, a customized controller and the abstraction of the Optical Packet Switch node, which was implemented with an FPGA, they achieved optical packet switching . Furthermore, by assigning priority to flows of different applications, Quality of Service can be guaranteed. Real-time monitoring is another feature that was implemented by collecting statistics from the network agents through OpenFlow . From these case studies we can conclude that SDN is the key to control and to use resources efficiently in complex networks. TCP/IP is the name commonly used to refer to the set of network protocols behind the internet. TCP stands for Transmission Control Protocol and Internet Protocol. This is a practical implementation of the theoretical reference model, OSI . Due to the complexity of computer networks, organizing the protocols in independent layers with specific purposes makes it easier to implement, provision and debug communication links all around the world. The OSI reference model has seven layers, while TCP/IP condenses all in fewer layers. So far we have introduced research projects in technologies for reconfigurable optical networks, with applications in data centers and High Performance Computing . Specifically in the physical layer. Now we will cover the impact of link reconfiguration in upper layers. We focus on transport layer, following the TCP congestion control mechanism and the reliable data transfer between hosts when there is an event in the optical paths in the middle. A retransmission timer is used to guarantee data delivery when the receiver does not confirm reception of packets. It is defined as Retransmission Timeout, RTO, in internet standards.

We discuss this timer in our results in Chapter 4. Network traffic in our testbed is generated with iPerf, a tool that can be configured with TCP or UDP. The first one is known for reliable communication among hosts, thus we choose that protocol in our experiments. Nevertheless, it was originally designed for WANs, where the data Round-Trip Time is in the order of hundreds of millisecond due to large geographic distances between nodes, but 2-3 orders of magnitude higher than RTT in datacenters. Such a large RTO in this context impacts in latency and throughput. Reducing the RTO might be a solution, but the challenge is that most systems do not have high resolution timers. Furthermore, varying the RTO helps to act fast against packet loss, but it yields to spurious retransmissions. Researchers have found that optical reconfigurations raise RTO events. RTT in datacenters is generally in the sub-millisecond scale, while optical switching can reach tens of milliseconds if using MEMS technologies. TCP waits for a certain time , ebb and flood table then it attempts to send data again. The default RTO varies across operating systems. It is set to 200 ms in Linux, 300ms in Windows . A new trend in transport protocols points towards programmable NICs and FPGAs, to leverage the optimized latency that state of the art distributed datacenter applications require. The High Precision Congestion Control and NanoTransport projects present transport protocols and congestion control schemes in dedicated programmable hardware. This topic is out of the scope of this thesis, and is left as future work to test novel transport protocol schemes in reconfigurable optical networks.An optical reconfiguration operation consists of the following steps: decide when to make the reconfiguration, select a new topology based on specific optimization goals, and finally migrate the traffic to the new path. Service halts arise amid topology migrations, in particular when a new light path is provisioned dynamically. That is, when the old link is removed and the new one is configured afterwards. To reduce the outage impact, which depends on the link setup time, a make-before-break approach is advised. If the optical channels are placed in the network prior to the reconfiguration, they will be ready to carry traffic instantly. However, this technique involves using additional resources, because more links must be operational simultaneously. Quality-of-Service and network performance in general are improved if bandwidth is reserved before the traffic transition, since the length of disturbance is minimized. Hitless reconfiguration in optical networks was defined in 1996 as the reconfiguration process where not even a single ATM cell is lost. ATM stands for Asynchronous Transfer Mode, a standard in telecommunications for data transfer between user-network or network-network nodes, prior to the wide adoption of IP based networks. Bit Error Rate and Forward Error Correction are useful metrics to monitor the quality of a link in an Optical Transport Network . Specific thresholds must be specified for minimizing or preventing packet loss. As long as these metrics are within the desired range, the link is considered optimal .

Research in hitless optical reconfiguration have demonstrated a switching of less than 1µs, without deteriorating the real-time BER, using fast tunable lasers. Other studies implemented a testbed as well, with commercial transceivers and a channel spacing of a minimum frequency step of 0.5GHz to keep BER in a desired range. By adding SDN elements to manage reconfiguration in an AWGR-based optical network via wavelength tuning, the total switching time reached only millisecond scale, and the packet loss was reduced by 50%. For the rest of this thesis, we consider hitless reconfiguration as the update in the topology that generates 0% packet loss, end-to-end. Reconfigurable optical networks have been studied in recent years, in both simulations and testbeds. On the experimental side, we find that SDN-controlled systems are practical to prevent packet loss and throughput drop due to light path updates. With SDN in hybrid networks, we can perform the reconfiguration in different steps: take the traffic from the ports to be updated, reconfigure the topology with the optical switch, synchronizing the transceivers in the new physical routes, and finally route the traffic through the new paths. In terms of reconfiguration latency, we find systems with delays of different orders of magnitude.ProjecTor is another testbed with a similar architecture, with a reconfiguration latency of 12µs. In the nanosecond level we find Sirius. These projects are mainly prototypes that integrate several blocks to build a reconfigurable optical network. Our testbed was built with commercial solutions such as an EdgeCore electronic packet switch, DWDM transceivers, a Polatis MEMS optical switch, along with Linux and a python-based SDN controller . If the reader is interested in the state of the art of optical technologies for datacenters and future trends, I recommend the paper ”Prospects and Challenges of Photonic Switching in Data Centers and Computing Systems”. Simulators are tools that researchers use to demonstrate models, algorithms, devices and other elements of networking and computing systems to improve their performance for large scale and high performance applications. To validate the simulation studies, it becomes essential to execute testbed experiments, which is the main focus of this thesis. We describe the testbed in terms of architecture, infrastructure and software tools. First, we will discuss the general design of the system, the purpose of each block and how they interact with others. Second, we will discuss how the system is implemented with servers, switches, wires, fibers, racks and any other physical device. Third, we will explain the software tools we used to orchestrate our experiments. We cover virtualization, network monitoring and traffic generators that we used in our investigation. In this chapter we start with the architecture of our testbed. Similar to Emulab, we connected physical and virtual hosts to different networks on top of a single infrastructure. The first is the management network, which helps to connect remotely to our testbed elements from anywhere. It is practical as it allows researchers from our team to handle experiments through the UC Davis VPN and an internet access point without being connected with a wire to the hosts nor restricted to UC Davis LAN . The second is the control network, which orchestrates our experiments and collect statistics from our computing hosts and network nodes. The control and application planes are encompassed here. The third is the experimental network data plane, a reconfigurable optical network composed of electronic and optical switches with 10 Gbps transceivers and optical fibers connecting our computing nodes and carrying data with rates up to 10 Gbps. Figure 2.1 illustrates the general architecture of our testbed. The data plane incorporates four electronic packet switches , an optical switch and optical fibers that interconnect four computing nodes .

They are not, nor ever have been, pre-determined or natural classifications. As laws, land use regulations, as well as national and local power relations shift, so do the definitions of crimes and criminals . Thus, remote sensing cannot detect crime as it might detect a stand of a certain tree species: crimes, their perpetrators and their forms are defined by the dominant forces in society rather than spectral signatures or texture patterns. Because remotely sensed images are collected remotely , they lack detailed or nuanced definitions of crime drawn from the context of the landscapes they seek to analyze; they do not tell us why certain things happened or by whom, specifically. They leave understandings of causality and attribution to their interpreters. Despite the serious imbalances and problems that may arise from the remote sensing of crime, it continues apace, as we have seen from increasing discussions in the popular press and academic journals about the use of unmanned aircraft systems , increasing availability of micro-satellites and Google Earth images in the detection of crime . The continued and increasing use of remote sensing for these purposes brings us to the third limitation that we will mention here: the issue of validation. As remote sensing scholars, such as Jensen, Congalton and Foody note, validation is a critical part of any remote sensing exercise, and these scholars and others have laid forth strict protocols for validation exercises. Validating that crimes are actually occurring in the places that remote sensing algorithms say they are is not a simple task, however. On the ground, verification of potential illicit drug production, arms and drug smuggling or even illegal logging, flood table activities which are often protected by, or associated with, armed guards or agents, is often dangerous.

The lack of validation in the remote sensing of crime is troubling, however, because drastic military or police actions are often used to intervene where crimes are detected with lasting ecological, economic and social impacts: lives, security and livelihoods can be at stake, not to mention law enforcement credibility and resources. In short, classifying an action as a crime or a person as a criminal may have much higher costs than other classification mistakes. Thus, we must be doubly sure of what we classify as crime using remotely sensed images before we act. Further, such validation may add nuance and greater contextual understanding of the images used for analysis, which may allow for a more fair and balanced law enforcement response. Although all three of the above limitations are important to consider, this paper will take a methodological approach to engage with the issue of the validation of remotely sensed crime. We believe a focus on validation is critical, because as remotely sensed products become increasingly available to our desktops and smartphones, a rising trend of validation-free analysis is emerging. In these circumstances, products, like Google Earth, are used with the assumption that their images portray “the truth”, which should be acted upon. Despite the ease with which these data now flow to us, validation of our findings based on these images remains critical; competing sensors, processing methodologies and the familiarity of analysts with the limitations of the data they are using can present very real challenges to the ethical and accurate use of remote sensing in law enforcement and/or litigation. In this paper, we will first analyze how remote sensing technologies have been used to aid in the detection of crimes that might otherwise go undetected. As other authors have shown, “satellite imagery highlights the spatial footprint of human actors in very real and compelling ways” . Here, we review the literature that discusses how satellite and airborne technologies have been used in the active detection of felony cases of drug production, smuggling and extra-legal migrations.

We use the term “extra-legal” here, rather than “illegal,” in order to highlight the fact that though these acts are prohibited by USA or international law, the prohibition of these actions is often highly political and may not be deemed illegal in all cultures or by all groups. Forensic remote sensing has also been critical in the detection of environmental crimes, such as extra-legal mining and timber extraction, as well as in detecting oil spills and hazardous waste dumping. While the use of remote sensing in environmental forensics of this kind are important, many of the articles on these topics are embedded in larger land-clearance, deforestation and oceanographic literatures that deal with licit, illicit and accidental extraction or pollution, making the attribution of legality associated with the event difficult. Forensic remote sensing can also be used to identify the location of single and mass grave sites, but because most of these studies are experimental or historically oriented, we excluded them from our review. Remote sensing has also been used to find bodies, munitions and toxic waste that may have drifted based on water-current analysis. While our scope is narrower than that of forensic remote sensing, we do draw upon the advances in crime detection and validation that these studies have advanced in our analysis. Second, building on this literature review, we consider what kinds of validation protocols for the remote sensing of crime have been attempted and what the limitations to these protocols are, geographically, financially, as well as in terms of personnel and time. Third, we seek to generate a discussion on new and less traditional ways that crime may be sensed remotely or validated. While “first order” validation protocols, such as the collection of ground reference data, over flights and the use of higher spectral or spatial resolution images, are critical to assessing the accuracy of remotely sensed processes, they may not always be useful, possible or sufficient in the context of criminal investigations. Here, we propose going beyond the “first order” validation protocols that are standard in remote sensing to ensure accurate assessments of remotely sensed crime are occurring in ethical and contextually-situated ways. Here, we define the remote sensing of crime as the use of airborne and satellite remote imagery to detect crimes that have heretofore gone unreported or undetected. Lein describes forensic remote sensing as considering “the investigative use of image processing technology to support policy decisions regarding the environment and the regulation of human activities that interact with environmental process and amenities.” In this definition the term “forensic” refers to detailed investigation rather than a criminological one . As Lien points out, forensic remote sensing seeks to generate information pertaining to a specific event rather than “provide a broad thematic explanation”. As we note above, not all crimes are well suited to detection by remote sensing, however. Those crimes that have been most successfully detected using remote sensing technologies generally have the following three characteristics: first, they occur over relatively large geographic areas, so that their patterns may be easily detected, even with moderate or low spatial resolution imagery, like Landsat or MODIS ; second, the crimes or their evidence are generally visible for extended periods of time, allowing for their detection by satellites or airborne sensors over the length of a day, week or month; and third, they generally have characteristic spatial or spectral patterns that can be recognized from above using object-based analysis or spectral analysis.

This paper focuses on the utility of remote sensing in detecting crimes that are deemed a felony offense under U.S. federal law and are recognized as crimes internationally: arms, drug and human trafficking, 4×8 flood tray repeat extra-legal migration and drug production/possession . While there exists a plethora of academic papers that test methods that could theoretically be used for the remote sensing of crime—testing algorithms, detection techniques or spectral reflectances of illicit crops and smuggling trails—there are relatively few studies that document the use of remote sensing in the active reconnaissance of criminal activities. In this section, we review studies of active reconnaissance that exist in peer reviewed journals, as well as in gray literature in relationship to drug production, smuggling and extra-legal migrations. The characteristics of these activities fit those described above: they often occur in large geographic and temporal scales and may be uniquely identifiable from the surrounding landscape using aerial images. Because of these attributes, they represent the most common examples in papers regarding remote sensing used in the active detection of crimes. We reviewed 61 papers, reports from the United Nations Office on Drugs and Crime and master’s theses on these topics that were found through searches in the Google Scholar, Web of Science and Jstor search databases using a number of combined words and phrases . Some of these reports involved multiple case studies. Though, as Figure 1 shows, there were thousands of results that came from these combinations of search terms, very few of these results dealt with the active reconnaissance of crimes using remote sensing. We do acknowledge that there are probably many more reports and papers available on this topic in the law enforcement literature that are not available to the public. Government agencies, like Homeland Security, the Federal Bureau of Investigation and the Central Intelligence Agency, as well as international law enforcement agencies, like Interpol, may have extensive documentation on these topics that we were unable to access. Most prevalent in literature involving remote sensing of crime were studies on the detection of the cultivation of illicit substances. While the criminalization of each of these plants and their use is fraught with important political, cultural, economic and militaristic implications, an in-depth discussion of the reasoning behind these criminalizations and their ethics is beyond the purview of this article. Rather, we narrow our focus to the application of remote sensing products to actively detect “crime”, as it is construed by international or national governing powers. The use of remote sensing to detect the cultivation of illicit crops is a trend that has increased over time, perhaps because of the opening of the Landsat archives in 2008, and perhaps because of interest in opium growing in Afghanistan and South East Asia . We gathered the publicly available literature on the remote sensing of drug production in Afghanistan, Myanmar, Thailand, Laos, Bolivia, Colombia and Peru, countries targeted for drug production monitoring both by the UN’s Office of Drugs and Crime and academic researchers, due to these countries’ historically high exports of illicit substances . Using remote sensing to detect the growth of illicit drugs can be extremely helpful to those seeking to eradicate these plants, apprehend their cultivators, and limit the trade of the substances they produce. Unlike in-person surveys actually does conduct in some areas, which are labor intensive, time consuming, expensive, and potentially life threatening, remote sensing allows a small number of analysts to survey vast stretches of land to locate scattered sites of illicit crop production. Further, illicit crop detection methods that utilize remote sensing enable more frequent and complete surveys of the landscape than in-person surveys would. These techniques can focus the efforts of law enforcement officers, defoliant missions, and outreach programs. Remote sensing techniques may also allow governments and international groups to target drug production sites without putting their agents in harm’s way, or tipping off producers that some kind of action may be taken against them . Although the war on drugs began in the 1970s, the first publicly available papers we found on the active detection of illicit crop growth using remote sensing technologies were Sadler’s discussion of opium in Afghanistan and Chuinsiri and others’ detection of opium growth in Thailand. It was not until 1999 that groups like the UNODC’s Illicit Crop Monitoring Program began using remote sensing techniques to detect the growing of drug crops, particularly coca and opium poppies. The first UNODC cannabis survey was carried out in collaboration with the Afghan Ministry of Counter Narcotics and was not carried out until 2009. Like the criminalization of drug production, the criminalization of human movements across national borders either for migration or trade is also fraught with problematic social, political, economic, and militaristic issues and implications. Here, again, in-depth discussion of the reasoning behind these criminalizations and their ethics is beyond the purview of this article and we narrow our focus to the application of remote sensing products to actively detect “crime”, as it is construed by international or national governing powers.

These findings, while far from definitive, do not suggest a clear and direct link between cannabis use and crime. This makes it difficult for researchers to infer the extent to which a certain behaviors can be attributed to specific substances. Furthermore, because of the way that marijuana is metabolized by the human body, positive tests for marijuana only indicate use within the past month, and therefore do not necessarily signify that a particular crime was committed while under the influence . In fact, in some studies cannabis has been shown to inhibit aggression and violence . Thus, although it may appear that marijuana use is associated with criminal arrests, there are many reasons to be skeptical about that correlation. The drug-crime link, in psychopharmacological terms, is stronger for alcohol than it is for illicit drugs . “In the case of marijuana,” Resignato concludes, “the assumed psychopharmacological connection between use and violent crime has been almost completely disproved in the research” . Research on economic-compulsive drug related crime tends to focus on drugs with higher addictive potentials than cannabis, most notably heroin and cocaine . Perhaps the most compelling mechanism through which drugs might lead to crime is through the occurrence of systemic violence . The violence associated with markets for illegal drugs is at least indirectly caused by drug prohibition and enforcement, “a relationship that may be underestimated by many policy officials” . It is plausible that this would apply to retail vendors of medical marijuana—although arguably less so than the illicit dealers of the drug, who are displaced by legal or quasi-legal cannabis businesses .

This is the dynamic explored by the present study. I conclude from the available literature that cannabis drying rack has no significant relationship with crime via its psychopharmacological effects or its capacity to bring about economic-compulsive criminal behavior in its users . I argue that the only plausible link between cannabis and crime lies in the extent to which the drug attracts “systemic violence”, due to its illicit status and high market value. The following chapter presents a conceptual model that can be used to test empirically whether or not medical cannabis dispensaries are associated with crime in city neighborhoods. Do medical cannabis dispensaries increase crime? It depends who you ask. Empirical evidence is scant and is almost entirely overshadowed by anecdotal reports and sensationalized hearsay. For example, a 2009 report compiled by the Coalition for a Drug-Free California alleges that “marijuana escalates the level of mental illness, crime and all related problems” . But the report offers little empirical evidence in support of these claims. The CaliforniaPolice Chiefs Association —an organization representing California’s municipal law enforcement agencies—has also been a vocal critic of dispensaries.  Its 2009 White Paper on Medical Marijuana Dispensaries concludes that the presence of dispensaries “poses a clear violation of federal and state law; they invite more crime; and they compromise the health and welfare of law-abiding citizens” . The underlying evidence is entirely anecdotal: the CPCA presents no statistical analysis supporting the conclusion that medical cannabis dispensaries cause crime at a higher rate than any other business. The CPCA’s assertion that dispensaries increase crime stands in conflict with an analysis conducted by the Police Department of Denver, Colorado, which in 2010 projected that dispensaries attract crime at a similar rate as pharmacies and a lower rate than banks or liquor stores. A recent study conducted by researchers at the UCLA Luskin School of Public Affairs examined crime data in 95 census tracts in Sacramento .

No clear link was found between the density of marijuana dispensaries and the rate of violent or property crime, suggesting that dispensaries do not increase crime and that some security steps taken by dispensaries may actually reduce local crime. Despite the insistence of organizations such as the Coalition for a Drug-Free California and the California Police Chiefs Association, there does not appear to be an obvious link between medical cannabis dispensaries and criminal behavior in surrounding areas. Limited reports from California and Colorado suggest a neutral or negative correlation between MCDs and crime, but more empirical research is needed to substantiate a generalized claim to that effect. This study aims to extend current knowledge about the relationship between MCDs and crime through a geospatial analysis of crime data from San Francisco.Thus routine activities theory attempts to explain crime by looking at the ecological circumstances in which it occurs, while other criminological approaches tend to focus on the characteristics of criminal offenders. Both are useful to the present study, which analyzes whether crime is related to MCD presence in city neighborhoods but is also interested in controlling for demographic characteristics related to crime across those neighborhoods. Regarding the number and concentration of motivated offenders in an area, MCDs could have a positive, negative, or neutral effect on crime. If cannabis use directly or indirectly leads to criminal behavior, then MCDs might increase crime in a neighborhood by concentrating a large number of cannabis users in one place. It is also possible that MCDs could reduce criminal behavior in a neighborhood by displacing illicit dealers of the drug. And it is of course possible that MCDs have no effect whatsoever on the number or concentration of motivated criminal offenders in an area. From a routine activities perspective, the most likely link between MCDs and crime is probably in the extent to which MCDs present suitable targets for crime. Components of target suitability include value, visibility, and accessibility . With respect to value, MCDs tend to possess large amounts of cash and cannabis, which are high-value targets for theft. As Felson notes, “lions look for deer near their watering hole” . Patients, vendors, and especially staff are potential targets of crime: “Employees of the dispensaries can be at-risk for violent crimes, such as robbery or assault, as they are gatekeepers to both the marijuana products and the cash at the site” .

In California it is estimated that MCDs conduct roughly $1.9 billion in gross sales annually. Beyond the fairly obvious point that criminals like to steal things of value—which is just as true for MCDs as it is for banks, pharmacies, and other retail businesses—there are other valid reasons to believe that criminals would perceive MCDs as suitable targets. Most MCDs are open systems that are constantly seeking new members through advertising and other means. Thus they present, in many cases, highly visible targets for crime. Although few empirical studies have examined the relationship between MCDs and crime, existing research has explored the criminogenic effects of other land uses A study by Roncek and Lobosco reported that high schools elevate local crime rates, probably through the concentration of likely offenders . Brantingham and Brantingham found an inverse relationship between crime rates and distance from the nearest McDonald’s. As Felson explains, the restaurants themselves may be safe—but they attract customers who are “in prime offending and victim ages, producing high crime risk for nearby properties” . There is strong evidence to suggest that bars and other establishments that serve alcohol meet the criteria for target suitability . This provides an interesting point of comparison for medical cannabis dispensaries and other retail businesses. A criminal might reasonably perceive that a patron entering or leaving such businesses would be in possession of some amount of cash and therefore be an attractive target for theft . The establishments themselves operate largely in cash and are accessible to the public, vertical grow system in many cases advertising themselves in an effort to increase their accessibility. The perception that these would be easy targets is compounded by the perception that patrons and staff might be medically ill or intoxicated . Thus, as Roncek and Maier conclude in the case of bars, “the patrons and the businesses have all the components of target suitability” . The degree to which MCDs present suitable targets for crime—a notion that is subject to considerable debate—is largely dependent on the effectiveness of MCD security measures. Here we see an inverse relationship between target suitability and the third core component of routine activities theory, capable guardianship. As guardianship increases, a potential target becomes less and less accessible to predatory crime. By definition, members of MCDs suffer from medical conditions that qualify for medical cannabis treatment. This could create a perception of vulnerability that is attractive to criminals seeking to obtain cannabis and/or cash without a fight. It is also possible that criminals perceive MCD operators to be less likely to report crime due to their precarious legal existence and a resulting incentive not to attract attention from law enforcement. Thus it is plausible that the presence of MCDs might increase crime in a neighborhood by presenting, in the terms of routine activities theory, accessible targets for crime.

But it is also possible that criminals do not perceive MCDs to be suitable targets for crime, or that they consider them no more attractive than other retail businesses with high-value inventories and large amounts of cash. Furthermore, it is possible that—compared to other potential targets in the neighborhood—criminals actually perceive MCDs to be unsuitable targets. This largely depends on the effectiveness of guardianship in a neighborhood to prevent crime. Compared to other businesses, MCDs might represent superior guardianship in a neighborhood and thereby serve to reduce the frequency of crime. Security protocols are one way in which an MCD might do this. Many dispensaries implement security protocols—in order to comply with local mandates or simply to protect their patients, vendors, and staff—that might serve to increase the level of guardianship in a community and thereby reduce crime in a neighborhood, as routine activities theory suggests. In a recent working paper for the California Center for Population Research at UCLA, Nancy Williams and colleagues present a routine activities approach for examining the link between MCDs and crime. They examined 95 census tracts in Sacramento and found that tracts containing dispensaries were not significantly associated with higher rates of crime when controlling for other neighborhood characteristics . This study borrows from their work in applying a routine activities approach to MCDs in San Francisco.Social disorganization researchers have identified several neighborhood characteristics that are positively associated with crime. This study borrows from their work in selecting control variables to address the fact that social and demographic characteristics vary widely across city neighborhoods, with significant implications for social and economic activity, public health and safety, and other outcomes. Whereas routine activities theory focuses on the circumstances in which crime occurs, social disorganization theorists point to the social and demographic characteristics of surrounding communities in explaining outcomes of high crime and violence. Social disorganization has been concisely summarized by Sampson and Groves: “The general hypothesis is that low economic status, ethnic heterogeneity, residential mobility, and family disruption lead to community social disorganization, which, in turn, increases crime and delinquency rates” . This approach is summarized in Figure 2.2 below. According to this theory, crime is associated with what Sampson and Groves call “exogenous sources of social disorganization” . This study controls for three such categories of neighborhood characteristics: economic deprivation, residential instability, and family disruption. Low socioeconomic status translates to lower levels of formal and informal social control. High residential turnover disrupts social relations and erodes collective efficacy. Higher rates of family disruption, i.e. a higher proportion of single-parent versus married-couple households, results in decreased parental supervision and a relative lack of guardianship . These conceptual links to crime, expounded originally by Shaw and McKay , have received more nuanced theoretical attention from Kornhauser , Sampson and Groves , and Veysey and Messner . The explanatory power of their empirical correlates is discussed in the following section, which describes the measures to be analyzed in the present study. In the original test of social disorganization theory by Sampson and Groves , low SES was found to be significantly associated with crime. The link between economic deprivation and crime may be more complex than the simplistic explanation that poor people have higher incentives to commit crime and suffer lower opportunity costs for doing so. For example, Sampson reports in an earlier work that low SES neighborhoods have higher levels of police supervision, independent of actual law violate behavior .

Shoyoma et al published the chemical shifts of CBGVA in CD3OD, so by direct comparison of our NMR spectra to the published chemical shifts we conclude that we produced CBGVA. This is further supported by the work conducted by Bohlmann, which suggests that if the prenylation occurred at the C5 site, we would observe a proton with a chemical shift around 5.8 ppm, which we did not observe, Figure 2-15. We placed olivetolate in the active site of NphB in six different starting positions denoted as Olivetolate P1-6 in Table 2-2. We ran ROSETTA 5 times for each olivetolate position for a total of 30 designs. The mutations predicted in each design are listed in Table 2-2. For each olivetolate position we chose a consensus set of mutations to evaluate further: Consensus Group A through F . We then sought to evaluate the relative importance of each ROSSETTA suggested mutation. For each Consensus Group, we set the mutations back to WT residue, one at a time, and used ROSETTA to calculate the change in energy score . Those that caused the largest change in energy were deemed to be the most important mutants to include in the library for experimental testing. To model the olivetolic acid, we took the 4MX.sdf 3-D structure of olivetolate from the 5B09 crystal structure and added hydrogen atoms to the structure assuming pH 7 using Open Babel 2.3.1.39 A rotamer library was generated for olivetolic acid using the Bio Chemical Library molecule: Conformer Generator 3.5 using the PDB library.The olivetolic acid molecule was then manually placed into the co-crystal structure of NphB with GST and DHN with the DHN and crystallographic waters removed using pymol. The olivetolic acid was placed in 6 different positions in the active site with the plane of the olivetolate aromatic ring parallel to the GST alkyl tail and the desired prenylation site 3.7 angstroms away from the eventual carbocation mirroring the placement of DHN in the 1ZB6 crystal structure.

Residues 49, 162, 213, 224, 232, 233, 234, 271, 286, and 288 were allowed to be any amino acid during the Rosetta design with other sidechains held in a fixed position and the backbone fixed. The designed residues were in direct contact with the olivetolate and not in direct contact with GST. The reactions were incubated for 12 hours at room temperature, vertical grow systems then extracted 3 times with 100 µL of ethyl acetate. The organic extract was pooled for each reaction and the solvent was removed using a vacuum centrifuge. The samples were redissolved in 100 µL of methanol and subjected to HPLC analysis. The initial rate was plotted vs the concentration of substrate, and fit with the Michaelis-Menten equation to determine the kinetic parameters kcat and KM . Each Michaelis-Menten curve was performed in triplicate. The average and standard deviation of the kinetic parameters are reported. The time courses with olivetolate as the substrate were as follows: for WT, M1, M10 and M30 the time course was 3, 6, 9, and 12 minutes. For M25 the reactions were quenched at 1, 2, 4 and 8 minutes, and for M31 the reactions were quenched at 1, 2, 4 and 6 minutes. The conditions were altered slightly to characterize the constructs with divarinic acid as the substrate. For M31, the time course was 0.5, 1, 1.5 and 2 minutes. For M23, the time course was 5, 10, 15 and 20 minutes, and for WT NphB the time course was 8, 16, 24 and 32 minutes. The enzyme concentration for the mutants was ~27 µM, and the concentration of WT NphB was ~ 35 µM.Samples were dissolved in 200 µL of ethyl acetate. GC-MS measurements were carried out using an Agilent Model 7693 Autosampler, 7890B Gas Chromatograph, and 7250 Q-TOF Mass Selective Detector in the Electron Ionization mode. Sample injection was carried out in split mode with inlet temperature set to 280o C. Separation was carried out on an Agilent HP5-MS column with dimensions 30m x 250 µm x 0.25 µm. Ultra High Purity Grade He was used as carrier gas with the flow set to 1.1 mL/min in constant flow mode. The initial oven temperature was set to 120o C for 1 min followed by a 20o C/min ramp to a final temperature of 300o C which was maintained for 4 min. A 3.0 min solvent delay was used. EI energy was set to 15 eV.

The MSD was set to scan the 50 – 500 m/z range. Data collection and analysis were performed using Mass Hunter Acquisition and Qualitative Analysis software . Due to the increased temperature of the GC inlet, CBGA undergoes spontaneous decarboxylation as described by Radwan et al, resulting in an M+ ion at 316 m/z. The retention time corresponding to the 316 m/z ion for the CBGA standard was 10.48 minutes.A PyOx/PTA reaction was set up as detailed above. A 500 µL nonane overlay was added to the reaction in a 2 ml glass vial which was covered with 2 layers of breathable cell culture film. 2 18-gauge needles were inserted into a 15 mL falcon tube at the ~750 µL mark and the 3.5 mL mark. Luer locks to tubing connectors were connected to the needles and Viton tubing was connected to the other end of the luer lock. 18-gauge needles were connected to the other end of the tubing via a luer lock connector and inserted through the mesh covering so they were only touching the nonane layer and not the reaction. 2 mL of Tris buffer [pH 8.5] was added to the 15 mL conical tube, and 6 mL of nonane was added. The nonane was pumped through the system using a peristaltic pump such that the nonane flowed from the top of the reaction, through the buffered solution . The nonane pumped into the reservoir separated into the top layer of the 15 mL conical tube. The nonane from the top of the 15 mL conical tube was pumped into the top of the reaction vial . This essentially diluted the CBGA throughout the system driving the diffusion of CBGA into the nonane layer and out of the reaction. A gene block of CBDAS with the signaling peptide was ordered from IDT codon optimized for Pichia pastoris. The signal sequence was removed by PCR amplifying from the 28th residue of the protein sequence through the end of the protein, with overhangs compatible with the pPICZα vector. The PCR product was cloned into the pPICZα vector digested with EcoRI and XbaI using the Gibson cloning method. The product of the assembly reaction wastransformed into BL21 Gold cells a clone with the correct sequence isolated. The plasmid was digested with PmeI for 2 hours, and then purified using the Qiagen PCR purification protocol. The plasmid was transformed into Pichia pastoris X33 using electroporation. Immediately following electroporation, the cells were incubated in 1 mL of cold 1 M sorbitol and 1 mL of YPD media without shaking for 2 hours. The cells were plated on YPDS plates with 500 µg/mL of zeocin.

Colonies were screened using PCR for the presence of the CBDAS gene between the AOX1 promoter and terminator. For screening, pruning cannabis the colonies were re-suspended in 15 µL of sterile water and 5 µL of the resuspended colony was transferred into a PCR tube with 0.2% SDS. The samples were heated for 10 minutes at 99ºC, and then 1 µL was used as the template for PCR. Six colonies with positive colony PCR hits were screened for the expression of CBDAS. The six colonies were grown overnight at 30ºC in 25 mL of BMGY to obtain a saturated culture. The overnight cultures were used to inoculate a 25 mL culture in BMGY media and grown to an OD of ~2. The cells were harvested by centrifugation at 2,000 x g for 10 minutes. The cell pellet was re-suspended in 90 mL of BMMY media, and incubated at 30ºC for 5 days. Each day, 1 mL of the culture was removed for SDS-PAGE analysis, and 500 µL of methanol was added to the remaining culture. On day 3 the cultures were screened for CBDAS activity. The 1 mL culture samples were centrifuged to pellet the cells . 50 µL of the media was used in a subsequent activity assay, and the remainder of the media was stored at -80ºC in addition to the cell pellet. The assay conditions were as follows: 100 µL of 200 mM citrate buffer, 100 µM CBGA, 5 mM MgCl2, 5 mM KCl, 1 mM FAD and 50 µL of the expression media. in a final volume of 200 µL. The reactions were incubated overnight at room temperature and then extracted 3 times with 200 µL of ethyl acetate. The ethyl acetate extractions were pooled for each sample, and removed using a vacuum centrifuge. The samples were re-suspended in 200 µL of methanol and analyzed by HPLC. All clones produced active CBDAS. To convert the precursors CBGA and CBGVA into CBDA and CBGVA respectively, a secondary reaction was set up with cannabidiolic acid synthase . To produce CBDA, a PyOx/PTA enzymatic system was set up as detailed above to produce CBGA. After 24 hours 200 µL of the nonane overlay from the CBGA reaction was transferred to a CBDAS reaction vessel. In the aqueous layer: 50 mM Hepes [pH 7.0], 5 mM MgCl2, 5 mM KCl, 25 µM FAD, 0.1 mg/mL CBDAS concentrate. The reaction was incubated at 30ºC with gentle shaking. Reactions were quenched at 12, 24, 48, 72 and 96 hours. To produce CBDVA, HPLC purified CBGVA was converted to CBDVA using CBDAS. The final reaction volume was 200 µL, with 50 mM Hepes [pH 7.0], 5 mM MgCl2, 5 mM KCl, 25 µM FAD and 0.1 mg/mL of CBDAS concentrate. A 200 µL nonane overlay was added, and the reactions were incubated at 30 ºC with gentle shaking. The reactions were quenched at ~ 24, 48, 72 and 96 hours.Glucose is broken down to pyruvate through a modified glycolysis pathway that includes a purge valve system. The purge valve allows carbon flux to continue through the glycolysis pathway without building up excess NADPH. Pyruvate is converted to acetyl-CoA through the PDH bypass outlined in light blue. Acetyl-CoA is then converted into GPP via the mevalonate pathway . Finally, the GPP from the mevalonate pathway is used to prenylate aromaticpolyketide. Shown here is the prenylation of olivetolate to produce CBGA; however, olivetolate could be replaced with a wide range of aromatic substrates to generate various prenylated products. An example of the conversion of CBGA into CBD by the action of CBDAS and a spontaneous decarboxylation is shown.This brief review will cover potential benefits of cannabis in reducing persistent in- flammation and immune activation in virally suppressed people with HIV and the possible resulting clinical benefits. While no randomized clinical trials have been performed, both pre-clinical and clinical evidence supports these potential benefits. We discuss sources of inflammation in HIV, their clinical impact, the endocannabinoid system , effects of exogenous cannabinoids on the ECS and inflammation, particularly neuroinflammation, and potential treatment implications. This review attempts to weave together research threads from multiple areas: clinical, pre-clinical, in vivo and in vitro. The goal is to be integrative, not exhaustive. Overall, the observations reviewed here suggest a program of future basic and clinical research to explore the potential benefits of cannabinoids for the treatment of inflammation-related disorders in PWH. Additional work in this area is reviewed by Yadav-Samudrala and Fitting.The proportion of PWH who use cannabis is 2–3 times higher than in the general population < 10%, in part because many PWH use cannabis to manage symptoms such as nausea, sleep disorders, musculoskeletal and neuropathic pain, anxiety, and depression. There is, however, great heterogeneity in findings on therapeutic benefits of cannabis, likely due in part to extensive variation in the formulations being used. Components of cannabis, present in varying degrees depending on the formulation, include the principal psychoactive component,tetrahydrocannabinol , identified in the 1960s, cannabidiol , cannabinol , cannabigerol , cannabidivarin , and other compounds, such as terpenes. Each of these exerts unique pharmacological actions, with considerable evidence suggesting that the whole is greater than the sum of its parts , reflecting therapeutic synergies between all of the phytocannabinoids and phytoterpenoids.