Medical Marijuana

States and cities that have opted to legally regulate adult social use and/or medical use of marijuana:

Marijuana Legalization
(24): Alaska, Arizona, California, Colorado, Connecticut, Delaware, Illinois, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, Montana, Nevada, New Jersey, New Mexico, New York, Ohio, Oregon, Rhode Island, Vermont, Virginia, Washington.
*Note: Marijuana is also legal in Washington, DC, Guam, and the Marshall Islands, however these are not states.

Marijuana Decriminalization
(14): Connecticut, Delaware, Maryland, Hawaii, Minnesota, Mississippi, Missouri, Nebraska, New Hampshire, North Carolina, North Dakota, Ohio, Rhode Island

Medical Marijuana Legalization
(38): Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Hawaii, Illinois, Kentucky*, Louisiana*, Maine, Maryland, Massachusetts, Michigan, Minnesota*, Mississippi, Missouri, Montana, Nevada, New Hampshire, New Jersey, New Mexico, New York*, North Dakota, Ohio*, Oklahoma, Oregon, Pennsylvania*, Rhode Island, South Dakota, Utah, Vermont, Virginia, Washington, West Virginia* (also, Washington, DC)

*no smoking allowed

Medical Marijuana Legalization - CBD Oil Only
(14): Alabama, Georgia, Indiana, Iowa, Kansas, Kentucky, Mississippi, North Carolina, South Carolina, Tennessee, Texas, Virginia, Wisconsin, Wyoming

Hemp Legalization*
Hemp is now federally legal. Only two states in the country - Idaho and Mississippi - do not allow cultivation of hemp for commercial, research or pilot programs.

Cities That Have Legalized Marijuana
(5): Breckenridge, CO; Denver, CO; Portland, ME; South Portland, ME; Washington, DC

Cities That Have Decriminalized or Depenalized Marijuana
(57): Albuquerque, NM; Allentown, PA; Ann Arbor, MI; Athens, OH; Atlanta, GA; Austin, TX; Bellaire, OH; Berkeley, CA; Berkley, MI; Chicago, IL; Cincinnati, OH; Cocoa Beach, FL; Columbia, MO; Dayton, OH; Daytona Beach, FL; Detroit, MI; East Lansing, MI; Eau Claire, WI; Ferndale, MI; Flint, MI; Fremont, OH; Grand Rapids, MI; Houston, TX; Huntington Woods, MI; Jackson, MI; Jersey City, NJ; Kansas City, MO; Keego Harbor, MI; Lancaster, PA; Logan, OH; Madison, WI; Miami, FL; Milwaukee, WI; Monona, WI; Mount Pleasant, MI; New Orleans, LA; Newark, OH; Norfolk, VA; Norwood, OH; New York, NY; Oregon, OH; Orlando, FL; Philadelphia, PA; Pittsburgh, PA; Pleasant Ridge, MI; Portage, MI; Port Huron, MI; Roseville, OH; Saginaw, MI; State College, PA; Santa Fe, NM; St. Louis, MO; Tampa, FL; Toledo, OH; Wichita, KS; Windham, OH; York, PA

Cities That Have Made Marijuana Arrests the Lowest Priority
(12): Eureka Springs, AR; Fayetteville, AR; Hailey; ID; Kalamazoo, MI; Oakland, CA; San Francisco, CA; Santa Barbara, CA; Santa Cruz, CA; Santa Monica, CA; Seattle, WA; Tacoma, WA; Tampa, FL; West Hollywood, CA

States That Have Decriminalized Entheogenic Plants (including psilocybin)
(3): Colorado, New Jersey*, Oregon

*for possessing an ounce or less of mushrooms from a third-degree crime to a disorderly-persons offense

Cities That Have Decriminalized Entheogenic Plants (including psilocybin)
(8): Ann Arbor, MI; Cambridge, MA; Denver, CO; Oakland, CA; Santa Cruz, CA; Somerville, MA; Vancouver, BC; Washington, DC

Nations That Have Decriminalized Possession of Marijuana
Brazil

Nations That Have Legalized Marijuana
(4): Canada, Uruguay, Malta, Germany

Nations That Have Decriminalized Possession of Controlled Substances
(2): Portugal, Czechia

"In summary, current evidence does not support the hypothesis that MML passage is associated with increased marijuana use prevalence among adolescents in states that have passed such laws up until 2014. Based on this evidence, we recommend several steps to advance the understanding of current and future marijuana policy effects. First, continued exploration of the effects of these state policies on different measures of use among adolescents is warranted. While evidence is clear regarding MML effects on annual and past-month prevalence, evidence regarding effects on daily/near-daily use, marijuana abuse/dependence and intensity of use have not been explored as thoroughly, and warrant additional consideration in light of decreasing national trends in marijuana risk perceptions among adolescents [54,86]. Secondly, continued monitoring of adolescent marijuana use in MML states is critical in light of differential development of commercialized markets. Recent studies have shown a rapid diffusion of medical marijuana stores and increased commercialization in selective states following the 2009 Ogden memo,which de-prioritized federal enforcement against individuals compliant with state MMLs [51,75,87–89]. Studies evaluating the impact of this rapid commercialization on youth marijuana use have shown a more consistently positive effect [51,90,91]. Such findings are particularly relevant in light of recent recreational marijuana laws, all of which so far allow commercial distribution systems [92]. Thirdly, further studies should be conducted in adults, for which the limited literature suggests a positive effect of MMLs on marijuana use [65,69,75]. Fourthly, investigators should experiment with process-based models of information and product diffusion that can estimate MML effects even in the presence of spill-over effects into non-MML states [93]. Finally, increased coordination among researchers across multiple disciplines is needed to maximize efficiency in studying these urgent research questions in the context of rapidly changing marijuana policy."

"Determining exactly how many patients use medical marijuana with state approval is difficult. According to a 2002 study published in the Journal of Cannabis Therapeutics, an estimated 30,000 California patients and another 5,000 patients in eight other states possessed a physician’s recommendations to use cannabis medically.⁶⁷ More recent estimates are much higher. The New England Journal of Medicine reported in August 2005, for example, that an estimated 115,000 people have obtained marijuana recommendations from doctors in the states with programs.⁶⁸
"Although 115,000 people may be approved medical marijuana users, the number of patients who have actually registered is much lower. A July 2005 CRS telephone survey of the state programs revealed a total of 14,758 registered medical marijuana users in eight states.⁶⁹ (Maine and Washington do not maintain state registries, and Rhode Island, New Mexico, and Michigan had not yet passed their laws.) This number vastly understates the number of medical marijuana users, however, because California’s state registry was in pilot status, with only 70 patients so far registered."

"Moving marijuana from Schedule I to Schedule III, without other legal changes, would not bring the state-legal medical or recreational marijuana industry into compliance with federal controlled substances law. With respect to medical marijuana, a key difference between placement in Schedule I and Schedule III is that substances in Schedule III have an accepted medical use and may lawfully be dispensed by prescription, while Substances in Schedule I cannot. However, prescription drugs must be approved by the Food and Drug Administration (FDA). Although FDA has approved some drugs derived from or related to cannabis, marijuana itself is not an FDA-approved drug. Moreover, if one or more marijuana products obtained FDA approval, manufacturers and distributors would need to register with DEA and comply with regulatory requirements that apply to Schedule III substances in order to handle those products. Users of medical marijuana would need to obtain valid prescriptions for the substance from medical providers, subject to federal legal requirements that differ from existing state regulatory requirements for medical marijuana. 

"Rescheduling marijuana would not affect the medical marijuana appropriations rider. Thus, so long as the current rider remains in effect, participants in the state-legal medical marijuana industry who comply with state law would be shielded from federal prosecution. If the rider were to lapse or be repealed, these persons would again be subject to prosecution at the discretion of DOJ. 

"With respect to the manufacture, distribution, and possession of recreational marijuana, if marijuana were moved to Schedule III, such activities would remain illegal under federal law and potentially subject to federal prosecution regardless of their status under state law. 

"Some criminal penalties for CSA violations depend on the schedule in which a substance is classified. If marijuana were moved to Schedule III, applicable penalties for some offenses would be reduced. However, CSA penalties that apply to activities involving marijuana specifically, such as the quantity-based mandatory minimum sentences discussed above, would not change as a result of rescheduling. DEA is not required to set annual production quotas for Schedule III controlled substances. 

"The prohibition on business deductions in Section 280E of the Internal Revenue Code applies to any trade or business that “consists of trafficking in controlled substances (within the meaning of schedule I and II of the Controlled Substances Act) which is prohibited by Federal law or the law of any State in which such trade or business is conducted.” Because the provision applies only to activities involving substances in Schedule I or II, moving marijuana from Schedule I to Schedule III would allow marijuana businesses to deduct business expenses on federal tax filings. Other collateral legal consequences would continue to attach to unauthorized marijuana-related activities."

"The primary care sample of patients who used cannabis (n = 1463 patient respondents weighted to primary care population who used cannabis) was predominantly middle-aged (weighted mean [SD] age, 47.4 [16.8] years); female (748 [weighted proportion, 61.9%] vs 715 male [weighted proportion, 38.1%]), and commercially insured (935 [61.1%]) (Table 1). By self-report, 12 patients (weighted proportion, 0.2%) were American Indian or Alaska Native, 56 (weighted proportion, 2.4%) were Asian, 120 (weighted proportion, 4.9%) were Black, 10 (weighted proportion, 0.2%) were Native Hawaiian or Other Pacific Islander, 1029 (weighted proportion, 78.6%) were White, 95 (weighted proportion, 5.3%) reported multiple races, and 141 (weighted proportion, 8.3%) were of another or unknown race; 151 (weighted proportion, 3.5%) reported Hispanic ethnicity and 1239 (weighted proportion, 9.3%) non-Hispanic ethnicity.

"Among patients who used cannabis, the prevalence of patient reasons for cannabis use included 42.4% (95% CI, 31.2%-54.3%) reporting medical use only, 25.1% (95% CI, 17.8%-34.2%) reporting nonmedical use only, and 32.5% (95% CI, 25.3%-40.8%) reporting both reasons for use. Patients reporting medical use only tended to be older (mean [SD] age, 53.6 [14.6] years), were mostly female (142 [76.5%]), retired (67 [33.6%]), and mostly had Medicare (84 [33.7%]). The prevalence of patients who reported any medical cannabis use (ie, medical use only or both reasons for use) was 74.7% (95% CI, 65.7%-82.1%), while the prevalence of any reported nonmedical cannabis use (ie, nonmedical use only or both reasons for use) was 57.5% (95% CI, 45.6%-68.6%).

"The prevalence of any CUD was 21.3% (95% CI, 15.4%-28.6%) and did not differ depending on patient reasons for use (Table 2). The prevalence of moderate to severe CUD was 6.5% (95% CI, 5.0%-8.6%) and differed across groups: 1.3% (95% CI, 0.0%-2.8%) for medical use only; 7.2% (95% CI, 3.9%-10.4%) for nonmedical use only; and 7.5% (95% CI, 5.7%-9.4%) both reasons for use (P = .01). For all groups, the most prevalent CUD symptoms were tolerance, uncontrolled escalation of use and craving. Compared with patients with medical use only, patients with nonmedical use only or both reasons for use were more likely to report withdrawal, use in hazardous situations, continue use despite consequences, time spent on use, interference with obligations, and activities given up."

"In this cross-sectional study of primary care patients in a state with legal recreational cannabis use, CUD was common among patients who used cannabis, with 21% having CUD and 6% having moderate to severe CUD. Patients who used cannabis for medical reasons only were mostly older and likely to use applied products. Patients who reported any nonmedical use were at greatest risk of moderate to severe CUD (7.2% to 7.5%). While the prevalence of moderate to severe CUD was lowest among patients who reported medical use only (1.3%), 13.4% met criteria for mild, moderate, or severe CUD.

"The prevalence of CUD among patients who use cannabis found here is comparable to recent studies of patients who use cannabis in states with legal medical and recreational use.^12,27 Moreover, comparable to the study by Browne et al,¹² the prevalence of moderate to severe CUD in this study was significantly lower for patients reporting medical use only.

"The finding that CUD was common among primary care patients in a state with legal recreational use, where more than 20% of the population reports cannabis use,¹³ underscores the importance of assessing patient cannabis use in clinical settings. Population-based screening with a validated single-item screen can identify patients who use cannabis and may be at risk of CUD.²² Knowledge of patient use provides an opportunity to discuss risks and limited benefits of cannabis use and potentially safer treatment alternatives for those using cannabis for medical reasons.²⁸ For patients with higher risk cannabis use (eg, daily), psychometrically valid brief assessments for DSM-5 symptoms of CUD can identify and gauge CUD severity.²⁹ Such knowledge can support engagement around symptoms, shared decision-making, and offering of treatment if desired, especially for patients with moderate to severe CUD who may benefit most from treatment. Yet research is needed on how best to assess and document patient reasons for cannabis use and to engage individuals with CUD in treatment."

"Concerns about laws and policy measures that may inadvertently affect youth drug use merit careful consideration. Our study does not show evidence of a clear relationship between legalization of marijuana for medical purposes and youth drug use for any age group, which may provide some reassurance to policymakers who wish to balance compassion for individuals who have been unable to find relief from conventional medical therapies with the safety and well-being of youth. Further research is required to track the trends in marijuana use among adolescents, particularly with respect to different types of marijuana laws and implementation of laws in each state."

"Recent developments suggest that non-psychotropic phytocannabinoids exert a wide range of pharmacological effects (Figure 1), many of which are of potential therapeutic interest. The most studied among these compounds is CBD, the pharmacological effects of which might be explained, at least in part, by a combination of mechanisms of action (Table 1, Figure 1). CBD has an extremely safe profile in humans, and it has been clinically evaluated (albeit in a preliminary fashion) for the treatment of anxiety, psychosis, and movement disorders. There is good pre-clinical evidence to warrant clinical studies into its use for the treatment of diabetes, ischemia and cancer. The design of further clinical trials should: i) consider the bell-shaped pattern of the dose–response curve that has been observed in pre-clinical pharmacology, and ii) establish if CBD is more effective or has fewer unwanted effects than other medicines. A sublingual spray that is a standardized Cannabis extract containing approximately equal quantities of CBD and D9-THC (Sativex^®), has been shown to be effective in treating neuropathic pain in multiple sclerosis patients [76].
"The pharmacology of D9-THCV (i.e. CB1 antagonism associated with CB2 agonist effects) is also intriguing because it has the potential of application in diseases such as chronic liver disease or obesity—when it is associated with inflammation—in which CB1 blockade together with some CB2 activation is beneficial.
"The plant Cannabis is a source of several other neglected phytocannabinoids such as CBC and CBG. Although the spectrum of pharmacological effects of these compounds is largely unexplored, their potent action at TRPA1 and TRPM8 might make these compounds new and attractive tools for pain management."

"Cannabis preparations exert numerous therapeutic effects. They have antispastic, analgesic, antiemetic, neuroprotective, and anti-inflammatory actions, and are effective against certain psychiatric diseases. Currently, however, only one cannabis extract is approved for use. It contains THC and CBD [cannabidiol] in a 1:1 ratio and was licensed in 2011 for treatment of moderate to severe refractory spasticity in multiple sclerosis (MS). In June 2012 the German Joint Federal Committee (JFC, Gemeinsamer Bundesausschuss) pronounced that the cannabis extract showed a 'slight additional benefit' for this indication and granted a temporary license valid up to 2015.
"The cannabis extract, which goes by the generic name nabiximols, has been approved by regulatory bodies in Germany and elsewhere for use as a sublingual spray. In the USA, dronabinol has been licensed since 1985 for the treatment of nausea and vomiting caused by cytostatic therapy and since 1992 for loss of appetite in HIV/Aids-related cachexia. In Great Britain, nabilone has been sanctioned for treatment of the side effects of chemotherapy in cancer patients (Box 1).
"In addition to these confirmed indications, there is solid evidence from a large number of small controlled trials that cannabinoid receptor agonists have an analgesic action, particularly in neuropathic pain; however, no country has yet approved their use for this purpose."

"Evidence is accumulating that cannabinoids may be useful medicine for certain indications. Control of nausea and vomiting and the promotion of weight gain in chronic inanition are already licensed uses of oral THC (dronabinol capsules). Recent research indicates that cannabis may also be effective in the treatment of painful peripheral neuropathy and muscle spasticity from conditions such as multiple sclerosis [58]. Other indications have been proposed, but adequate clinical trials have not been conducted. As these therapeutic potentials are confirmed, it will be useful if marijuana and its constituents can be prescribed, dispensed, and regulated in a manner similar to other medications that have psychotropic effects and some abuse potential. Given that we do not know precisely which cannabinoids or in which combinations achieve the best results, larger and more representative clinical trials of the plant product are warranted. Because cannabinoids are variably and sometimes incompletely absorbed from the gut, and bioavailability is reduced by extensive first pass metabolism, such trials should include delivery systems that include smoking, vaporization, and oral mucosal spray in order to achieve predictable blood levels and appropriate titration. Advances in understanding the medical indications and limitations of cannabis in its various forms should facilitate the regulatory and legislative processes."

"We synthesised available evidence on the safety and efficacy of cannabinoids as an adjunctive treatment to conventional AEDs [Antiepileptic Drugs] in treating drug-resistant epilepsy. In many cases, there was qualitative evidence that cannabinoids reduced seizure frequency in some patients, improved other aspects of the patients’ quality of life and were generally well tolerated with mild-to-moderate AEs [Adverse Events]. We can be much more confident about this statement in the case of children than adults, because the recent, larger, well-conducted RCTs [Randomized Controlled Trials] were performed in children and adolescents.

"In studies where there was greater experimental control over the type and dosage of cannabinoid used, there was evidence that adjuvant use of CBD reduced the frequency of seizures, particularly in treatment-resistant children and adolescents, and that patients were more likely to achieve complete seizure freedom. There was a suggestion that the benefits of adding CBD may be greater when patients were also using clobazam.^{11 12} However because clobazam and CBD are both metabolised in the cytochrome P450 pathway, the pharmacokinetic interactions of these two drugs still need to be fully determined ⁵⁶ Further randomised, double-blind studies with a placebo or active control are needed to strengthen this conclusion.

"Non-RCT evidence was consistent with RCT evidence that suggested cannabinoids may reduce the frequency of seizures. In most of these studies, cannabinoid products and dosages were less well-controlled, and outcomes were based on self-report (often by parents). These studies provide lower quality evidence compared with RCTs due to the potential for selection bias in the study populations, and other weaknesses in study design. There was also some evidence that studies at very high risk of bias had higher reported proportions of participants reporting reductions in seizures and lower proportions reporting AEs. In RCTs, and most of the non-RCTs, cannabinoids were used as an adjunctive therapy rather than as a standalone intervention, so at present there is little evidence to support any recommendation that cannabinoids can be recommended as a replacement for current standard AEDs."

"The opioid epidemic is a public health crisis that is at least partially driven by harms associated with POM [Prescription Opioid Medication] use. States are passing laws allowing use of MC [Medical Cannabis] and patients are using MC, but currently there is little understanding of how this influences POM use or of MC-related harms. This literature review provides preliminary evidence that states with MC laws have experienced reported decreases in POM use, abuse, overdose, and costs. However, existing evidence is limited by significant methodological shortcomings; so, general conclusions are difficult to draw.

"The use of MC as an alternative to POMs for pain management warrants additional empirical attention as a potential harm reduction strategy. NASEM (2017) recommends more clinical trials to elucidate appropriate MC forms, routes of administration, and combination of products for treating pain, but access to MC products to fully evaluate these questions is challenging due to federal regulations. However, the recently funded National Institutes of Health longitudinal study to research the impacts of MC on opioid use is a critical step in the right direction (National Institute of Health, 2017, Williams, 2017). MCs potential as an alternative pain treatment modality to help mitigate the major public health opioid crisis, could be a missed opportunity if data on safety, efficacy, and outcomes are not collected and explored. Health care practitioners, particularly nurses who are charged with ensuring patient comfort, have a vested interest in providing viable alternatives to POMs when appropriate, as part of an integrative approach to pain management, and must advocate for more research to better understand the public health implications and risks and benefits of such alternatives."

"In conclusion, our study of self-reported marijuana use by adolescents in states with a medical marijuana policy compared with a sample of geographically similar states without a policy does not demonstrate increases in marijuana use among high school students that may be attributed to the policies."

"The use of MC [Medical Cannabis] as an alternative to POMs [Prescription Opioid Medications] for pain management warrants additional empirical attention as a potential harm reduction strategy. NASEM (2017) recommends more clinical trials to elucidate appropriate MC forms, routes of administration, and combination of products for treating pain, but access to MC products to fully evaluate these questions is challenging due to federal regulations. However, the recently funded National Institutes of Health longitudinal study to research the impacts of MC on opioid use is a critical step in the right direction (NIH, 2017; Williams, 2017). MCs potential as an alternative pain treatment modality to help mitigate the major public health opioid crisis, could be a missed opportunity if data on safety, efficacy, and outcomes are not collected and explored. Health care practitioners, particularly nurses who are charged with ensuring patient comfort, have a vested interest in providing viable alternatives to POMs when appropriate, as part of an integrative approach to pain management, and must advocate for more research to better understand the public health implications and risks and benefits of such alternatives."

"Essentially a herbal cannabinoid drug, the resin-secreting flowers of select varietals of the female cannabis plant contain approximately 6 dozen of different phytocannabinoids or plant-derived cannabinoids; these compounds are generally classified structurally as terpenophenolics with a 21-carbon molecular scaffold.²⁴ Other compounds, such as terpenoids, flavonoids, and phytosterols, which are common to many other botanicals, are also produced by cannabis and have some demonstrated pharmacologic properties.^25,26 The best known naturally produced analgesic cannabinoids generally found in highest concentrations are THC and cannabidiol. They occur in their acid forms in herbal cannabis and must be decarboxylated to become activated. Five minutes of heating at 200 to 210°C has been determined as the optimal conditions for maximal decarboxylation; with a flame, where temperatures of 600°C are achieved, only a few seconds are needed.²⁷"

"Some studies indicate that under certain circumstances, CBD acute anxiolytic effects in rats were reversed after repeated 14-day administration of CBD.2 However, this finding might depend on the used animal model of anxiety or depression. This is supported by a study, where CBD was administered in an acute and “chronic” (2 weeks) regimen, which measured anxiolytic/antidepressant effects, using behavioral and operative models (OBX=olfactory bulbectomy as model for depression).18 The only observed side effects were reduced sucrose preference, reduced food consumption and body weight in the nonoperated animals treated with CBD (50 mg/kg). Nonetheless, the behavioral tests (for OBX-induced hyperactivity and anhedonia related to depression and open field test for anxiety) in the CBD-treated OBX animals showed an improved emotional response. Using microdialysis, the researchers could also show elevated 5-HT and glutamate levels in the prefrontal cortex of OBX animals only. This area was previously described to be involved in maladaptive behavioral regulation in depressed patients and is a feature of the OBX animal model of depression. The fact that serotonin levels were only elevated in the OBX mice is similar to CBD differential action under physiological and pathological conditions.

"A similar effect was previously described in anxiety experiments, where CBD proved to be only anxiolytic in subjects where stress had been induced before CBD administration. Elevated glutamate levels have been proposed to be responsible for ketamine's fast antidepressant function and its dysregulation has been described in OBX mice and depressed patients. Chronic CBD treatment did not elicit behavioral changes in the nonoperated mice. In contrast, CBD was able to alleviate the affected functionality of 5HT1A receptors in limbic brain areas of OBX mice.18 and references therein

"Schiavon et al. cite three studies that used chronic CBD administration to demonstrate its anxiolytic effects in chronically stressed rats, which were mostly mediated via hippocampal neurogenesis.19 and references therein For instance, animals received daily i.p. injections of 5 mg/kg CBD. Applying a 5HT1A receptor antagonist in the DPAG (dorsal periaqueductal gray area), it was implied that CBD exerts its antipanic effects via these serotonin receptors. No adverse effects were reported in this study."

"Various studies on CBD and psychosis have been conducted.²⁰ For instance, an animal model of psychosis can be created in mice by using the NMDAR antagonist MK-801. The behavioral changes (tested with the prepulse inhibition [PPI] test) were concomitant with decreased mRNA expression of the NMDAR GluN1 subunit gene (GRN1) in the hippocampus, decreased parvalbumin expression (=a calcium-binding protein expressed in a subclass of GABAergic interneurons), and higher FosB/ΔFosB expression (=markers for neuronal activity). After 6 days of MK-801 treatment, various CBD doses were injected intraperitoneally (15, 30, 60 mg/kg) for 22 days. The two higher CBD doses had beneficial effects comparable to the atypical antipsychotic drug clozapine and also attenuated the MK-801 effects on the three markers mentioned above. The publication did not record any side effects.²¹

"One of the theories trying to explain the etiology of bipolar disorder (BD) is that oxidative stress is crucial in its development. Valvassori et al. therefore used an animal model of amphetamine-induced hyperactivity to model one of the symptoms of mania. Rats were treated for 14 days with various CBD concentrations (15, 30, 60 mg/kg daily i.p.). Whereas CBD did not have an effect on locomotion, it did increase brain-derived neurotrophic factor (BDNF) levels and could protect against amphetamine-induced oxidative damage in proteins of the hippocampus and striatum. No adverse effects were recorded in this study.²²

"Another model for BD and schizophrenia is PPI of the startle reflex both in humans and animals, which is disrupted in these diseases. Peres et al., list five animal studies, where mostly 30 mg/kg CBD was administered and had a positive effect on PPI.20 Nonetheless, some inconsistencies in explaining CBD effects on PPI as model for BD exist. For example, CBD sometimes did not alter MK-801-induced PPI disruption, but disrupted PPI on its own.²⁰ If this effect can be observed in future experiments, it could be considered to be a possible side effect."

"Today, CBD is used for the treatment of a wide range of medical conditions. This started with the somewhat serendipitous discovery (by parents experimenting with self-medication for their children) that CBD had a therapeutic effect on a serious form of epilepsy in children, called Dravet syndrome [8]. This effect is now under clinical investigation with the pharmaceutical CBD product Epidiolex®, which is currently in phase 3 trials with encouraging results [9, 10]. The media attention generated by its effect on severely ill children gave CBD the push needed to become a much desired medicine almost overnight [11]. Other medical indications that may be treated with CBD, and are supported to some extent by clinical proof, include Parkinson’s disease [12], schizophrenia [13], and anxiety disorder [14]. However, although research into the therapeutic effects of CBD is rapidly increasing, most current uses of CBD are not (yet) supported by clinical data. The popular use of these products means that physicians may be confronted with the effects of CBD oil even when they do not prescribe it themselves.

"An excellent example is the use of CBD (and also THC) products for the self-medicating of cancer, with the intention of fully curing it [15]. This is based on an increasing body of preclinical evidence showing cannabinoids to be capable, under some conditions, of inhibiting the development of cancer cells in vitro or in vivo by various mechanisms of action, including induction of apoptosis, inhibition of angiogenesis, and arresting the cell cycle [16]. This is certainly exciting news, and research is ongoing around the world, but there is no solid clinical evidence yet to support that cannabinoids – whether natural or synthetic – can effectively and safely treat cancer in actual humans [17]. In fact, there are indications that certain types of cancer may even accelerate when exposed to cannabinoids [18]. This becomes problematic when patients choose to refuse chemotherapy treatment because they firmly believe in the rumored curative properties of cannabinoids. As a result, recommendation of cannabinoids for treating cancer should be done with great care, and with distinction as to the type of cancer being treated [19]."

"Generally, as analgesics, cannabinoids have minimal toxicity and present no risk of lethal overdose.⁴⁸ End-organ failure secondary to medication effect has not been described and no routine laboratory monitoring is required in patients taking these medications."

"CBD, which is nonhedonic, can reduce heroin-seeking behavior after, for example, cue-induced reinstatement. This was shown in an animal heroin self-administration study, where mice received 5 mg/kg CBD i.p. injections. The observed effect lasted for 2 weeks after CBD administration and could normalize the changes seen after stimulus cue-induced heroin seeking (expression of AMPA, GluR1, and CB1R). In addition, the described study was able to replicate previous findings showing no CBD side effects on locomotor behavior.²³"

"There are various mechanisms underlying neuroprotection, for example, energy metabolism (whose alteration has been implied in several psychiatric disorders) and proper mitochondrial functioning.²⁴ An early study from 1976 found no side effects and no effect of 0.3–300 μg/mg protein CBD after 1 h of incubation on mitochondrial monoamine oxidase activity in porcine brains.²⁵ In hypoischemic newborn pigs, CBD elicited a neuroprotective effect, caused no side effects, and even led to beneficial effects on ventilatory, cardiac, and hemodynamic functions.²⁶

"A study comparing acute and chronic CBD administration in rats suggests an additional mechanism of CBD neuroprotection: Animals received i.p. CBD (15, 30, 60 mg/kg b.w.) or vehicle daily, for 14 days. Mitochondrial activity was measured in the striatum, hippocampus, and the prefrontal cortex.²⁷ Acute and chronic CBD injections led to increased mitochondrial activity (complexes I-V) and creatine kinase, whereas no side effects were documented. Chronic CBD treatment and the higher CBD doses tended to affect more brain regions. The authors hypothesized that CBD changed the intracellular Ca2+ flux to cause these effects. Since the mitochondrial complexes I and II have been implied in various neurodegenerative diseases and also altered ROS (reactive oxygen species) levels, which have also been shown to be altered by CBD, this might be an additional mechanism of CBD-mediated neuroprotection.^1,27

"Interestingly, it has recently been shown that the higher ROS levels observed after CBD treatment were concomitant with higher mRNA and protein levels of heat shock proteins (HSPs). In healthy cells, this can be interpreted as a way to protect against the higher ROS levels resulting from more mitochondrial activity. In addition, it was shown that HSP inhibitors increase the CBD anticancer effect in vitro.²⁸ This is in line with the studies described by Bergamaschi et al., which also imply ROS in CBD effect on (cancer) cell viability in addition to, for example, proapoptotic pathways such as via caspase-8/9 and inhibition of the procarcinogenic lipoxygenase pathway.¹

"Another publication studied the difference of acute and chronic administration of two doses of CBD in nonstressed mice on anxiety. Already an acute i.p. administration of 3 mg/kg was anxiolytic to a degree comparable to 20 mg/kg imipramine (an selective serotonin reuptake inhibitor [SSRI] commonly prescribed for anxiety and depression). Fifteen days of repeated i.p. administration of 3 mg/kg CBD also increased cell proliferation and neurogenesis (using three different markers) in the subventricular zone and the hippocampal dentate gyrus. Interestingly, the repeated administration of 30 mg/kg also led to anxiolytic effects. However, the higher dose caused a decrease in neurogenesis and cell proliferation, indicating dissociation of behavioral and proliferative effects of chronic CBD treatment. The study does not mention adverse effects.¹⁹"

"Numerous studies show the CBD immunomodulatory role in various diseases such as multiple sclerosis, arthritis, and diabetes. These animal and human ex vivo studies have been reviewed extensively elsewhere, but studies with pure CBD are still lacking. Often combinations of THC and CBD were used. It would be especially interesting to study when CBD is proinflammatory and under which circumstances it is anti-inflammatory and whether this leads to side effects (Burstein, 2015: Table 1 shows a summary of its anti-inflammatory actions; McAllister et al. give an extensive overview in Table 1 of the interplay between CBD anticancer effects and inflammation signaling).^29,30

"In case of Alzheimer's disease (AD), studies in mice and rats showed reduced amyloid beta neuroinflammation (linked to reduced interleukin [IL]-6 and microglial activation) after CBD treatment. This led to amelioration of learning effects in a pharmacological model of AD. The chronic study we want to describe in more detail here used a transgenic mouse model of AD, where 2.5-month-old mice were treated with either placebo or daily oral CBD doses of 20 mg/kg for 8 months (mice are relatively old at this point). CBD was able to prevent the development of a social recognition deficit in the AD transgenic mice.

"Moreover, the elevated IL-1 beta and TNF alpha levels observed in the transgenic mice could be reduced to WT (wild-type) levels with CBD treatment. Using statistical analysis by analysis of variance, this was shown to be only a trend. This might have been caused by the high variation in the transgenic mouse group, though. Also, CBD increased cholesterol levels in WT mice but not in CBD-treated transgenic mice. This was probably due to already elevated cholesterol in the transgenic mice. The study observed no side effects.^{31 and references within}

"In nonobese diabetes-prone female mice (NOD), CBD was administered i.p. for 4 weeks (5 days a week) at a dose of 5 mg/kg per day. After CBD treatment was stopped, observation continued until the mice were 24 weeks old. CBD treatment lead to considerable reduction of diabetes development (32% developed glucosuria in the CBD group compared to 100% in untreated controls) and to more intact islet of Langerhans cells. CBD increased IL-10 levels, which is thought to act as an anti-inflammatory cytokine in this context. The IL-12 production of splenocytes was reduced in the CBD group and no side effects were recorded.³²

"After inducing arthritis in rats using Freund's adjuvant, various CBD doses (0.6, 3.1, 6.2, or 62.3 mg/day) were applied daily in a gel for transdermal administration for 4 days. CBD reduced joint swelling, immune cell infiltration. thickening of the synovial membrane, and nociceptive sensitization/spontaneous pain in a dose-dependent manner, after four consecutive days of CBD treatment. Proinflammatory biomarkers were also reduced in a dose-dependent manner in the dorsal root ganglia (TNF alpha) and spinal cord (CGRP, OX42). No side effects were evident and exploratory behavior was not altered (in contrast to Δ9-THC, which caused hypolocomotion).³³"

"Although the mean annual opioid analgesic overdose mortality rate was lower in states with medical cannabis laws compared with states without such laws, the findings of our secondary analyses deserve further consideration. State-specific characteristics, such as trends in attitudes or health behaviors, may explain variation in medical cannabis laws and opioid analgesic overdose mortality, and we found some evidence that differences in these characteristics contributed to our findings. When including state-specific linear time trends in regression models, which are used to adjust for hard-to-measure confounders that change over time, the association between laws and opioid analgesic overdose mortality weakened. In contrast, we did not find evidence that states that passed medical cannabis laws had different overdose mortality rates in years prior to law passage, providing a temporal link between laws and changes in opioid analgesic overdose mortality. In addition, we did not find evidence that laws were associated with differences in mortality rates for unrelated conditions (heart disease and septicemia), suggesting that differences in opioid analgesic overdose mortality cannot be explained by broader changes in health. In summary, although we found a lower mean annual rate of opioid analgesic mortality in states with medical cannabis laws, a direct causal link cannot be established."

"Of key importance in the findings are the unmet health needs of these youth. Health issues such as depression, insomnia, and anxiety were significant problems that interfered with these youths' ability to function at school, maintain relationships with family and friends, and feel that they could live a normal life. The level of distress associated with these health concerns, along with the lack of effective interventions by heath care providers and family members appeared to leave them with few alternatives. Researchers have reported that when adolescents in rural communities experience barriers to seeking health care, they think they can take care of the problems themselves [30]. Similarly, our study participants believed that their best option was to assume responsibility for treating their problems by using marijuana. Unpleasant side effects with prescribed medications and long, ineffective therapies resulted in little hope that the medical system could be counted on as beneficial. In contrast, marijuana provided these youth with immediate relief for a variety of health concerns. Nevertheless, the regular use of marijuana put youth at risk. Cannabis use has been identified as a risk factor for mental illness such as psychosis, schizophrenia [21,31,32] and psychiatric symptoms such as panic attacks [33]. Teens who smoked marijuana at least once per month in the past year were found to be three times more likely to have suicidal thoughts than non-users [34], and there is evidence that exposure to cannabis may worsen depression in youth [35]. Marijuana use among youth has also been associated with other substance use and school failure [36]. What is interesting is that the findings of this study suggest that youth have little awareness of some of these risks; rather, some are using marijuana to counteract these very problems (e.g., depression, school failure). Teens' perceptions that their health concerns were not addressed suggest that more attention is needed to assess these issues and ensure that other options are available to them. Parents and health care providers need to make a concerted effort to not only understand the pressures and influences on youth [37], but also gain a better understanding of the effect of youths' health problems on their ability to engage in healthy lifestyle choices."

"We replicated the findings of Wall et al. (2) that marijuana use was higher in states that have passed MMLs, and our analysis suggests this is unlikely to be a causal association. Our difference-in-differences estimates suggest little detectable effects of passing MMLs on marijuana use or perceived riskiness of use among adolescents or adults, which is consistent with some limited prior evidence on arrestees and emergency department patients (17). Future analyses that take advantage of additional policy changes may provide further evidence on this question, but our results suggest that such analyses should adequately control for potential confounding by unmeasured state characteristics."

"We found no evidence of intermediate-term effects of passage of state MMLs on the prevalence or frequency of adolescent nonmedical marijuana use in the states evaluated, with 2 minor exceptions. From 2003 through 2009, adolescent lifetime prevalence of marijuana use and frequency of daily marijuana use decreased significantly in Montana, as compared with a more modest decrease in lifetime prevalence and an increase in daily frequency observed in Delaware (Ps = .03). These 2 statistically significant findings do not appear to represent real effects. Our difference-in-differences study design involved 40 planned comparisons (before---after differences in treatment vs comparison states), and naturally 2 significant results (at the P < .05 level) of a possible 40 can be expected according to chance alone.
"Moreover, the pattern is not consistent with an effect of MMLs. A significant effect was found for lifetime marijuana use but not past-month marijuana use. Self-reported lifetime use requires a much longer recall period than past-month use and is characterized by higher measurement error.13 Also, one would expect the 30-day use measure to be more sensitive than lifetime use to the effects of a change in MMLs, because most of the period covered by respondents’ lifetime reports occurred before passage of an MML.
"Finally, the significant increase in daily marijuana use was observed for the comparison state of Delaware, which had not enacted an MML during the years under evaluation, whereas the frequency of daily marijuana use in Montana decreased. This is the opposite of
what would be expected if MMLs had the deleterious effect of increasing the frequency of nonmedical marijuana use.
"Conversely, the significant effects observed were found between the 2 states that differed the most on the timing of MML enactment, maximizing the length of the follow-up period. Hence, it is reasonable to suspect that enacting an MML may influence the prevalence and frequency of adolescent nonmedical marijuana use half a decade later, despite no evidence of more proximal effects."

"Underlying problems related to youth health concerns also need to be addressed. In many situations, the participants' symptoms appeared to be directly related to their life circumstances. Along with the challenges inherent in being an adolescent in today's complex world, some teens were also trying to deal with significant losses (death of a close friend or family member), extremely difficult family relationships, disappointments with friends, school and sports, and a fragile family and peer support network. The risk of substance use increases substantially when youth are attempting to deal with these kinds of situations in isolation. Although marijuana provided the youth with temporary relief, the underlying situation often went unattended – leading the teens into a regular pattern of use. Appropriate guidance and targeted support from counselors and health care providers must be sensitive to meeting the needs of youth as they work through such situations and life altering events. In addition, adults working with youth must find better ways to talk with young people about how they are coping with their health issues, including their marijuana use. Based on the experiences of youth in this study, there is a wide range of support that may benefit youth including counseling, stress management, social skills training, anger management, study skills, pain management, and sleep hygiene. The youth in this study had minimal access to these types of resources."

"A growing body of literature provides compelling evidence that CBD has anxiolytic effects and recent studies have established a role for CBD in regulating learned fear by dampening its expression, disrupting its reconsolidation, and facilitating its extinction. The opposing effects of CBD on fear memory reconsolidation and extinction make it particularly attractive as a potential adjunct to psychological therapy as both may lead to lasting reductions in learned fear expression. Our novel data also suggests that CBD reduces the expression of fear memory related to both discrete and contextual cues. Although we found no effect of CBD on auditory fear extinction, decreasing fear expression during extinction without interfering in its encoding is still a useful property that has clinical implications. In this respect CBD might be an improvement over other available drugs used for treating the fear-related symptoms of phobias and PTSD, which can impair extinction (e.g., benzodiazepines) or have a less favorable side effect profile (e.g., antidepressants)."

"The central finding gleaned from the present study was that MML [Medical Marijuana Legalization] is not predictive of higher crime rates and may be related to reductions in rates of homicide and assault. Interestingly, robbery and burglary rates were unaffected by medicinal marijuana legislation, which runs counter to the claim that dispensaries and grow houses lead to an increase in victimization due to the opportunity structures linked to the amount of drugs and cash that are present. Although, this is in line with prior research suggesting that medical marijuana dispensaries may actually reduce crime in the immediate vicinity [8]."

"In sum, these findings run counter to arguments suggesting the legalization of marijuana for medical purposes poses a danger to public health in terms of exposure to violent crime and property crimes. To be sure, medical marijuana laws were not found to have a crime exacerbating effect on any of the seven crime types. On the contrary, our findings indicated that MML precedes a reduction in homicide and assault. While it is important to remain cautious when interpreting these findings as evidence that MML reduces crime, these results do fall in line with recent evidence [29] and they conform to the longstanding notion that marijuana legalization may lead to a reduction in alcohol use due to individuals substituting marijuana for alcohol [see generally 29, 30]. Given the relationship between alcohol and violent crime [31], it may turn out that substituting marijuana for alcohol leads to minor reductions in violent crimes that can be detected at the state level. That said, it also remains possible that these associations are statistical artifacts (recall that only the homicide effect holds up when a Bonferroni correction is made)."

"Given that the current results failed to uncover a crime exacerbating effect attributable to MML [Medical Marijuana Legalization], it is important to examine the findings with a critical eye. While we report no positive association between MML and any crime type, this does not prove MML has no effect on crime (or even that it reduces crime). It may be the case that an omitted variable, or set of variables, has confounded the associations and masked the true positive effect of MML on crime. If this were the case, such a variable would need to be something that was restricted to the states that have passed MML, it would need to have emerged in close temporal proximity to the passage of MML in all of those states (all of which had different dates of passage for the marijuana law), and it would need to be something that decreased crime to such an extent that it ‘‘masked’’ the true positive effect of MML (i.e., it must be something that has an opposite sign effect between MML [e.g., a positive correlation] and crime [e.g., a negative correlation]). Perhaps the more likely explanation of the current findings is that MML laws reflect behaviors and attitudes that have been established in the local communities. If these attitudes and behaviors reflect a more tolerant approach to one another’s personal rights, we are unlikely to expect an increase in crime and might even anticipate a slight reduction in personal crimes."

"The use of a vaporizing device may mitigate some of these symptoms. Cannabis vaporization is a technique aimed at suppressing the formation of irritating respiratory toxins by heating cannabis to a temperature where active cannabinoids are volatilized, but below the point of combustion where smoke and associated toxins form. The use of a vaporizer is associated with higher plasma THC concentrations than smoking marijuana cigarettes, little if any carbon monoxide production, and significantly fewer triggered respiratory symptoms."

In 1988, the DEA's Administrative Law Judge, Francis Young, concluded: "In strict medical terms marijuana is far safer than many foods we commonly consume. For example, eating 10 raw potatoes can result in a toxic response. By comparison, it is physically impossible to eat enough marijuana to induce death. Marijuana in its natural form is one of the safest therapeutically active substances known to man. By any measure of rational analysis marijuana can be safely used within the supervised routine of medical care."

“Placebo-Controlled, Double Blind Trial of Medicinal Cannabis in Painful HIV Neuropathy”
Ronald J. Ellis, M.D., Ph.D., University of California, San Diego
(cannabis and HIV neuropathy) "The primary objective of this study also was to evaluate the efficacy of smoked cannabis when used as an analgesic in persons with HIV-associated painful neuropathy. In a double-blind, randomized, clinical trial of the short-term adjunctive treatment of neuropathic pain in HIV-associated distal sensory polyneuropathy, participants received either smoked cannabis or placebo cannabis cigarettes. A structured dose escalation-titration protocol was used to find an individualized, effective, safe, and well-tolerated dose for each subject. Participants continued on their usual analgesic medications throughout the trial, with the dose and amount of these medications being recorded daily.
"The full results of this study were published in the journal Neuropsychopharmacology (Ellis, et al., 2008 – see reference list). In brief, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among completers, pain relief was significantly greater with cannabis than placebo. The proportion of subjects achieving at least 30% pain relief was again significantly greater with cannabis (46%) compared to placebo (18%). It was concluded that smoked cannabis was generally well-tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV-associated neuropathy."

"• Cannabinoids, the active components of Cannabis sativa and their derivatives, act in the organism by mimicking endogenous substances, the endocannabinoids, that activate specific cannabinoid receptors. Cannabinoids exert palliative effects in patients with cancer and inhibit tumour growth in laboratory animals.
"• The best-established palliative effect of cannabinoids in cancer patients is the inhibition of chemotherapy-induced nausea and vomiting. Today, capsules of ?9-tetrahydrocannabinol (dronabinol (Marinol)) and its synthetic analogue nabilone (Cesamet) are approved for this purpose.
"• Other potential palliative effects of cannabinoids in cancer patients — supported by Phase III clinical trials — include appetite stimulation and pain inhibition. In relation to the former, dronabinol is now prescribed for anorexia associated with weight loss in patients with AIDS.
"• Cannabinoids inhibit tumour growth in laboratory animals. They do so by modulating key cell-signalling pathways, thereby inducing direct growth arrest and death of tumour cells, as well as by inhibiting tumour angiogenesis and metastasis.
"• Cannabinoids are selective antitumour compounds, as they can kill tumour cells without affecting their non-transformed counterparts. It is probable that cannabinoid receptors regulate cell-survival and cell-death pathways differently in tumour and non-tumour cells.
"• Cannabinoids have favourable drug-safety profiles and do not produce the generalized toxic effects of conventional chemotherapies. The use of cannabinoids in medicine, however, is limited by their psychoactive effects, and so cannabinoid-based therapies that are devoid of unwanted side effects are being designed.
"• Further basic and preclinical research on cannabinoid anticancer properties is required. It would be desirable that clinical trials could accompany these laboratory studies to allow us to use these compounds in the treatment of cancer."

"In an analysis of death certificate data from 1999 to 2010, we found that states with medical cannabis laws had lower mean opioid analgesic overdose mortality rates compared with states without such laws. This finding persisted when excluding intentional overdose deaths (ie, suicide), suggesting that medical cannabis laws are associated with lower opioid analgesic overdose mortality among individuals using opioid analgesics for medical indications. Similarly, the association between medical cannabis laws and lower opioid analgesic overdose mortality rates persisted when including all deaths related to heroin, even if no opioid analgesic was present, indicating that lower rates of opioid analgesic overdose mortality were not offset by higher rates of heroin overdose mortality. Although the exact mechanism is unclear, our results suggest a link between medical cannabis laws and lower opioid analgesic overdose mortality."

“A Double-Blind, Placebo-Controlled Crossover Trial of the Antinociceptive Effects of Smoked Marijuana on Subjects with Neuropathic Pain“
"Barth Wilsey, M.D., University of California, Davis"
"This study’s objective was to examine the efficacy of two doses of smoked cannabis on pain in persons with neuropathic pain of different origins (e.g., physical trauma to nerve bundles, spinal cord injury, multiple sclerosis, diabetes). In a double-blind, randomized clinical trial participants received either lowdose, high-dose, or placebo cannabis cigarettes. As customary in CMCR trials, participants were allowed to continue their usual regimen of pain medications (e.g., codeine, morphine, and others).
"The full results of this study have been published in the Journal of Pain (Wilsey, et al., 2008 – see reference list). Thirty-eight patients underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis; of these, 32 completed all three smoking sessions. The study demonstrated an analgesic response to smoking cannabis with no significant difference between the low and the high dose cigarettes. The study concluded that both low and high cannabis doses were efficacious in reducing neuropathic pain of diverse causes."

"The primary objective of this study was to evaluate the efficacy of smoked cannabis when used as an analgesic in persons with neuropathic pain from HIV-associated distal sensory polyneuropathy (DSPN). In a double blind, randomized, five-day clinical trial patients received either smoked cannabis or placebo cannabis cigarettes. Patients continued on any concurrent analgesic medications (e.g., gabapentin, amitriptyline, narcotics, NSAIDs) which they were prescribed prior to the trial; the dose and amount of the medications were recorded daily.
"The full results of this study appear in the journal Neurology (Abrams, et al., 2007– see reference list). In brief, 55 patients were randomized and 50 completed the entire trial. Smoked cannabis reduced daily pain by 34% compared to 17% with placebo. The study concluded that a significantly greater proportion of patients who smoked cannabis (52%) had a greater than 30% reduction in pain intensity compared to only 24% in the placebo group."

"In this randomized clinical trial, smoked cannabis at maximum tolerable dose (1–8% THC), significantly reduced neuropathic pain intensity in HIV-associated DSPN [distal sensory predominant polyneuropathy] compared to placebo, when added to stable concomitant analgesics. Using verbal descriptors of pain magnitude from DDS [Descriptor Differential Scale], cannabis was associated with an average reduction of pain intensity from ‘strong’ to ‘mild to moderate’. Also, cannabis was associated with a sizeable (46%) and significantly greater (vs 18% for placebo) proportion of patients who achieved what is generally considered clinically meaningful pain relief (eg X30% reduction in pain; Farrar et al, 2001). Mood disturbance, physical disability, and quality of life all improved significantly for subjects during study treatments, regardless of treatment order."

"We observe significant improvement of symptoms of FM [fibromyalgia] in patients using cannabis in this study although there was a variability of patterns. This information, together with evidence of clinical trials and emerging knowledge of the endocannabinoid system and the role of the stress system in the pathopysiology of FM suggest a new approach to the suffering of these patients. The present results together with previous evidence seem to confirm the beneficial effects of cannabinoids on FM symptoms."

"By providing a medical geographic patient utilization 'snapshot' of 236.4 patient-years of the use of MC [Medical Cannabis] at a regional pain clinic, this study provides further insight into the applicability of cannabinoid botanicals in the management of a broad range of refractory chronic pain conditions in adults, from myofascial pain and discogenic back pain to neuropathic pain and central pain syndromes. With physicians employing proper chart documentation of appropriate use, efficacy, and side effects at patient visits, in a manner similar to that used in opioid management of pain, there will hopefully be additional reports in the future on MC use in pain management to add to the clinical database.
"Such a literature can grow only if certain stereotypes and myths about MC use are dispelled amongst pain management specialists and their regulators. The results presented here should help to deconstruct mythologies about the kinds of patients accessing MC treatment, including their young age or their propensity to malinger or feign disease. One prominent mythology is that patients who receive treatment with MC are not 'truly sick.'⁴⁵ An examination of the chart review data, which includes both subjective and objective diagnostic data substantiating patients’ chronic pain illnesses, helps to deflate this concern."

"We found that 25 mg herbal cannabis with 9.4% tetrahydrocannabinol, administered as a single smoked inhalation three times daily for five days, significantly reduced average pain intensity compared with a 0% tetrahydrocannabinol cannabis placebo in adult participants with chronic post-traumatic or postsurgical neuropathic pain. We found significant improvements in measures of sleep quality and anxiety. We have shown the feasibility of a single-dose delivery method for smoked cannabis, and that blinding participants to treatment allocation is possible using this method."

"This study used an experimental model of neuropathic pain to determine whether pain induced by the injection into the skin of capsaicin, a compound which is the 'hot' ingredient in chili peppers, could be alleviated by smoked cannabis. Another aim of the study was to examine the effects of 'dose' of cannabis, and the time course of pain relief. In a randomized double-blinded placebo controlled trial, volunteers smoked low, medium, and high dose cannabis (2%, 4%, 8% THC by weight) or placebo cigarettes.
"The full results of this study were published in the journal Anesthesiology (Wallace, et al., 2007 – see reference list). Nineteen healthy volunteers were enrolled, and 15 completed all four smoking sessions. In brief, five minutes after cannabis exposure, there was no effect on capsaicin-induced pain at any dose. By 45 minutes after cannabis exposure there was a significant decrease in capsaicin-induced pain with the medium dose (4%) and a significant increase in pain with the high dose (8%). There was no significant effect seen with low dose (2%). There was a significant inverse relationship between pain perception and plasma THC. In summary, this study suggested that there may be a 'therapeutic window' (or optimal dose) for smoked cannabis: low doses were not effective; medium doses decreased pain; and higher doses actually increased pain. These results suggest the mechanism(s) of cannabinoid analgesia are complex, in some ways like non-opioid pain relievers (e.g., aspirin, ibuprofen) and in others like opioids (e.g., morphine)."

"The information reviewed above indicates that cannabis has a long established history of efficacy in migraine treatment. Clinical use of the herb and its extracts for headache has waxed and waned for 1200 years, or perhaps much longer, in a sort of cannabis interruptus. It is only contemporaneously that supportive biochemical and pharmacological evidence for the indication is demonstrable. Cannabis’ unique ability to modulate various serotonergic receptor subtypes, inhibit glutamatergic-mediated toxicities, simultaneously provide antiinflammatory activity and provide acute symptomatic and chronic preventive relief make it unique among available treatments for this disorder."

"The role of the endocannabinoid system in the control of GI functions under physiological and pathological conditions has recently received increased interest. Within the last 5 years, more than half of all studies on the roles of the endocannabinoid system in the GI tract have been published. The current state of knowledge of the physiology and pharmacology of cannabinoids has largely increased, providing new potential tools for the treatment of several GI diseases. The symptoms of the most common GI disorders, IBS and inflammatory bowel disease, affect more than 20% of the population in Western countries and cause great discomforts [106]. Intestinal cramping, nausea, chronic diarrhoea and inflammation are all symptoms onto which the cannabinoids may be effective. Cannabis derivatives and other newly developed cannabinoids may represent promising tools for the treatment of different GI disorders because they can act at multiple sites, covering a wide spectrum of symptoms."

"This study was designed to determine how therapeutic users of cannabis rate its effectiveness as an anti-emetic, and particularly as a treatment for nausea and vomiting of pregnancy. In general (not specific to pregnancy), the vast majority of our respondents considered cannabis to be extremely effective or effective as a therapy for nausea (93%) and vomiting (75%), and as an appetite stimulant (95%). In the context of pregnancy, cannabis was rated as extremely effective or effective by 92% of the respondents who had used it as a therapy for nausea and vomiting (morning sickness)."

Cannabis and Multiple Sclerosis

"Using an objective measure, we saw a beneficial effect of inhaled cannabis on spasticity among patients receiving insufficient relief from traditional treatments. Although generally well-tolerated, smoking cannabis had acute cognitive effects. Larger, long-term studies are needed to confirm our findings and determine whether lower doses can result in beneficial effects with less cognitive impact."

"We found evidence that combined extracts of THC and CBD [cannabidiol] may reduce symptoms of spasticity in patients with MS. Although the subjective experience of symptom reduction was generally found to be significant, objective measures of spasticity failed to provide significant changes. In a previous study of spasticity-related pain, MS patients also reported a subjective perception of symptom reduction with cannabinoids [10]. However, since at least one past animal study has provided objective, physiological evidence for the antispastic properties of cannabinoids [7], the distinction between perceived symptom relief and objective physiological changes in humans should therefore be primary in future research efforts.

"Given that adverse events occurred in each reviewed trial, we also encourage future comparison studies of cannabis treatments at a wide range of dosage in order to balance potential side effects with maximum therapeutic benefit.

"Finally, there is evidence that cannabinoids may provide neuroprotective and anti-inflammatory benefits in MS. Neuroinflammation, found in autoimmune diseases such as MS, has been shown to be reduced by cannabinoids through the regulation of cytokine levels in microglial cells [25]. The therapeutic potential of cannabinoids in MS is therefore comprehensive and should be given considerable attention."

“Short-Term Effects of Cannabis Therapy on Spasticity in Multiple-Sclerosis”
Jody Corey-Bloom, M.D., University of California, San Diego
(cannabis and muscle spasticity) "This objective of this study was to determine the potential for smoked cannabis to ameliorate marked muscle spasticity (chronic painful contraction of muscles), a severe and disabling symptom of multiple sclerosis. In a placebo-controlled, randomized clinical trial spasticity and global functioning was examined before and after treatment with smoked cannabis. Patients were allowed to continue their usual treatments for spasticity and pain while participating in the research.
"The full results of this study are being submitted for publication. Initial results were presented at the meeting of the American College of Neuropsychopharmacology in 2007. Thirty patients with multiple sclerosis were enrolled. Compared to placebo cigarettes, cannabis was found to significantly reduce both an objective measure of spasticity, and pain intensity. This study concluded that smoked cannabis was superior to placebo in reducing spasticity and pain in patients with multiple sclerosis, and provided some benefit beyond currently prescribed treatments."

Cannabis and HIV/AIDS

(Medical Cannabis and HIV Treatment) "This study provides evidence that short-term use of cannabinoids, either oral or smoked, does not substantially elevate viral load in individuals with HIV infection who are receiving stable antiretroviral regimens containing nelfinavir or indinavir. Upper confidence bounds for all estimated effects of cannabinoids on HIV RNA level from all analyses were no greater than an increase of 0.23 log10 copies/mL compared with placebo. Because this study was randomized and analyses were controlled for all known potential confounders, it is very unlikely that chance imbalance on any known or unknown covariate masked a harmful effect of cannabinoids. Study participants in all groups may have been expected to benefit from the equivalent of directly observed antiretroviral therapy, as well as decreased stress and, for some, improved nutrition over the 25-day inpatient stay."

(Medical Cannabis and HIV) "Conclusions: Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment."

"Short-term use of smoked cannabis did not affect viral load in 15 HIV-positive patients and also is associated with adherence to therapy and reduced viral loads in 16 patients with hepatitis C infections."

"Cannabinoids have a favourable drug safety profile. Acute fatal cases due to cannabis use in humans have not been substantiated, and median lethal doses of THC in animals have been extrapolated to several grams per kilogram of body weight. Cannabinoids are usually well tolerated in animal studies and do not produce the generalized toxic effects of most conventional chemotherapeutic agents. For example, in a 2-year administration of high oral doses of THC to rats and mice, no marked histopathological alterations in the brain and other organs were found. Moreover, THC treatment tended to increase survival and lower the incidence of primary tumours. Similarly, long-term epidemiological surveys, although scarce and difficult to design and interpret, usually show that neither patients under prolonged medical cannabinoid treatment nor regular cannabis smokers have marked alterations in a wide array of physiological, neurological and blood tests."

"The length of this review, necessitated by the steady growth in the number of indications for the potential therapeutic use of cannabinoid-related medications, is a clear sign of the emerging importance of this field. This is further underlined by the quantity of articles in the public database dealing with the biology of cannabinoids, which numbered ~200 to 300/year throughout the 1970s to reach an astonishing 5900 in 2004. The growing interest in the underlying science has been matched by a growth in the number of cannabinoid drugs in pharmaceutical development from two in 1995 to 27 in 2004, with the most actively pursued therapeutic targets being pain, obesity, and multiple sclerosis (Hensen, 2005)."

(Endocannabinoid Deficiency) "Baker et al. have described how endocannabinoids may demonstrate an impairment threshold if too high, and a range of normal function below which a deficit threshold may be crossed [112]. Syndromes of CECD [Clinical Endocannabinoid Deficiency] may be congenital or acquired. In the former case, one could posit that genetically-susceptible individuals might produce inadequate endocannabinoids, or that their degradation is too rapid. The same conditions might be acquired in injury or infection."

Anti-Tumor Properties

(Cannabinoids and Skin Cancer) "The present data indicate that local cannabinoid administration may constitute an alternative therapeutic approach for the treatment of nonmelanoma skin cancer. Of further therapeutic interest, we show that skin cells express functional CB2 receptors. The synergy between CB1 and CB2 receptors in eliciting skin tumor cell apoptosis reported here is nonetheless intriguing because it is not observed in the case of cannabinoid-induced glioma cell apoptosis (21, 22). In any event, the present report, together with the implication of CB2- or CB2-like receptors in the control of peripheral pain (40–42) and inflammation (41), opens the attractive possibility of finding cannabinoidbased therapeutic strategies for diseases of the skin and other tissues devoid of nondesired CB1-mediated psychotropic side effects."

"It is clear, however, that cannabis use did not compromise substance abuse treatment amongst the medical marijuana using group. In fact, medical marijuana users seemed to fare equal to or better than non-medical marijuana users in every important outcome category. Movement from more harmful to less harmful drugs is an improvement worthy of consideration by treatment providers and policymakers. The economic cost of alcohol use in California has been estimated at $38 billion [30]. Add to this the harm to individuals, families, communities, and society from methamphetamine, heroin, and cocaine, and a justification can be made for medical marijuana in addictions treatment as a harm reduction practice. As long as marijuana use is not associated with poorer outcomes, then replacing other drug use with marijuana may lead to social and economic savings."

(Cannabidiol (CBD) and Breast Cancer) "Our results, which were obtained in a clinically relevant animal model of ErbB2-positive breast cancer, suggest that these highly aggressive and low responsive tumors could be efficiently treated with nonpsychoactive CB2-selective agonists without affecting the surrounding healthy tissue."

(Potential Antitumor Properties of Cannabinoids) "In conclusion, our data indicate that cannabidiol, and possibly Cannabis extracts enriched in this natural cannabinoid, represent a promising nonpsychoactive antineoplastic strategy. In particular, for a highly malignant human breast carcinoma cell line, we have shown here that cannabidiol and a cannabidiol-rich extract counteract cell growth both in vivo and in vitro as well as tumor metastasis in vivo. Cannabidiol exerts its effects on these cells through a combination of mechanisms that include either direct or indirect activation of CB2 and TRPV1 receptors and induction of oxidative stress, all contributing to induce apoptosis."

(Cannabis and Mantle Cell Lymphoma) "In conclusion, our study demonstrates that the cannabinoid receptor agonists R(+)-MA and Win55 induce a sequence of signaling events leading to cell death of MCL [Mantle Cell Lymphoma] cells. The requirement of ligation of both CB1 and CB2 [receptors] raises the possibility that cannabinoids may be used to selectively target MCL cells to undergo apoptosis."
^{Note: According to the study authors: "MCL is a malignant B-cell lymphoma with an aggressive course and generally a poor clinical outcome. MCL tumors respond to chemotherapy, but the remissions are short and the median survival is only 3 years."}

(Potential of Cannabinoids in Cancer Therapy) "The use of cannabinoids in medicine is limited by the psychoactive effects mediated by neuronal CB1 receptors (1, 2). Although these adverse effects are within the range of those accepted for other medications, especially in cancer treatment, and tend to disappear with tolerance upon continuous use, it is obvious that cannabinoid-based therapies devoid of side effects would be desirable (3–5). Because glioma cells express functional CB2 receptors (7), we tested the effect of the nonpsychoactive, CB2 receptor-selective agonist JWH-133 and found that it indeed depresses MMP-2 expression in vivo. Likewise, the use of CB receptor type–selective antagonists indicates that CB2 receptors participate in THC-induced inhibition of MMP-2 expression in glioma cells. As selective CB2 receptor activation to mice has been shown to inhibit the growth and angiogenesis of gliomas (11, 13, 27), skin carcinomas (8) and melanomas (15), our observations further support the possibility of finding cannabinoid-based antitumoral strategies devoid of nondesired psychotropic side effects."

(Cannabinoids and Cancer Cells) "Cannabinoids, the active components of marijuana and their other natural and synthetic analogues have been reported as useful adjuvants to conventional chemotherapeutic regimens for preventing nausea, vomiting, pain, and for stimulating appetite. Before the discovery of specific cannabinoid systems and receptors, it was speculated that cannabinoids produced their effects via nonspecific interaction with cell membranes. Cannabinoids are proving to be unique based on their targeted action on cancer cells and their ability to spare normal cells. Variation in the effects of cannabinoids in different cell lines and tumor model could be due to the differential expression of CB1 and CB2 receptors. Thus, overexpression of cannabinoid receptors may be effective in killing tumors, whereas low or no expression of these receptors could lead to cell proliferation and metastasis because of the suppression of the antitumor immune response."

(Cannabidiol (CBD) and Cancer Therapy) "In conclusion, a cannabinoid-based therapeutic strategy for neural diseases devoid of undesired psychotropic side effects could find in CBD [a cannabinoid] a valuable compound in cancer therapies along with the perspective of evaluating a synergistic effect with other cannabinoid molecules and/or with other chemotherapeutic agents as well as with radiotherapy. Whatever the precise mechanism underlying the CBD effects, the present results suggest a possible application of CBD as a promising, nonpsychoactive, antineoplastic agent."

Cannabis and Diabetes

(Cannabinoids and Diabetic Cardiomyopathy) "Remarkably, CBD [Cannabidiol] attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-
B activation, and cell death in primary human cardiomyocytes.
"Conclusions: Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis."

(Cannabidiol (CBD) and Diabetic Retinopathy) "Drugs that enhance extracellular adenosine signaling have been of clinical interest in treatment of inflammation after myocardial or cerebral ischemia.^25,26 CBD as an anti-inflammatory drug is an attractive alternative to smoking marijuana because of its lack of psychoactive effects.²⁷ CBD is known to be nontoxic in humans,²⁸ which has previously been a problem for other nucleoside inhibitor drugs.^29,30"

"Recent evidence suggests that local inflammation plays a major role in the pathogenesis of diabetic retinopathy. The function of CBD as an antioxidant to block oxidative stress and as an inhibitor of adenosine reuptake to enhance a self-defense mechanism against retinal inflammation represents a novel therapeutic approach to the treatment of ophthalmic complications associated with diabetes."

"Our results provide evidence that the non-cannabimimetic constituent of marijuana, cannabidiol, exerts clinically relevant antipsychotic effects that are associated with marked tolerability and safety, when compared with current medications."

Substance Abuse and Mental Health Treatment

(Cannabidiol's (CBD's) Potential in Substance Abuse Treatment) "The current study has revealed unique properties of the phytocannabinoid CBD and underscores the contrasting characteristics of the main constituents of cannabis in relation to addiction vulnerability. Compared with the documented effects of THC to enhance heroin self-administration (Solinas et al., 2004; Ellgren et al., 2007), the present data demonstrated that CBD specifically inhibited reinstatement of cue-induced heroin seeking. The specificity of CBD to cue-induced reinstatement was also emphasized by the observation that the compound still inhibited drug relapse behavior in animals extinguished to the environmental context (self-administration chamber) previously associated with heroin. The results are striking given the very selective and protracted effects of CBD."
"Overall, the observations of this study suggest the potential for CBD as a treatment strategy given its specificity to attenuate cue-induced drug-seeking behavior, preferential impact on mesolimbic neuronal populations, and enduring neural actions. Clearly, greater attention needs be given to the potential role of CBD in the treatment of addiction and other mental health disorders."

(Cannabidiol (CBD) and Schizophrenia Treatment) "These studies suggest, therefore, that CBD has an antipsychotic-like profile in healthy volunteers and may possess antipsychotic properties in schizophrenic patients, but not in the resistant ones. Confirming this suggestion, a preliminary report from a 4-week, double-blind controlled clinical trial, using an adequate number of patients and comparing the effects of CBD with amisulpride in acute schizophrenic and schizophreniform psychosis, showed that CBD significantly reduced acute psychotic symptoms after 2 and 4 weeks of treatment when compared to baseline. In this trial CBD did not differ from amisulpride except for a lower incidence of side effects (49).
"In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed."

"A chart review of patients diagnosed with PTSD who were referred to a private psychiatric clinic suggests that the synthetic cannabinoid, nabilone, has beneficial effects beyond its official indication in regard to abolishing or greatly reducing nightmares that persisted in spite of treatment with conventional PTSD medications.
"The subjects concomitantly received nabilone in addition to the one or more psychiatric medications that they were already taking for 2 years or more. No tolerance to nabilone was observed among the patients. This may indicate its potential longer-term safety and efficacy.
"The author recognizes the limits of this study (e.g., there was no placebo control, the measurements were limited to subjective reports to nightmare changes, the study was on a small number of patients, and there was a selective bias by nature of referrals to a specific clinic from which the patients were selected). Nonetheless, on the basis of these retrospective findings, nabilone appears to be a significant treatment for nightmares in the PTSD population."

"Eighty five percent of the BPG [Berkeley Patients Group] sample reported that cannabis has much less adverse side effects than their prescription medications. Additionally, the top two reasons listed by participants as reasons for substituting cannabis for one of the substances previously mentioned were less adverse side effects from cannabis (65%) and better symptom management from cannabis (57.4%).

"Conclusion
"The substitution of one psychoactive substance for another with the goal of reducing negative outcomes can be included within the framework of harm reduction. Medical cannabis patients have been engaging in substitution by using cannabis as an alternative to alcohol, prescription and illicit drugs."

"Indeed, all 11 states that have passed medical marijuana laws ranked above the national average in the percentage of persons 12 or older reporting past-month use of marijuana in 1999, as shown in Table 2. It is at least possible, however, that this analysis confuses cause with effect. It is logical to assume that the states with the highest prevalence of marijuana usage would be more likely to approve medical marijuana programs, because the populations of those states would be more knowledgeable of marijuana’s effects and more tolerant of its use.

"It is also the case that California, the state with the largest and longest-running medical marijuana program, ranked 34th in the percentage of persons age 12-17 reporting marijuana use in the past month during the period 2002-2003, as shown in Table 1. In fact, between 1999 and 2002-2003, of the 10 states with active medical marijuana programs, five states (AK, HI, ME, MT, VT) rose in the state rankings of past-month marijuana use by 12- to 17-year-olds and five states fell (CA, CO, NV, OR, WA).¹¹¹ Of the five states that had approved medical marijuana laws before 1999 (AK, AZ, CA, OR, WA), only Alaska’s ranking rose between 1999 and 2002-2003, from 7th to 4th, with 11.08% of youth reporting past-month marijuana use in 2002-2003 compared with 10.4% in 1999. No clear patterns are apparent in the state-level data. Clearly, more important factors are at work in determining a state’s prevalence of recreational marijuana use than whether the state has a medical marijuana program."

"The findings of this study provide one of the first in-depth descriptions of youths' use of marijuana for non-recreational purposes, adding to the growing body of research on the use of drugs to self-medicate among young people. Teens involved in regular and long-term use of marijuana for relief constructed their use of marijuana as essential to feeling better or 'normal' in situations where they perceived there were few other options available to them. Unlike the spontaneity typically involved in recreational use, these youth were thoughtful and prescriptive with their marijuana use – carefully monitoring and titrating their use to optimize its therapeutic effect. The findings also point to important contextual factors that further support youth's use of marijuana for relief that extend beyond the availability of marijuana and dominant discourses that construct marijuana as a natural product with medicinal properties."

Marinol and Dronabinol

(Dronabinol) "Dronabinol (?-9-tetrahydrocannabinol [THC]) is an alternative treatment for nausea and vomiting caused by chemotherapy. THC is the principal psychoactive component of marijuana. Its mechanism of antiemetic action is unknown, but cannabinoids bind to opioid receptors in the forebrain and may indirectly inhibit the vomiting center. Dronabinol is administered in doses of 5 mg/m2 po 1 to 3 h before chemotherapy, with repeated doses q 2 to 4 h after the start of chemotherapy (maximum of 4 to 6 doses/day). However, it has variable oral bioavailability, is not effective for inhibiting the nausea and vomiting of platinum-based chemotherapy regimens, and has significant adverse effects (eg, drowsiness, orthostatic hypotension, dry mouth, mood changes, visual and time sense alterations). Smoking marijuana may be more effective. Marijuana for this purpose can be obtained legally in some states. It is used less commonly because of barriers to availability and because many patients cannot tolerate smoking."
<sup>Notes
1. "Dronabinol, the active ingredient in MARINOL® (dronabinol) Capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana)."
2. "Dronabinol is a name of a particular isomer of a class of chemicals known as tetrahydrocannabinols (THC). Specifically, dronabinol is the United States Adopted Name (USAN) for the (-)-isomer of [Delta]\9\-(trans)- tetrahydrocannabinol [(-)-[Delta]\9\-(trans)-THC], which is believed to be the major psychoactive component of the cannabis plant (marijuana)."
3. "A United States Adopted Name (USAN) is the "US generic name for any compound to be used as a drug."
4. Dronabinol is the generic name for THC or tetrahydrocannabinol.</sup>

MARINOL^® (dronabinol) Capsules
"CLINICAL PHARMACOLOGY
"Pharmacodynamics
"After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration.
"INDICATIONS AND USAGE
"MARINOL Capsules is indicated for the treatment of:
"1. anorexia associated with weight loss in patients with AIDS; and
"2. nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.
"ADVERSE REACTIONS"
"A cannabinoid dose-related “high” (easy laughing, elation and heightened awareness) has been reported by patients receiving MARINOL® Capsules in both the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%)
"DRUG ABUSE AND DEPENDENCE
"MARINOL Capsules is one of the psychoactive compounds present in cannabis, and is abusable and controlled [Schedule III (CIII)] under the Controlled Substances Act. Both psychological and physiological dependence have been noted in healthy individuals receiving dronabinol, but addiction is uncommon and has only been seen after prolonged high dose administration.
"Chronic abuse of cannabis has been associated with decrements in motivation, cognition, judgement, and perception. The etiology of these impairments is unknown, but may be associated with the complex process of addiction rather than an isolated effect of the drug. No such decrements in psychological, social or neurological status have been associated with the administration of MARINOL Capsules for therapeutic purposes.
"In an open-label study in patients with AIDS who received MARINOL Capsules for up to five months, no abuse, diversion or systematic change in personality or social functioning were observed despite the inclusion of a substantial number of patients with a past history of drug abuse.
"OVERDOSAGE
"Signs and symptoms following MILD MARINOL Capsules intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following MODERATE intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following SEVERE intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders.
^{Note: Marinol® is now marketed by Abbott Laboratories.}

Other Laws & Policies

"Medical experts emphasize the need to reclassify marijuana as a Schedule II drug to facilitate rigorous scientific evaluation of the potential therapeutic benefits of cannabinoids and to determine the optimal dose and delivery route for conditions in which efficacy is established.² This research could provide the basis for regulation by the Food and Drug Administration. Current roadblocks to conducting clinical trials, however, make this more rational route of approval unlikely and perpetuate the development of state laws that lack consistency or consensus on basic features of an evidence-based therapeutic program."

"Not surprisingly, the Obama Administration would have been more successful had it simply legalized medical marijuana.¹⁴³ In fact, the CSA [Controlled Substances Act] authorizes the Attorney General to do so, in consultation with the Secretary of Health and Human Services and the DEA.¹⁴⁴ In other words, the President would not need the consent of the Congress to make this, more fundamental change to federal law."

"It is a judicial fluke that the National Institute on Drug Abuse has provided medical marijuana to a handful of patients (never more than 32, currently 4 surviving) as the outcome of the settlement in a lawsuit pressed in 1976 by a man with cannabis-responsive glaucoma. That settlement became the basis for the FDA’s Compassionate Investigational New Drug Study program for patients with marijuana responsive conditions. No patient has been enrolled since 1992, when the George H. W. Bush administration suspended new registration in reaction to a large influx of applications from AIDS patients."

"Only two limited exceptions to the federal ban on marijuana have been made. The first, a compassionate use program created under President Carter, is superficially analogous to extant state medical use programs; it allows patients to use marijuana legally for therapeutic purposes. The marijuana for the program is supplied by a federally approved grow-site at the University of Mississippi (the only federally approved grow-site in the United States). However, the program stopped accepting new applications in 1992, and only eight (yes, eight) patients currently receive marijuana through it. Over its entire history, only thirty-six patients have been enrolled.⁵² The second and only other way to obtain marijuana legally under federal law is by participating in an FDA-approved research study. But since the federal government approves so few marijuana research projects—eleven since 2000⁵³—only a small fraction of the population that currently qualifies for state exemptions could participate."

Cannabis (marijuana) is listed in Schedule I of the 1970 Controlled Substance Act. Schedule 1 classification is supposed to mean: "(A) The drug or other substance has a high potential for abuse. (B) The drug or other substance has no currently accepted medical use in treatment in the United States. (C) There is a lack of accepted safety for use of the drug or other substance under medical supervision."

(History) "For most of American history, growing and using marijuana was legal under both federal law and the laws of the individual states. By the 1840s, marijuana’s therapeutic potential began to be recognized by some U.S. physicians. From 1850 to 1941 cannabis was included in the United States Pharmacopoeia as a recognized medicinal.⁴ By the end of 1936, however, all 48 states had enacted laws to regulate marijuana.⁵ Its decline in medicine was hastened by the development of aspirin, morphine, and then other opium-derived drugs, all of which helped to replace marijuana in the treatment of pain and other medical conditions in Western medicine.⁶"

"Although Raich established Congress’s constitutional authority to enact the existing federal prohibition on marijuana, principles of federalism prevent the federal government from mandating that the states support or participate in enforcing the federal law. While state resources may be helpful in combating the illegal use of marijuana, Congress’s ability to compel the states to enact similar criminal prohibitions, to repeal medical marijuana exemptions, or to direct state police officers to enforce the federal law remains limited. The Tenth Amendment likely prevents such an intrusion into state sovereignty."

(Medical Cannabis and the Constitution's Commerce Clause) "Congress has exercised its Commerce Clause authority to categorically ban marijuana. The Supreme Court has upheld this plenary prohibition.¹⁹ In Gonzales v Raich, a divided Court held that the Commerce Clause enables Congress to prohibit the local cultivation and use of marijuana, despite more permissive regulations under California law.²⁰ Writing for the majority, Justice Stevens found that precedent 'firmly established' Congress’ power under the Commerce Clause to regulate purely local activities that have a substantial effect on interstate commerce.²¹ The Raich majority held that Congress can prohibit local marijuana cultivation and use, because it was part of a 'class of activities' constituting the national black market for marijuana.²² The Court reasoned that local cultivation and use, even for limited medical purposes, affected supply and demand in the national black market, making regulation over local use 'essential' to undermining the broader underground industry nationwide.²³ The majority distinguished Raich from earlier precedent that circumscribed Congress’ Commerce Clause power, finding that those earlier cases involved statutes that regulated purely non-economic activities, while this one aims to nullify a particular application of a valid statutory scheme.²⁴"

Beginning in 1978, thirty-seven states enacted some form of medicinal cannabis legislation other than effective laws. These include:
Therapeutic Research Programs (state-run therapeutic research programs, not operable because of federal obstruction): Alabama, California, Georgia, Illinois, Massachusetts, Minnesota, New Jersey, New York, South Carolina, Texas.
Symbolic Prescriptions (patients allowed to possess cannabis only if obtained through prescription, not operable because the CSA bars physicians from writing prescriptions for Schedule I drugs): Arizona, California, Connecticut, District of Columbia, Iowa, New Hampshire, Tennessee, Virginia, Wisconsin.
State Rescheduling (not operable because federal scheduling supersedes state schedules): Alaska, Iowa, Montana, Tennessee, and the District of Columbia.
Non-binding Resolutions Urging Federal Rescheduling: California, Michigan, Missouri, New Hampshire, New Mexico, Rhode Island, Washington.

"Beginning in the late 1970s, a number of state governments sought to give large numbers of patients legal access to medical marijuana through federally approved research programs.

"While 26 states passed laws creating therapeutic research programs, only seven obtained all of the necessary federal permissions, received marijuana and/or THC (tetrahydrocannabinol, the primary active ingredient in marijuana) from the federal government, and distributed the substances to approved patients through approved pharmacies. Those seven states were California, Georgia, Michigan, New Mexico, New York, Tennessee, and Washington.

"Typically, patients were referred to the program by their personal physicians. These patients, who often had not responded well to conventional treatments, underwent medical and psychological screening processes. Then, the patients applied to their state patient qualification review board, which resided within the state health department. If granted permission, they would receive marijuana from approved pharmacies. Patients were required to monitor their usage and marijuana’s effects, which the state used to prepare reports for the FDA. (Interestingly, former Vice President Al Gore’s sister received medical marijuana through the Tennessee program while undergoing chemotherapy for cancer in the early 1980s.)

"These programs were designed to enable patients to use marijuana. The research was not intended to generate data that could lead to FDA approval of marijuana as a prescription medicine. For example, the protocols did not involve doubleblind assignment to research and control groups, nor did they involve the use of placebos.

"Such programs were discontinued by the mid-1980s, and the federal government has since made it more difficult for researchers to obtain marijuana for study, preferring to approve only those studies that are well-controlled clinical trials designed to yield essential scientific data."

"If a Veteran obtains and uses medical marijuana in manner consistent with state law, testing positive for marijuana would not preclude the Veteran from receiving opioids for pain management in the Department of Veteran Affairs (VA) facility. The Veteran would need to inform his provider of the use of medical marijuana, and of any other non-VA prescribed medications he or she is taking to ensure that all medications, including opioids, are prescribed in a safe manner. Standard pain management agreements should draw a clear distinction between use of illegal drugs, and legal medical marijuana. However, the discretion to prescribe, or not prescribe, opioids in conjunction with medical marijuana, should be determined on clinical grounds, and thus will remain the decision of the individual health care provider. The provider will take the use of medical marijuana into account in all prescribing decisions, just as the provider would for any other medication. This is a case-by-case decision, based on the provider's judgment, and the needs of the patient."

"'It is the shared responsibility of professional nursing organizations to speak for nurses collectively in shaping health care and to promulgate change for the improvement of health and health care' (ANA, 2015, p. 36). Therefore, the ANA strongly supports:

"#&149; Scientific review of marijuana’s status as a federal Schedule I controlled substance and relisting marijuana as a federal Schedule II controlled substance for purposes of facilitating research.

"• Development of prescribing standards that includes indications for use, specific dose, route, expected effect and possible side effects, as well as indications for stopping a medication.

"• Establishing evidence-based standards for the use of marijuana and related cannabinoids.

"• Protection from criminal or civil penalties for patients using therapeutic marijuana and related cannabinoids as permitted under state laws.

"• Exemption from criminal prosecution, civil liability, or professional sanctioning, such as loss of licensure or credentialing, for health care practitioners who discuss treatment alternatives concerning marijuana or who prescribe, dispense or administer marijuana in accordance with professional standards and state laws."

(Categories of Cannabinoid Medicines) "They [cannabinoid medicines] fall into three categories: single molecule pharmaceuticals, cannabisbased liquid extracts, and phytocannabinoid-dense botanicals–the main focus of this article (Figure 2). The first category includes US Food and Drug Administration (FDA)-approved synthetic or semisynthetic single molecule cannabinoid pharmaceuticals available by prescription. Currently, these are dronabinol, a Schedule III drug and nabilone, a Schedule II drug. Though both are also used offlabel, dronabinol, a (-)trans-[delta]9-tetrahydrocannabinol (THC) isomer found in natural cannabis, has been approved for two uses since 1985 and 1992, respectively: the treatment of nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments and the treatment of anorexia associated with weight loss in patients with AIDS.^10,11 Nabilone, a synthetic molecule shaped similarly to THC, has also been approved since 1985 for use in the treatment of nausea and vomiting associated with cancer chemotherapy.^12,13
"The second category of cannabinoid medicines being used in the United States includes a line of cannabis-based medicinal extracts developed by several companies. The industry leader is GW Pharmaceuticals, a UK-based biopharmaceutical company whose lead product is currently undergoing FDA-approved, multisite Phase IIb clinical trials for the treatment of opioid-refractory cancer pain in the United States¹⁴ and has received prior approval for Phase III clinical trials in the United States. This botanical drug extract which goes by the nonproprietary name nabiximols has already secured approval in Canada for use in the treatment of central neuropathic pain in multiple sclerosis (in 2005) and in the treatment of intractable cancer pain (in 2007).¹⁵ It is also available on a named patient basis in the United Kingdom and Catalonia,^16,17 a scheme which allows a doctor to prescribe an unlicensed drug to a particular “named patient,” and has been exported to 22 countries to date.
"The third category of cannabinoid medicines currently being used in the United States includes the Schedule I medicinal plant Cannabis sativa L. itself, which, while currently unavailable for general prescription use in the United States, is in use in the context of two active controlled clinical trials,^18,19 33 completed controlled clinical trials,^20-52 and one on-going, yet essentially defunct, three-decade investigational clinical study.^53,54"

“Vaporization as a ‘Smokeless’ Cannabis Delivery System”
Donald Abrams, M.D., University of California, San Francisco
(vaporization of cannabis) "The aim of this study was to evaluate the use of a vaporization system (the Volcano; VAPORMED® Inhalatoren; Tüttlingen, Germany) as a “smokeless” delivery system for inhaled cannabis. Because of concerns regarding the practicality and palatability of using cannabis cigarettes as a standard treatment, there has been an interest in developing alternative delivery systems. Participants were randomly assigned to receive low, medium, or high dose (1.7, 3.4, or 6.8% tetrahydrocannabinol) cannabis cigarettes delivered by smoking or by the vaporization
system on six study days.
"The full results of this study have been published in the journal Clinical Pharmacology & Therapeutics (Abrams, et al., 2007 – see reference list). Eighteen healthy volunteers were recruited to participate in the research. The analysis indicated that the blood levels of vaporized cannabis are similar to those of smoked cannabis over a six hour period. However, blood concentrations of THC at 30 and 60 minutes after inhalation were significantly higher in vaporized cannabis as compared to smoked cannabis. In addition, carbon monoxide levels were significantly reduced with vaporization compared with smoked cannabis. Fourteen participants preferred vaporization, 2 preferred smoking, and 2 reported no preference. In summary, vaporization of cannabis was found to be a safe mode of delivery, and participants had a preference for vaporization over smoking as a delivery system in this trial."

"CMA [California Medical Association] policy has acknowledged the criminalization of cannabis to be a failed public health policy (HOD 704a-09) and has recognized a public movement toward the legalization of cannabis (HOD 101a-10). Cannabis illegality has perpetuated the effective prohibition of clinical research on the properties of cannabis and has prevented the development of state and national standards governing the cultivation, manufacture, and labeling of cannabis products, similar to those governing food, tobacco and alcohol products, most of which are promulgated by federal agencies."

(Ethics of Recommending Medical Cannabis to Patients) "Portions of the American Medical Association’s Code of Medical Ethics, Opinion 1.02 – The Relation of Law and Ethics reads, 'Ethical values and legal principles are usually closely related, but ethical obligations typically exceed legal duties. In some cases, the law mandates unethical conduct.' 'In exceptional circumstances of unjust laws, ethical responsibilities should supersede legal obligations.'[56] An 'exceptional circumstance of unjust laws' may be interpreted as the federal ban on cannabis for medical use. Sixteen states and the District of Columbia found the federal government’s prohibition on prescribing and using medicinal cannabis so unjust as to create laws in direct violation of federal statute. Therefore, one could surmise that prescribing cannabis for the purpose of harm reduction is ethical even though it violates federal law. In addition, Hayry suggests that the idea of 'freedom' also provides an ethical reason for prescribing cannabis and he writes, '… whatever the legal situation, respect for the freedom of the individual would imply that requests like this (for medicinal cannabis) should be granted, either by health professionals, or by society as a whole.'[57]"

(Dispensaries and Crime) "The cross-sectional results suggest that dispensaries are not associated with crime rates; however, current media and policy efforts have focused their attention on the place-based regulation of these dispensaries to protect the public against crime (California Police Chief’s Association, 2009; City of Los Angeles, 2010; Lopez, 2010). Based on the limited evidence presented by this study, it is unclear if place-based policies will be effective."

(Federally-Subsidized Public Housing and Medical Cannabis) "In sum, PHAs [Public Housing Agencies] and owners may not grant reasonable accommodations that would allow tenants to grow, use, or otherwise possess, or distribute medical marijuana, even if in doing so tenants are complying with state laws authorizing medical marijuana-related conduct. Further, PHAs and owners must deny admission to those applicant households with individuals who are, at the time of consideration for admission, using marijuana. See 42 U.S.C. § 13661(b)(1)(A); Lester Memorandum at 2.
"We note, however, that PHAs and owners have statutorily-authorized discretion with respect to evicting or refraining from evicting current residents on account of their use of medical marijuana. See 42 U.S.C. § 13662(b)(1); Lester Memorandum at 5-7. If a PHA or owner desires to allow a resident who is currently using medical marijuana to remain as an occupant, the PHA or owner may do so as an exercise of that discretion, but not as reasonable accommodation. HUD regulations provide factors that PHAs and owners may consider when determining how to exercise their discretion to terminate tenancies because of current illegal drug use. See 24 C.F.R. § 966.4(1)(5)(vii)(B)(factors for PHAs); 5.852 (factors for PHAs and owners operating other assisted housing programs)."

US-Based Medical and Scientific Organizations Which Support Access to Medical Cannabis:
The American Academy of Family Physicians (1989, 1995); American Academy of HIV Medicine (2003); American College of Physicians (2008); American Medical Association's Council on Scientific Affairs (2001); American Medical Students Association (1993); American Nurses Association (2003); American Preventive Medical Association (1997); American Public Health Association (1995); Association of Nurses in AIDS Care (1999); Federation of American Scientists (1994); HIV Medicine Association (2006); Institute of Medicine (1982 & 1999); Kaiser Permanete (1997); Lymphoma Foundation of America (1997); National Association for Public Health Policy (1998); National Nurses Society on Addictions (1995); and Physicians Association for AIDS Care.

"Cannabis indica became available in American pharmacies in the 1850’s following its introduction to western medicine by William O'Shaughnessy (1839).⁶ In its original pharmaceutical usage, it was regularly consumed orally, not smoked. The first popular American account of cannabis intoxication was published in 1854 by Bayard Taylor, writer, world traveler and diplomat."

IOM's Marijuana and Medicine: Assessing the Science Base (1999)

"At this point, our knowledge about the biology of marijuana and cannabinoids allows us to make some general conclusions:
"· Cannabinoids likely have a natural role in pain modulation, control of movement, and memory.
"· The natural role of cannabinoids in immune systems is likely multi-faceted and remains unclear.
"· The brain develops tolerance to cannabinoids.
"· Animal research demonstrates the potential for dependence, but this potential is observed under a narrower range of conditions than with benzodiazepines, opiates, cocaine, or nicotine.
"· Withdrawal symptoms can be observed in animals but appear to be mild compared to opiates or benzodiazepines, such as diazepam (Valium)."

The Institute of Medicine's 1999 report on medical marijuana examined the question whether the medical use of marijuana would lead to an increase of marijuana use in the general population and concluded that, "At this point there are no convincing data to support this concern. The existing data are consistent with the idea that this would not be a problem if the medical use of marijuana were as closely regulated as other medications with abuse potential." The report also noted that, "this question is beyond the issues normally considered for medical uses of drugs, and should not be a factor in evaluating the therapeutic potential of marijuana or cannabinoids."

In the Institute of Medicine's report on medical marijuana, the researchers examined the physiological risks of using marijuana and cautioned, "Marijuana is not a completely benign substance. It is a powerful drug with a variety of effects. However, except for the harms associated with smoking, the adverse effects of marijuana use are within the range of effects tolerated for other medications."

"The abundance of CB1 receptors in basal ganglia and reports of animal studies showing the involvement of cannabinoids in the control of movement suggest that cannabinoids would be useful in treating movement disorders in humans. Marijuana or CB1 receptor agonists might provide symptomatic relief of chorea, dystonia, some aspects of parkinsonism, and tics."

"Advances in cannabinoid science of the past 16 years have given rise to a wealth of new opportunities for the development of medically useful cannabinoid-based drugs. The accumulated data suggest a variety of indications, particularly for pain relief, antiemesis, and appetite stimulation. For patients such as those with AIDS or who are undergoing chemotherapy, and who suffer simultaneously from severe pain, nausea, and appetite loss, cannabinoid drugs might offer broad-spectrum relief not found in any other single medication."

The Institute of Medicine's 1999 report on medical marijuana stated, "The accumulated data indicate a potential therapeutic value for cannabinoid drugs, particularly for symptoms such as pain relief, control of nausea and vomiting, and appetite stimulation."

"For most people, the primary adverse effect of acute marijuana use is diminished psychomotor performance. It is, therefore, inadvisable to operate any vehicle or potentially dangerous equipment while under the influence of marijuana, THC, or any cannabinoid drug with comparable effects."