Medical Marijuana

1. States That Legally Regulate Medical and/or Adult Social Use of Marijuana

As of June 25, 2019, a total of 32 states plus the District of Columbia and Guam have what are called "effective" state medical marijuana laws. These states include: Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Hawaii, Illinois, Maine, Maryland, Massachusetts, Michigan, Minnesota, Missouri, Montana, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island, Utah, Vermont, Washington state, and West Virginia.

As of June 25, 2019, eleven states have legalized adult (aged 21 and older) personal use of marijuana: Alaska, California, Colorado, Illinois, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington state. In addition, ten of those eleven states - Vermont is the exception - legally regulate the production, distribution, and sale of marijuana. The District of Columbia has also legalized limited personal possession and cultivation of marijuana by adults aged 21 and older.

Marijuana Policy Project, "State by State Medical Marijuana Laws 2015 with a December 2016 Supplement - How to Remove the Threat of Arrest," (Washington, DC: MPP, February 2017), p. 1, last accessed September 27, 2017.
https://www.mpp.org...
West Virginia: https://www.mpp.org/states/wes...
Vermont: "Governor Phil Scott Signs H.511," Office of the Governor of Vermont, News Release, Jan. 22, 2018.
http://governor.vermont.gov/pr...
"An act relating to eliminating penalties for possession of limited amounts of marijuana by adults 21 years of age or older"
https://legislature.vermont.go...
Oklahoma: Oklahoma State Question 788, Medical Marijuana Legalization Initiative (June 2018) https://ballotpedia.org/...
Michigan, Missouri, and Utah: http://www.drugpolicy.org/pres...
Illinois: HB 1438

2. More Than 148 Million Americans Live In a State With Effective Medical Marijuana Laws

"In all, more than 148 million Americans — about 47% of the U.S. population — now live in the 23 states, or the federal district, with effective medical marijuana laws. Eighty-five percent live in a state that has some form of medical cannabis legislation on the books."

Marijuana Policy Project, "State by State Medical Marijuana Laws 2015 with a December 2016 Supplement - How to Remove the Threat of Arrest," (Washington, DC: MPP, March 2017), p. 10, last accessed April 26, 2017.
https://www.mpp.org/issues/med...

3. Impact of Medical Marijuana Laws on Marijuana Use by Young People

"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."

Sarvet, A. L., Wall, M. M., Fink, D. S., Greene, E., Le, A., Boustead, A. E., Pacula, R. L., Keyes, K. M., Cerdá, M., Galea, S., and Hasin, D. S. (2018) Medical marijuana laws and adolescent marijuana use in the United States: a systematic review and meta‐analysis. Addiction, 113: 1003–1016. doi: 10.1111/add.14136.
https://onlinelibrary.wiley.co...
https://onlinelibrary.wiley.co...

4. Number of Approved Medical Cannabis Patients in the US

"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."

Eddy, Mark, "Medical Marijuana: Review and Analysis of Federal and State Policies," Congressional Research Service (Washington, DC: March 31, 2009), p. 19.
http://www.fas.org/sgp/crs/mis...

5. Impact of Medical Marijuana Laws on Adolescent Marijuana Use

"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."

Choo, Esther K. et al. (2014), "The Impact of State Medical Marijuana Legislation on Adolescent Marijuana Use," Journal of Adolescent Health, Volume 55, Issue 2, p. 160 - 166.
http://www.jahonline.org/artic...
http://www.jahonline.org/artic...

6. Potential Therapeutic Uses of Cannabidiol (CBD)

"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."

Izzo, Angelo A.; Borrelli, Francesca; Capasso, Raffaele; Di Marzo, Vincenzo; and Mechoulam, Raphael, "Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb," Trends in Pharmacological Sciences (London, United Kingdom: October 2009) Vol. 30, Issue 10, pp. 525-526.
http://www.ncbi.nlm.nih.gov/pu...
http://cannabisinternational.o...

7. Known Therapeutic Benefits From Medicinal Cannabinoids

"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."

Franjo Grotenhermen, Dr. med., and Kirsten Müller-Vahl, Prof. Dr. med., "The Therapeutic Potential of Cannabis and Cannabinoids," Deutsch Arzteblatt International, 2012 July; 109(29-30): 495–501. doi: 10.3238/arztebl.2012.0495
http://www.ncbi.nlm.nih.gov/pm...

8. Known Therapeutic Benefits From Medicinal Cannabinoids

"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."

Igor Grant, J. Hampton Atkinson, Ben Gouaux and Barth Wilsey, "Medical Marijuana: Clearing Away The Smoke," The Open Neurology Journal, 2012, 6:18-25. doi: 10.2174/1874205X01206010018.
http://www.ncbi.nlm.nih.gov/pm...

9. Medical Cannabis and Epilepsy

"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."

Stockings, Emily & Zagic, Dino & Campbell, Gabrielle & Weier, Megan & Hall, Wayne & Nielsen, Suzanne & K Herkes, Geoffrey & Farrell, Michael & Degenhardt, Louisa. (2018). Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence. Journal of Neurology, Neurosurgery & Psychiatry. jnnp-2017. 10.1136/jnnp-2017-317168.
https://www.ncbi.nlm.nih.gov/p...
http://jnnp.bmj.com/content/ea...

10. Use of Cannabis as a Response to the Overdose Crisis

"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."

Vyas, Marianne Beare et al. The use of cannabis in response to the opioid crisis: A review of the literature. Nursing Outlook, January-February 2018, Volume 66, Issue 1, 56 - 65.
https://www.ncbi.nlm.nih.gov/p...
www.nursingoutlook.org
www.nursingoutlook.org

11. Impact of State-Legal Medical Marijuana on Adolescent Marijuana Use

"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."

Choo, Esther K. et al., "The Impact of State Medical Marijuana Legislation on Adolescent Marijuana Use," Journal of Adolescent Health, August 2014, Volume 55, Issue 2, p. 160 - 166.
http://www.jahonline.org/...
http://www.jahonline.org/...

12. Medicinal Cannabis as an Alternative to Prescription Opioid Medicines

"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."

Vyas, Marianne Beare et al. The use of cannabis in response to the opioid crisis: A review of the literature. Nursing Outlook, Volume 66, Issue 1, 56 - 65.
https://www.nursingoutlook.org/...
https://www.nursingoutlook.org/...

13. CBD's Effects on Anxiety and Depression

"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."

Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
https://www.ncbi.nlm.nih.gov/p...

14. Cannabinoids and the Chemical Composition of Cannabis

"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"

Aggarwal, Sunil K., "Cannabinergic Pain Medicine: A Concise Clinical Primer and Survey of Randomized-controlled Trial Results," Clinical Journal of Pain (Philadelphia, PA: February 23, 2012), p. 2.
http://www.ncbi.nlm.nih.gov/pu...

15. CBD's Effects on Psychosis and Bipolar

"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."

Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
https://www.ncbi.nlm.nih.gov/p...

16. Safety of Cannabis

"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."

Aggarwal, Sunil K., "Cannabinergic Pain Medicine: A Concise Clinical Primer and Survey of Randomized-controlled Trial Results," Clinical Journal of Pain (Philadelphia, PA: February 23, 2012), p. 3.
http://www.ncbi.nlm.nih.gov/pu...

17. Therapeutic Effects of CBD

"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]."

Hazekamp A: The Trouble with CBD Oil. Med Cannabis Cannabinoids 2018;1:65-72. doi: 10.1159/000489287
https://www.karger.com/Article...

18. Effects of CBD on Addiction

"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"

Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
https://www.ncbi.nlm.nih.gov/p...

19. CBD, Neuroprotection, and Neurogenesis

"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"

Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
https://www.ncbi.nlm.nih.gov/p...

20. CBD and the Immune System

"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"

Iffland, Kerstin, and Franjo Grotenhermen. “An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.” Cannabis and cannabinoid research vol. 2,1 139-154. 1 Jun. 2017, doi:10.1089/can.2016.0034
https://www.ncbi.nlm.nih.gov/p...

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