Medical Cannabis Use in Glioma Patients Treated at a Comprehensive Cancer Center in Florida

Abstract

Background:

Glioma is a devastating primary tumor of the central nervous system with difficult-to-manage symptoms. Cannabis products have been postulated to potentially benefit glioma patients. Recent state legalization allowed investigators an opportunity to study glioma patients' adoption of medical marijuana (MM).

Objective:

Our goals were to: (1) determine the prevalence of marijuana use, both through physician recommendation and self-medication, and (2) evaluate its perceived risks and benefits in glioma patients.

Design:

Self-report data were collected and descriptive analyses were conducted.

Setting/Subjects:

Participants were adult, English-speaking patients undergoing treatment for primary non-recurrent malignant glioma in neuro-oncology clinics at an NCI-designated Comprehensive Cancer Center.

Measurements:

The survey on MM was adapted from previous research and included questions on knowledge and attitudes toward MM; use, frequency, type, and sourcing of MM; and reasons for use of MM and perceived symptom relief among users.

Results:

A total of 73 patients were surveyed. The majority of participants were aware that MM was legal in the state, and most reported learning of this through the media. Over 70% of participants reported having considered using MM, and a third reported using marijuana products after their diagnosis. Most received recommendations from friends/family rather than a medical provider, and only half of the users had obtained a physician's recommendation. Users generally reported benefits.

Conclusions:

With the increasing national conversation that accompanies legalization, glioma patients are pursuing marijuana for the treatment for their symptoms. More research and education is needed to bring health care providers into the conversation.

Introduction

Glioma is a devastating primary tumor of the central nervous system. Tumors arise from glial cells, including astrocytes and oligodendrocytes, which comprise >90% of brain volume.¹ Gliomas in adults include grade IV tumors (glioblastoma [GBM]; 9440–9441) that comprise ∼60% of all glioma diagnoses,² and grade III (9382, 9401, 9451) and grade II (9400, 9410, 9411, 9420, 9424, 9425, 9540) astrocytoma, oligodendroglioma, and oligoastrocytoma. In 2018, an estimated 23,880 new cases of brain and other nervous system cancers and 16,830 deaths will occur in the United States.³ The five-year relative survival rate in GBM, the most common and aggressive malignant brain tumor, is ∼5%.⁴ Florida has one of the highest annual average numbers of persons diagnosed with glioma in the nation.⁵ Common symptoms and side effects include seizure, nausea and vomiting, and headache.^6–8

To address the neurologic symptoms associated with glioma, patients are often prescribed glucocorticoids (levetiracetam followed by lacosamide or valproic acid are agents of choice); however, long-term steroid use may have adverse effects.⁹ While standard management for grade III–IV tumors—maximal safe resection followed by chemoradiation¹⁰—may be associated with temporary amelioration of symptoms, the majority of patients suffer declining functional and cognitive status as the tumor progresses.¹¹

Cannabinoid therapies, or medical marijuana (MM) including marijuana and cannabidiol (CBD) products, may be a useful adjunct to steroids and palliative therapies to improve symptom management.¹² Proposed properties of cannabis that may be of use in glioma patients include analgesia, muscle relaxation, sedation, improvement of mood, stimulation of appetite, and antiemesis.¹³ Moreover, the use of cannabinoid therapies could be effective in improving quality of life and compliance or adherence with life-extending treatments.¹⁴ Cannabinoids act in the body by mimicking endogenous substances—the endocannabinoids—that exert widespread physiological actions in the body through the activation of two cell surface receptors, cannabinoid type 1 (CB1) and CB2.¹⁵ CB1 is widely expressed in the brain,¹⁶ whereas CB2 is found primarily in the immune system. Both receptors are expressed by normal glial cells and by gliomas, and the activation of these receptors has been found to regulate cellular differentiation, function, and cell viability.^17,18 In vitro studies suggest a possible therapeutic role for cannabinoids via the inhibition of tumor proliferation and angiogenesis, induction of tumor cell death, and inhibition of invasiveness and stem cell-like properties of GBM.^19–21

While the neuroprotective effects of marijuana have been postulated,^22–24 chronic habitual recreational cannabis is associated with potential adverse side effects²⁵; in the brain, these include structural changes and functional impairments that may impact cognition.^26,27 Acutely, marijuana affects the cerebral blood flow²⁸ with transient changes in attention, memory, and impulse control.^29,30 Long-term marijuana use has been associated with psychiatric disorders^31–33 though evidence supporting a causal link is limited^34,35 and debated.³⁶ Two small studies suggested that marijuana may promote glioma development in the user³⁷ or in the children of maternal users.³⁸ The risks and benefits of marijuana use in patients with established glioma have not been studied.

The use of MM has increased sharply over the last several decades in the United States.³⁹ In 2013, ∼18 million American adults (7.6%) were current marijuana users.⁴⁰ About 10% of adult marijuana users report use for medical purposes,⁴¹ and the prevalence of self-medication with marijuana may be as high as 15–30%.⁴² Though still a schedule I drug at the federal level, in June 2017, Florida joined an increasing number of states and the District of Columbia in legalizing marijuana for medical uses though with a number of restrictions. Access to MM is limited to patients with a qualifying medical condition and who obtained an “MM card” upon the recommendation of a certified physician. MM must be obtained from 1 of ∼30 state-licensed dispensaries. Patients are not allowed under the current laws to grow or process their own cannabis. Legislation was accompanied by a mandate for research and education to guide statewide policy on MM use in the state.

The present report summarizes results of a six-month pilot project funded by the FL state legislature to study the adoption of MM by glioma patients at a neuro-oncology referral center in FL following its legalization in the state. Our goals were to: (1) determine the prevalence of marijuana use, both through physician recommendation and self-medication, and (2) evaluate MMs' perceived risks and benefits. Because MM use is expected to increase following its legalization in more states going forward, and eventually at the federal level, it is important to accelerate knowledge on MM use in this vulnerable patient population.

Subjects and Methods

Participants

Participants were recruited in neuro-oncology clinics at the Moffitt Cancer Center and Research Institute, an NCI-designated Comprehensive Cancer Center in Tampa, FL, between March 1, 2018 and August 31, 2018. Eligible patients had a histopathologically confirmed diagnosis of glioma; were aged ≥20 years; and were able to speak and write in English. All subjects provided written informed consent.

Procedures

Participants were recruited under an established protocol.^43–45 The study was reviewed and approved by the IRB at Moffitt. All patients completed a questionnaire on demographics, medical and psychosocial history, and use of MM. Whenever possible, questionnaires were completed in clinic via interview by a member of the study team. Otherwise, the patient was sent home with the questionnaire and a stamped, addressed return envelope. Given the sensitive nature of MM use, during consent discussion, patients were assured of the confidentiality of the data collected and that individual responses would not be shared with anyone outside of the research team, including health care providers. Survey questions on MM were adapted from those employed in previous research^46–51 and included sections on knowledge and attitudes toward MM; use, frequency, type, and sourcing; and reasons for use and perceived symptom relief among users. Participants were compensated $10 for completion of the survey.

Results

Of 91 patients approached, 73 (80%) consented and completed the questionnaire. Among nonparticipants, nine refused before (N = 7) or after (N = 2) providing informed consent, and nine either provided consent but died before completing the survey (N = 2) or failed to return the survey by mail and could not be reached by phone (N = 7).

Table 1 shows the demographic characteristics of our sample according to participation status. Participants had a median age of 51 (range 21–83), were 55% male, and 89% white. Approximately half (47%) had completed college, and most (72%) were currently married. All but one patient was a year-round resident of Florida. About half of the participants had a diagnosis of GBM (48%), were diagnosed within six months of the survey (52.1%), and had a high functional status (Karnofsky Performance Score ≥90; 43.8%). A spouse completed the survey for four of the participants (6%) who were in declining health. Compared with participants, nonparticipants as a group were slightly older (median age, 62 years) but were similar to participants in gender, education, marital status, Florida residence, and functional status. Nonparticipants were more likely to have high-grade tumors (78%) and to have been recently diagnosed with the brain tumor (72%).

Table 1.

Descriptive and Clinical Characteristics of Participants and Nonparticipants

	Nonparticipants ^a	Participants
Number	18	73
Median age at enrollment (range)	62 (30–81)	51 (21–83)

	%
Male	55.5	54.8
White	94.4	89.0
Completed college	50.0	47.9
Currently married	77.8	72.6
Year-round FL resident	100.0	98.6
Glioblastoma diagnosis	77.8	47.9
Diagnosed within six months	72.2	52.1
Karnofsky Performance Score ≥90	33.3	43.8
Survey completed by proxy	na	5.5

Nonparticipants refused before (N = 7) or after (N = 2) providing informed consent, or provided consent but were unable to complete the survey due to death occurring before completing the survey (N = 2), or failed to return the survey by mail and could not be reached by phone (N = 7).

Among the 73 respondents, 82% reported being aware that MM was legal in Florida. Participants reported becoming aware of the legalization of MM by reading the newspaper or watching television (67%), or were informed by a friend or family member (17%) or, less commonly, were told by a medical provider (3%). Six patients (10%) could not recall how they first became aware of MMs' legal status in FL.

A total of 51 (70%) respondents reported having considered using MM for brain tumor symptoms. Among the 22 patients that had not considered MM use, 6 did not think it would benefit them, 6 were worried about side effects, 2 thought it was illegal, and 4 reported another reason (e.g., unable due to employer drug policies, don't like drugs, no medical professional had advised it, wasn't available during chemoradiation treatment). Four patients did not answer the question.

Table 2 shows currency, frequency, and type of MM reported by brain tumor patients. A third of participants (n = 24; 32.8%) reported using marijuana or CBD oil at any time after their diagnosis, including 7 subjects that used in the past and 16 that were using it currently. Of those using it only in the past, patients reported a variety of reasons for noncurrent use (i.e., didn't need it any longer, it didn't work, lost it due to memory issues [can't remember where he put it], tumor recurred, didn't like the side effects). A total of 8 of 35 (22.9%) patients with GBM and 16 of 38 (42.1%) patients with lower-grade tumors reported ever using MM.

Table 2.

Use, Frequency, Type, and Sourcing of Medical Marijuana or Cannabidiol Oil Among Survey Respondents

		n (%)
Used marijuana or CBD oil at any time since brain tumor diagnosis		24 (32.8)
Currency^a	No	7 (29.2)
Currency^a	Yes	16 (70.8)
Type	Smoked or ingested marijuana only	12 (50.0)
	CBD oil only	8 (33.3)
	Marijuana and CBD oil	4 (16.7)
Frequency	Less than one day a week	6 (25.0)
	One to six days a week	4 (16.7)
	Once a day	5 (20.8)
	More than once a day	9 (37.5)
Doctor's prescription	No	13 (54.2)
Doctor's prescription	Yes	11 (45.8)
Who recommended^b	Friend	10 (41.6)
	Other family member	9 (37.5)
	Spouse	5 (20.8)
	Information obtained by patient (internet, TV)	4 (16.6)
	Oncologist	2 (8.3)
	Other health care provider	3 (12.5)
	Cancer support group	1 (4.1)
Where obtained^b	MM dispensary in FL	11 (45.8)
	Friends or family	11 (45.8)
	Online	2 (8.3)
	Retail (CBD oil users)	2 (8.3)
	From an unlicensed dealer	1 (4.2)
	Prefer not to answer	1 (4.2)

Currently using MM or CBD oil.

Subjects could select more than one response; counts sum to n > 24 MM users.

CBD, cannabidiol; MM, medical marijuana.

When considered by elapsed time since glioma diagnosis, among ever-users, 33% of those interviewed within six months of diagnosis and 67% of those interviewed more than six months after diagnosis reported such use.

Among 24 ever-users, 16 reported using smoked or ingested marijuana only (N = 12) or in combination with CBD oil (N = 4), and 8 reported using only CBD oil. Most ever-users reported at least daily use (N = 14). Among all users, a total of 11 participants (46%) had obtained a doctor's recommendation: 6 of 12 marijuana-only users, 2 of 8 CBD oil-only users, and 3 of 4 users of both marijuana and CBD oil. Friends and family members were most likely to have recommended MM use to the participant; only 5 patients reported that their oncologist or another health care provider had recommended MM. Among 16 marijuana users, 9 obtained it through a licensed dispensary, 6 obtained it from friends or family (none had a physician's recommendation), and 1 patient declined to answer this question; 1 patient that obtained marijuana through a dispensary also reported using CBD oil that was purchased online. Among eight CBD only-users, two obtained it through a dispensary, three reported obtaining it from family or friends, two purchased it at a retail establishment, and one purchased it online. Of note, several patients without a FL-issued MM card obtained MM through friends who obtained it for their own use in states (Colorado or California) where recreational marijuana is legal.

Table 3 displays reasons for MM use and reported symptom relief in respondents. Subjects were invited to report “all that apply” to a given list of symptoms. The most common reported indication for MM use was pain relief (14 of 24 users), followed by relief from nausea (13), as an appetite stimulant (12), for relaxation (13), to cope emotionally (10), for seizure management (5), or as a sleep aid (2). As a write-in response, three patients reported using MM to help shrink or control the growth of tumor. Overall, 20 of 24 marijuana users (83%) reported symptom relief from MM use, while the remaining 4 indicated it had no effect on their symptoms. No participant indicated worsening of symptoms due to MM use.

Table 3.

Reasons for Use of Medical Marijuana or Cannabidiol and Reported Symptom Relief Among Survey Respondents

	Symptom	Reported effect
	n (%)	Relief	No effect
Overall effect on symptoms		20 (83.3)	4 (16.7)
Symptoms
Pain relief	14 (58.3)	12 (85.7)	2 (14.3)
Nausea relief	13 (54.2)	12 (92.3)	1 (7.7)
Appetite stimulant	12 (47.8)	12 (100.0)	0
Relief through relaxation	13 (52.2)	13 (100.0)	0
Ability to cope emotionally	10 (39.1)	9 (90.0)	1 (10.0)
Decrease in spasm or tremors	5 (21.7)	5 (100.0)	0
Sleep aid	2 (8.7)	2 (100.0)	0

Discussion

Glioma often produces difficult symptoms for patients that may be compounded by the side effects of treatment. Given the challenges associated with the disease, it is unsurprising that many patients look for other means to help address symptoms and improve quality of life. With the recent legalization of MM, our results suggest that many glioma patients and their families are pursuing MM as a means to these ends. In our study, we found that a majority of glioma patients were open to MM use, and a third reported using MM for symptom relief, many on a daily basis. Notably, one-third of patients with a relatively recent diagnosis (diagnosed within six months of the interview) versus two-thirds of patients interviewed more than six months after the diagnosis reported ever using MM for the brain tumor, suggesting that patients increasingly seek such remedies over time.

Most participants in our study learned of legalization via the media, and previous research⁵² has shown that testimonials, such as those portrayed in the media, can impact patients' attitudes and beliefs about marijuana use. Media can portray a hyperbolic presentation of facts,⁵³ and misinformation can proliferate without regulation.⁵⁴ For example, several of the patients in our study reported, unprompted, that they were using marijuana to shrink their tumors. While there is promising early-stage research to this effect, there is currently no scientific evidence that this is true in humans. The lack of clear messaging may lead patients to believe untrustworthy sources and forego evidence-based treatments.

The majority of patients reported that friends and family members had suggested use of MM, whereas few indicated that a medical provider recommended doing so. Given the lack of reliable data on the potential risks and benefits, it is perhaps not surprising that providers are reluctant to discuss marijuana use with their patients.^55,56 Furthermore, physicians may not be aware of the regulations set forth in the enacted law⁵⁷ in their state. These facts have led to a call for MM to be included in medical curricula.⁵⁸

MM use was less commonly reported among patients with GBM (22.9%) than among patients with lower-grade tumors (42.1%). In parallel, more of the nonrespondents (four out of five) had a GBM, and nonparticipation was often related to poor health in these patients. Given the limited survival in many GBM patients, many do not survive long enough to seek out palliative symptom relief via MM.

Among MM users, the majority reported marijuana use, and 4 (17%) used both marijuana and CBD oil, whereas 8 (33%) reported using only CBD oil. CBD oil contains active ingredients of marijuana but without tetrahydrocannabinol (THC), the psychoactive component of marijuana. CBD oil is extracted from flowers, leaves, stem, and stalk of Cannabis sativa L. plants grown for marijuana and industrial hemp, a cannabis plant with low content of THC. In Florida, patients with a valid physician-recommended MM card can obtain CBD oil from a licensed dispensary. CBD oil from industrial hemp (i.e., with low THC content) can also be obtained legally, nationwide, from one of several companies operating under federal hemp legislation.⁵⁹ Among 12 CBD users in the current study, 2 reported purchasing it at a retail establishment (neither had a physician's recommendation), and since CBD-containing products cannot be purchased in this manner, CBD oil reported by these patients was likely to be hempseed oil, which can be purchased over the counter in FL as it contains little to no active CBD.⁶⁰ Data were too limited to examine the patterns of use according to MM subtype and any differences in reported subjective symptom relief.

Less than half (11/24; 46%) of MM users had obtained a physician's recommendation, all of whom obtained marijuana legally through a dispensary. A slight majority obtained marijuana from friends and family, online, or from an unlicensed dealer. Hence, the present data suggest that many patients and families seek out marijuana independent of the health care system in spite of legalization in the state.

Most participants reported marijuana use to be beneficial for symptoms such as pain, nausea, poor appetite, and anxiety, and none indicated adverse effects. This is in line with other studies supporting the benefits of marijuana for symptom management.¹² As noted above, several participants reported using marijuana to control the growth of primary tumor. While there is little evidence for this benefit in humans, laboratory studies suggest beneficial impacts on the indices of tumor control.^19–21 Whether MM has a therapeutic role in humans awaits results from observational research and randomized trials.

Research on the risks and benefits of MM is currently limited given the U.S. federal prohibition on marijuana and inconsistent^61,62 regulation by state and in other countries. In the face of conflicting evidence, some researchers support the continued therapeutic use of cannabis when conventional treatments are ineffective.⁶³ However, dose initiation and titration and monitoring patient response are important to ensure that patients are receiving enough active ingredients to be effective, but not more, and that patients do not experience adverse reactions.⁵⁶ More work is needed to create a scientific evidence base for educators and clinicians.⁵⁶

Strengths and Limitations

To the best of our knowledge, this is the first survey on the prevalence of MM use among glioma patients, and one of the first surveys of MM use in patients with any cancer diagnosis. A large proportion (80%) of eligible patients were enrolled, and nonparticipants were demographically similar to participants so that results should be generalizable to patients under care in an academic center (though, potentially, not to patients seeking treatment in other settings). However, due to the rapid progression of their tumors, nonparticipants were more likely to have a GBM diagnosis, and the prevalence of MM use in this subgroup is less certain. Data were too limited to link perceived benefits and risks to physical symptom changes as well as patients' quality of life; studies with these goals are under way.

Conclusion

Currently, a majority of glioma patients are exploring MM use, and many are doing so without input from their providers. Further research is needed on the benefits and risks of this practice to best advise patients as they cope with serious illnesses such as glioma.

Footnotes

Acknowledgments

The authors would like to thank the participants and their families from participating medical centers for their contributions. This work has been supported in part by the Survey Methods Core Facility at the H. Lee Moffitt Cancer Center and Research Institute, an NCI-designated Comprehensive Cancer Center (P30-CA076292). Funding was provided by the State of Florida Medical Marijuana Research and Education Coalition Pilot Grant Award (PI: K.M.E.).

Author Disclosure Statement

No competing financial interests exist.

References

Verkhratsky

, Butt

: Glial Neurobiology: A Textbook. Hoboken, NJ: John Wiley & Sons, 2007.

Ostrom

, Gittleman

, Liao

, et al.: CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol, 2017; 19:v1–v88.

Cronin

, Lake

, Scott

, et al.: Annual Report to the Nation on the Status of Cancer, part I: National cancer statistics. Cancer, 2018; 124:2785–2800.

Gittleman

, Boscia

, Ostrom

, et al.: Survivorship in adults with malignant brain and other central nervous system tumor from 2000–2014. Neuro Oncol, 2018; 20(Suppl 7):vii6–vii16.

American Cancer Society: Cancer Facts and Figures. Atlanta, GA: American Cancer Society, 2018.

Davies

, Clarke

: Early symptoms of brain tumours. J Neurol Neurosurg Psychiatry, 2004; 75:1205–1206.

Silvani

, Gaviani

, Lamperti

, et al.: Malignant gliomas: Early diagnosis and clinical aspects. Neurol Sci, 2011; 32(Suppl 2): S207–S208.

Rasmussen

, Hansen

, Laursen

, et al.: Epidemiology of glioma: Clinical characteristics, symptoms, and predictors of glioma patients grade I-IV in the the Danish Neuro-Oncology Registry. J Neurooncol, 2017; 135:571–579.

Deutsch

, Panageas

, Lassman

, Deangelis

: Steroid management in newly diagnosed glioblastoma. J Neurooncol, 2013; 113:111–116.

10.

Stupp

, Mason

, van den Bent

, et al.: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med, 2005; 352:987–996.

11.

Sizoo

, Pasman

, Dirven

, et al.: The end-of-life phase of high-grade glioma patients: A systematic review. Support Care Cancer, 2014; 22:847–857.

12.

Hall

, Christie

, Currow

: Cannabinoids and cancer: Causation, remediation, and palliation. Lancet Oncol, 2005; 6:35–42.

13.

Grotenhermen

: Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet, 2003; 42:327–360.

14.

Maida

, Daeninck

: A user's guide to cannabinoid therapies in oncology. Curr Oncol, 2016; 23:398–406.

15.

Howlett

, Abood

: CB1 and CB2 receptor pharmacology. Adv Pharmacol, 2017; 80:169–206.

16.

Matsuda

, Lolait

, Brownstein

, et al.: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature, 1990; 346:561–564.

17.

Stella

: Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia, 2010; 58:1017–1030.

18.

Zogopoulos

, Korkolopoulou

, Patsouris

, Theocharis

: The antitumor action of cannabinoids on glioma tumorigenesis. Histol Histopathol, 2015; 30:629–645.

19.

Dumitru

, Sandalcioglu

, Karsak

: Cannabinoids in glioblastoma therapy: New applications for old drugs. Front Mol Neurosci, 2018; 11:159.

20.

Guzman

: Cannabinoids: Potential anticancer agents. Nat Rev Cancer, 2003; 3:745–755.

21.

Likar

, Nahler

: The use of cannabis in supportive care and treatment of brain tumor. Neurooncol Pract, 2017; 4:151–160.

22.

Giacoppo

, Mandolino

, Galuppo

, et al.: Cannabinoids: New promising agents in the treatment of neurological diseases. Molecules, 2014; 19:18781–18816.

23.

Chiurchiu

, Leuti

, Maccarrone

: Cannabinoid signaling and neuroinflammatory diseases: A melting pot for the regulation of brain immune responses. J Neuroimmune Pharmacol, 2015; 10:268–280.

24.

Campos

, Fogaca

, Sonego

, Guimaraes

: Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res, 2016; 112:119–127.

25.

Cousijn

, Nunez

, Filbey

: Time to acknowledge the mixed effects of cannabis on health: A summary and critical review of the NASEM 2017 report on the health effects of cannabis and cannabinoids. Addiction, 2018; 113:958–966.

26.

Weinstein

, Livny

, Weizman

: Brain imaging studies on the cognitive, pharmacological and neurobiological effects of cannabis in humans: Evidence from studies of adult users. Curr Pharm Des, 2016; 22:6366–6379.

27.

Mandelbaum

, de la Monte

: Adverse structural and functional effects of marijuana on the brain: Evidence reviewed. Pediatr Neurol, 2017; 66:12–20.

28.

Amen

, Darmal

, Raji

, et al.: Discriminative properties of hippocampal hypoperfusion in marijuana users compared to healthy controls: Implications for marijuana administration in Alzheimer's dementia. J Alzheimers Dis, 2017; 56:261–273.

29.

Block

, O'Leary

, Hichwa

, et al.: Effects of frequent marijuana use on memory-related regional cerebral blood flow. Pharmacol Biochem Behav, 2002; 72:237–250.

30.

O'Leary

, Block

, Koeppel

, et al.: Effects of smoking marijuana on brain perfusion and cognition. Neuropsychopharmacology, 2002; 26:802–816.

31.

Fernandez-Espejo

, Viveros

, Nunez

, et al.: Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology (Berl), 2009; 206:531–549.

32.

Volkow

, Baler

, Compton

, Weiss

: Adverse health effects of marijuana use. N Engl J Med, 2014; 370:2219–2227.

33.

Hall

: What has research over the past two decades revealed about the adverse health effects of recreational cannabis use?. Addiction, 2015; 110:19–35.

34.

Ksir

, Hart

: Cannabis and Psychosis: A Critical Overview of the Relationship. Curr Psychiatry Rep, 2016; 18:12.

35.

Andrade

: Cannabis and neuropsychiatry, 1: Benefits and risks. J Clin Psychiatry, 2016; 77:e551–e554.

36.

Large

, Di Forti

, Murray

: Cannabis: Debated schizophrenia link. Nature, 2015; 527:305.

37.

Efird

, Friedman

, Sidney

, et al.: The risk for malignant primary adult-onset glioma in a large, multiethnic, managed-care cohort: Cigarette smoking and other lifestyle behaviors. J Neurooncol, 2004; 68:57–69.

38.

Kuijten

, Bunin

, Nass

, Meadows

: Gestational and familial risk factors for childhood astrocytoma: Results of a case-control study. Cancer Res, 1990; 50:2608–2612.

39.

Kerr

, Lui

, Ye

: Trends and age, period and cohort effects for marijuana use prevalence in the 1984–2015 US National Alcohol Surveys. Addiction, 2018; 113:473–481.

40.

Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-46. 2013.

41.

Compton

, Han

, Hughes

, et al.: Use of marijuana for medical purposes among adults in the United States. JAMA, 2017; 317:209–211.

42.

Braun

, Meyer

, Gagne

, et al.: Experts' perspectives on the role of medical marijuana in oncology: A semistructured interview study. Psychooncology, 2017; 26:1087–1092.

43.

Mulpur

, Nabors

, Thompson

, et al.: Complementary therapy and survival in glioblastoma. Neurooncol Pract, 2015; 2:122–126.

44.

Owens

, Craig

, Egan

, Reed

: Birth desires and intentions of women diagnosed with a meningioma. J Neurosurg, 2015; 122:1151–1156.

45.

Siegel

, Nabors

, Thompson

, et al.: Prediagnostic body weight and survival in high grade glioma. J Neurooncol, 2013; 114:79–84.

46.

Reinarman

, Nunberg

, Lanthier

, Heddleston

: Who are medical marijuana patients? Population characteristics from nine California assessment clinics. J Psychoactive Drugs, 2011; 43:128–135.

47.

Meersseman

, Vanhoutte

, Van Damme

, et al.: A comparative study of screening instruments and biomarkers for the detection of cannabis use. Subst Abus, 2016; 37:176–180.

48.

Cuttler

, Spradlin

: Measuring cannabis consumption: Psychometric properties of the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU). PLoS One, 2017; 12:e0178194.

49.

Webb

, Webb

: Therapeutic benefits of cannabis: A patient survey. Hawaii J Med Public Health, 2014; 73:109–111.

50.

McGriff

, Anderson

, Arneson

: Early survey results from the Minnesota Medical Cannabis Program. Minn Med, 2016; 99:18–22.

51.

Pergam

, Woodfield

, Lee

, et al.: Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer, 2017; 123:4488–4497.

52.

Sznitman

, Lewis

: Examining effects of medical cannabis narratives on beliefs, attitudes, and intentions related to recreational cannabis: A web-based randomized experiment. Drug Alcohol Depend, 2018; 185:219–225.

53.

Robledo

, Jankovic

: Media hype: Patient and scientific perspectives on misleading medical news. Mov Disord, 2017; 32:1319–1323.

54.

MacCoun

, Mello

: Half-baked—The retail promotion of marijuana edibles. N Engl J Med, 2015; 372:989–991.

55.

Brooks

, Gundersen

, Flynn

, et al.: The clinical implications of legalizing marijuana: Are physician and non-physician providers prepared?. Addict Behav, 2017; 72:1–7.

56.

Ziemianski

, Capler

, Tekanoff

, et al.: Cannabis in medicine: A national educational needs assessment among Canadian physicians. BMC Med Educ, 2015; 15:52.

57.

Sideris

, Khan

, Boltunova

, et al.: New York Physicians' perspectives and knowledge of the state medical marijuana program. Cannabis Cannabinoid Res, 2018; 3:74–84.

58.

Abazia

, Bridgeman

: Reefer madness or real medicine? A plea for incorporating medicinal cannabis in pharmacy curricula. Curr Pharm Teach Learn, 2018; 10:1165–1167.

59.

Mead

: The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy Behav, 2017; 70:288–291.

60.

Pavlovic

, Nenna

, Calvi

, et al.: Quality traits of “Cannabidiol Oils”: Cannabinoids content, terpene fingerprint and oxidation stability of European commercially available preparations. Molecules, 2018; 23:E1230.

61.

Kramer

: Medical marijuana for cancer. CA Cancer J Clin, 2015; 65:109–122.

62.

Pacula

, Powell

, Heaton

, Sevigny

: Assessing the effects of medical marijuana laws on marijuana use: The devil is in the details. J Policy Anal Manage, 2015; 34:7–31.

63.

Sachs

, McGlade

, Yurgelun-Todd

: Safety and toxicology of cannabinoids. Neurotherapeutics, 2015; 12:735–746.