Is Medical Cannabis Overly Promoted In Minnesota?

 

Karl Marx wrote his famous metaphor about religion being an opiate for the proletariat in 1843:

“Religious suffering is, at one and the same time, the expression of real suffering and a protest against real suffering. Religion is the sigh of the oppressed creature, the heart of a heartless world, and the soul of soulless conditions. It is the opium of the people.”

He suggests in the next paragraph that the abolition of religion would rid people of the illusory happiness and it would be more consistent with the goal of real happiness for the people.  Marx’s formulation has not withstood the test of time. There is no more happiness now with widespread secularism than there was in Marx’s day.  Despite that fact - his metaphor survives and I thought about it quite a lot as I read through the Minnesota Medical Cannabis Program Report (MMCP) Anxiety Disorder Review.  The main difference of course is that cannabis is an equivalent metaphor only at the level of the idea of what medical cannabis can do.  When some writers suggest that religion can cause people to sleep and dream unrealistically, cannabis can physically do the same thing.  But it is promoted as doing many other things for many people – despite a profound lack of evidence.

The MMCP has been around for a number of years. I have taken the longstanding position that the medical cannabis concept is basically a way to legitimize cannabis and eventually get it legalized. I have also taken the position that physicians should not be involved in what is essentially a political maneuver.  The grandest aspect of that political maneuver has been the MMCP acting as a mini-FDA and coming up with their own indications for cannabis use. Initially, the idea was to use cannabis for the treatment of chronic pain and hospice care. I attended one of the early CME courses where most of the speakers were pain doctors and oncologists. Psychiatric input on these decisions has generally been minimal, despite the fact that psychiatric populations are at the highest risk from cannabis exposure and psychiatrists typically see most of the complications of cannabis.  The initiative to treat anxiety (in all forms) has not been approved by the MMCP and they state that was the reason for a more detailed look at the literature on cannabis as a treatment for anxiety and producing the report. 

Reading the report is an interesting exercise. It is not written very much from a scientific standpoint. They are very explicit about what they are considering as evidence.  For example they consider a literature search, a small panel of experts that does not really come to any consensus, and the experience of other states with medical cannabis and the indication of anxiety to be the basis for the report.  There are significant problems with all of those sources. 

 

The Research Matrix

At first the Research Matrix of papers included in the appendix looks impressive. There are 30 papers listing the reference, study type, total number of participants, dose and results.  Reading through the studies - some are single person case reports, some are reviews, and there are 15 studies listed as randomized controlled trials (RCTs). Looking at the RCTs there are probably one or two studies with an adequate number of participants to be adequately powered to show a statistical difference. Additional problems include the lack of an actual anxiety diagnosis.  In fact the diagnoses involved were frequently not anxiety related at all. Three observational studies at the end probably had the most merit and their results were equivocal. So the research studies really add nothing toward answering the question of whether medical cannabis should be used to treat anxiety and certainly nothing about the dose, delivery, or cannabis subtype.

Experience of Other States

Tables 1 summarizes the information about how other states have handled the question about medical cannabis and anxiety.  The states listed are Nevada, New Jersey, North Dakota and Pennsylvania.  In Nevada and North Dakota, the legislatures were petitioned to add anxiety (as DSM-5 Generalized Anxiety Disorder) to the medical cannabis formulary.  In New Jersey and Pennsylvania it was a commissioner decision. The Pennsylvania Secretary of Health was described as being “proactive” by suggesting that medical cannabis for anxiety was a “tool in the toolbox” and recommended duration of use, specific formulations, and avoidance in teenagers.  In all 4 states where cannabis was approved, anxiety quickly rose to the top or second most frequent indication for prescribing medical cannabis. None of the states collects any outcome data. 

What about other countries with more experience with cannabis like the Netherlands?  I contacted a colleague there who forwarded my questions to 2 other psychiatrists who were anxiety experts and doing active research in the area.  They responded that medical cannabis was not prescribed for anxiety and that there was a medical cannabis site for the Netherlands.  The site suggests that a CBD product is recommended. They had the same concerns about THC causing anxiety and psychosis.  A direct comparison of the indications for medical cannabis use comparing the Minnesota program to the Netherlands is included in the following table and linked directly to the respective web sites.

Medical Cannabis Qualifying Conditions

Minnesota   Cancer associated with severe/chronic pain, nausea or severe vomiting, or cachexia or severe wasting Glaucoma HIV/AIDS Tourette syndrome Amyotrophic lateral sclerosis (ALS) Seizures, including those characteristic of epilepsy Severe and persistent muscle spasms, including those characteristic of multiple sclerosis Inflammatory bowel disease, including Crohn’s disease Terminal illness, with a probable life expectancy of less than one year* Intractable pain Post-traumatic stress disorder Autism spectrum disorder (must meet DSM-5) Obstructive sleep apnea Alzheimer's disease Chronic pain Sickle cell disease Chronic motor or vocal tic disorder

The Netherlands   Pain, muscle cramps and twitching in multiple sclerosis (MS) or spinal cord injury; nausea, loss of appetite, weight loss and weakness in cancer and AIDS; nausea and vomiting due to medication or radiation treatment for cancer, HIV infection and AIDS; long-lasting pain of a neurogenic nature (cause is in the nervous system) for example due to damage to a nerve pathway, phantom pain, facial pain or chronic pain that persists after shingles has healed; tics in Tourette's syndrome; treatment-resistant glaucoma

 Expert Consensus

In terms of the professional consensus, the participants were described as  3 psychiatrists, a pediatrician, a person in recovery, a primary care physician, and a marriage and family therapist. On a scale of recommendations, there was one vote for non-approval, one vote in favor of a limited pilot study and follow-up outcomes, one vote for neutral not opposed, three votes in favor of considering for generalized anxiety disorder, panic disorder, and agoraphobia. No consideration is given to the experience of the physicians or the asymmetry of expertise. It appears to be a political approach to neutralizing the opinion of the group of physicians (psychiatrists) who essentially are left treating the complications of cannabis use disorder.  Those complications include acute mania or psychosis, anxiety and panic, chronic depression and amotivational syndromes, and significant cognitive problems.  Cannabis obscures whether the patient has a true psychiatric diagnosis or not.  It also destabilizes psychiatric disorders. That is the common theme I noted above.  This is really not expert consensus – it is a man-on-the street poll.

Apart from the very weak lines of evidence, some of the conclusions in this document are even worse.  There are basically 6 common themes:

1:  Protect the brain: There are longstanding concerns about the new timetable for brain development extending into the mid to late 20s. This is a peak period for drug experimentation and heavy use of alcohol and most substances. There appears to be consensus on this theme and I would agree.

2:  Safer alternative to benzodiazepines: the rationale here is much rockier.  The authors in this case cite the increase in benzodiazepine overdose deaths in the state of Minnesota, but the quality of this data is not clear.  I took a look at the data and contacted the Minnesota Department of Health about it – specifically if opioids were excluded as a primary cause along with fentanyl being sold as benzodiazepines. I was informed by an epidemiologist that a T42.4 code was present and the coding is not mutually exclusive. In other words, more drugs may be involved and fentanyl may have been involved. The death certificates and toxicology confirmations are dependent on the county medical examiner. The accuracy of the data is therefore in question. There are clearly ways to safely prescribe benzodiazepines.  Benzodiazepines are research proven alternatives for severe anxiety when conventional treatments have failed as a tertiary medication and cannabis is not.

In terms of addiction risk, the risk with cannabis is 8-12% overall and 17% for people who start using cannabis in their teens (1-6).  That compares with an addiction liability of about 10% with benzodiazepines (7).  Benzodiazepines are used by people who are taking multiple addicting drugs to amplify the effect, treat withdrawal symptoms, and treat the anxiety and insomnia that accompanies chronic substance use or opioid agonist therapy.  This population is often acquiring benzodiazepines from non-medical sources. There is no real good evidence that medical cannabis will replace non-medical use of benzodiazepines in that setting, since benzodiazepines are easily acquired from non-medical sources.

3:  Therapy is the standard:  Therapy is not the standard. The standard is whatever works for a particular practice setting.  Psychiatrists see people who have already seen a therapist and quite probably a primary care physician where their anxiety was diagnosed with a rating scale. That means they will have failed therapy and at least one or two medication trials. Psychiatrists are not going to start treatment by repeating ineffective therapies. In many cases, substance use including cannabis use is the main reason for the anxiety disorder in the first place.

4: Health Equity:  This was perhaps the most unlikely reason for cannabis use. To emphasize how far this document goes off the rails I am going to quote this section directly:

 “Known disparities exist in the level of care available for anxiety disorder among historically disadvantaged communities. Medical cannabis may offer these individuals the option for an alternative to current medications, however this view was not shared by all participants.” (p.15)

Are the authors of this document really suggesting that disadvantaged communities should settle for a substance that has been inadequately studied, has known severe medical and psychiatric side effects, and is associated with higher rates of suicidal ideation and suicide attempts in these disadvantage communities (14) rather than providing them with standard care? That statement to me is quite unbelievable. It is the first time I have seen a recommendation to use a prescription substance to address a social problem.  It may happen by default – but if you really want to promote health equity equivalence evidence based treatments are the only acceptable standard.

When  "an alternative to current medications" is mentioned cost is not discussed as a factor. In my discussions with people who have received medical cannabis from the Minnesota dispensaries, high cost was often mentioned as a limiting factor. This current price list from one of the dispensing pharmacies shows that nearly all of their products are much more expensive than the generic antidepressants used to treat anxiety disorders.

5: Limited research:  Cannabis advocates point to the lack of research due to the fact that cannabis is a Schedule 1 compound. That means there is no known medical use and a high potential for abuse. Since certain compounds have been FDA approved for specific indications, I anticipate that these compounds will be rescheduled.  That is one of many hurdles in researching cannabis.  A few of the others would include the issue of subject selection (cannabis naïve or not), placebo controls, specific form (THC:CBD ratio), type of drug delivery, and a general methodology that would capture a good sample of persons with an anxiety disorder in adequate numbers for the trial.

6: Harm Reduction:  The authors suggest that medical cannabis could serve to limit exposure to other more harmful drugs obtained on the street to treat anxiety like benzodiazepines. There is no evidence that this would occur given the availability and preference for non-prescribed benzodiazepines.  The issue of polysubstance dependence is complex.  A significant number of opioid users also use benzodiazepines. Despite a black box warning about respiratory depression from using that combination, the FDA has been clear that the medications can be prescribed together. Further, a recent study suggests that retention in a methadone maintenance program was twice as likely if the patients received prescription benzodiazepines as opposed to non-prescription benzodiazepines (10).  No such data exists for cannabis.

In terms of substituting cannabis for benzodiazepines the only study I could find was a retrospective observational study of new patients in a cannabis clinic. Over the course of 2 months 30.1% were able to stop benzodiazepine use and at 6 months that number had increased to 45.2%.  These authors (11) conclude

“Without dependable safety data and evidence from randomized trials for this cohort, cannabis cannot be recommended as an alternative to benzodiazepine therapy.”

 The conclusion of this paper suggests the options of maintaining the status quo or no approval for anxiety, approve for a limited number of “subconditions” defined as specific anxiety disorders, or approve for anxiety disorders.  They list the pros and  cons associated with each approach but not much was added relative to the above discussion.  There are a few comments that merit further criticism. The risks of maintaining the status quo are seriously overstated.  From reviewing previous tabulated data from the MN Medical Cannabis program, it is unlikely that any meaningful real world data will be collected. It is not possible to collect non-randomized, uncontrolled data on a substance that is highly valued and reinforces its own use that has any meaning. The results will predictably be like the comments solicited by this program that are 96% favorable. There are similar speculative predictions of the direct consequences of not providing medical cannabis in terms of not seeking therapy if using cannabis off the street, suicides due to not tolerating SSRIs, and patient harm from “illicit use”. Similar speculation occurs throughout the remaining bullets points and there seems to be a strong pro-medical cannabis for anxiety disorders bias.

To summarize, I am not impressed with the Minnesota Medical Cannabis Program report on the use of medical cannabis for anxiety. It clashes with my 35 years of clinical experience where cannabis has been a major problem for the patients I treated in community mental health centers, clinics, substance use treatment centers, and hospitals. It suggests a great potential for a substance that has been around and used by man for over 7 millennia.  You would think with that history, man would have realized by now that it was a panacea for his most common mental health problem – anxiety. The report also ignores the commonest role of cannabis in American society and that is as an intoxicant and not a medication.  Physicians should not be prescribing intoxicants.  You don’t need a prescription to go to a liquor store and purchase alcoholic beverages. If the real goal is to get cannabis out to the masses, the option is legalization of cannabis not medical cannabis.

 

George Dawson, MD, DFAPA

 

References:

1:  Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol. 1994;2(3):244-268. doi:10.1037/1064-1297.2.3.244

2:  Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, et al. Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug Alcohol Depend. 2011;115(1-2):120-130. doi:10.1016/j.drugalcdep.2010.11.004

3:  Anthony JC. The epidemiology of cannabis dependence. In: Roffman RA, Stephens RS, eds. Cannabis Dependence: Its Nature, Consequences and Treat:ment. Cambridge, UK: Cambridge University Press; 2006:58-105.

4: NIDA. 2021, April 13. Is marijuana addictive?. Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana/marijuana-addictive on 2021, September 13.

5:  Moss HB, Chen CM, Yi HY (2012). Measures of substance consumption among substance users, DSM-IV abusers, and those with DSM-IV dependence disorders in a nationally representative sample. J Stud Alcohol Drugs 73: 820–828

6:  Perkonigg A, Goodwin RD, Fiedler A, Behrendt S, Beesdo K, Lieb R et al (2008). The natural course of cannabis use, abuse and dependence during the first decades of life. Addiction 103: 439–449 discussion 450–451.

7: Becker WC, Fiellin DA, Desai RA. . Non-medical use, abuse and dependence on sedatives and tranquilizers among U.S. adults: psychiatric and socio-demographic correlates. Drug Alcohol Depend. 2007; 90 2-3: 280- 7. DOI: 10.1016/j.drugalcdep.2007.04.009 PubMed PMID: 17544227.

 

Harm Reduction:

8: Okusanya BO, Asaolu IO, Ehiri JE, Kimaru LJ, Okechukwu A, Rosales C. Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: a systematic review. Syst Rev. 2020 Jul 28;9(1):167. doi: 10.1186/s13643-020-01425-3. PMID: 32723354; PMCID: PMC7388229.

9: Shover CL, Davis CS, Gordon SC, Humphreys K. Association between medical cannabis laws and opioid overdose mortality has reversed over time. Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):12624-12626. doi: 10.1073/pnas.1903434116. Epub 2019 Jun 10. PMID: 31182592; PMCID: PMC6600903.

10: Eibl JK, Wilton AS, Franklyn AM, Kurdyak P, Marsh DC. Evaluating the Impact of Prescribed Versus Nonprescribed Benzodiazepine Use in Methadone Maintenance Therapy: Results From a Population-based Retrospective Cohort Study. J Addict Med. 2019 May/Jun;13(3):182-187. doi: 10.1097/ADM.0000000000000476. PMID: 30543543; PMCID: PMC6553513.

11: Purcell C, Davis A, Moolman N, Taylor SM. Reduction of Benzodiazepine Use in Patients Prescribed Medical Cannabis. Cannabis Cannabinoid Res. 2019 Sep 23;4(3):214-218. doi: 10.1089/can.2018.0020. PMID: 31559336; PMCID: PMC6757237.

 

Cannabis and Psychosis:

12: Kuepper R, van Os J, Lieb R, Wittchen H, Höfler M, Henquet C et al. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study BMJ 2011; 342 :d738 doi:10.1136/bmj.d738

13: Murray RM, Mondelli V, Stilo SA, Trotta A, Sideli L, Ajnakina O, Ferraro L, Vassos E, Iyegbe C, Schoeler T, Bhattacharyya S, Marques TR, Dazzan P, Lopez-Morinigo J, Colizzi M, O'Connor J, Falcone MA, Quattrone D, Rodriguez V, Tripoli G, La Barbera D, La Cascia C, Alameda L, Trotta G, Morgan C, Gaughran F, David A, Di Forti M. The influence of risk factors on the onset and outcome of psychosis: What we learned from the GAP study. Schizophr Res. 2020 Nov;225:63-68. doi: 10.1016/j.schres.2020.01.011. Epub 2020 Feb 6. PMID: 32037203.

 

Cannabis Use and Suicide:

14:  Kelly LM, Drazdowski TK, Livingston NR, Zajac K. Demographic risk factors for co-occurring suicidality and cannabis use disorders: Findings from a nationally representative United States sample. Addict Behav. 2021 Nov;122:107047. doi: 10.1016/j.addbeh.2021.107047. Epub 2021 Jul 12. PMID: 34284313; PMCID: PMC8351371.

 

Cannabis Use and Life-Threatening Medical Problems:

15:  Ladha KS, Mistry N, Wijeysundera DN, Clarke H, Verma S, Hare GMT, Mazer CD. Recent cannabis use and myocardial infarction in young adults: a cross-sectional study. CMAJ. 2021 Sep 7;193(35):E1377-E1384. doi: 10.1503/cmaj.202392. PMID: 34493564.

16:  Parekh T, Pemmasani S, Desai R. Marijuana Use Among Young Adults (18-44 Years of Age) and Risk of Stroke: A Behavioral Risk Factor Surveillance System Survey Analysis. Stroke. 2020 Jan;51(1):308-310. doi: 10.1161/STROKEAHA.119.027828. Epub 2019 Nov 11. PMID: 31707926.

17:  Shah S, Patel S, Paulraj S, Chaudhuri D. Association of Marijuana Use and Cardiovascular Disease: A Behavioral Risk Factor Surveillance System Data Analysis of 133,706 US Adults. Am J Med. 2021 May;134(5):614-620.e1. doi: 10.1016/j.amjmed.2020.10.019. Epub 2020 Nov 9. PMID: 33181103.

18:  Desai R, Fong HK, Shah K, Kaur VP, Savani S, Gangani K, Damarlapally N, Goyal H. Rising Trends in Hospitalizations for Cardiovascular Events among Young Cannabis Users (18-39 Years) without Other Substance Abuse. Medicina (Kaunas). 2019 Aug 5;55(8):438. doi: 10.3390/medicina55080438. PMID: 31387198; PMCID: PMC6723728.

Pharmacokinetics and Adverse Effects of Cannabis:

19:  Schlienz NJ, Spindle TR, Cone EJ, Herrmann ES, Bigelow GE, Mitchell JM, Flegel R, LoDico C, Vandrey R. Pharmacodynamic dose effects of oral cannabis ingestion in healthy adults who infrequently use cannabis. Drug Alcohol Depend. 2020 Mar 21;211:107969. doi: 10.1016/j.drugalcdep.2020.107969. Epub ahead of print. PMID: 32298998; PMCID: PMC8221366.

20: Spindle TR, Cone EJ, Goffi E, Weerts EM, Mitchell JM, Winecker RE, Bigelow GE, Flegel RR, Vandrey R. Pharmacodynamic effects of vaporized and oral cannabidiol (CBD) and vaporized CBD-dominant cannabis in infrequent cannabis users. Drug Alcohol Depend. 2020 Jun 1;211:107937. doi: 10.1016/j.drugalcdep.2020.107937. Epub 2020 Apr 1. PMID: 32247649; PMCID: PMC7414803.

21:  Spindle TR, Martin EL, Grabenauer M, Woodward T, Milburn MA, Vandrey R. Assessment of cognitive and psychomotor impairment, subjective effects, and blood THC concentrations following acute administration of oral and vaporized cannabis. J Psychopharmacol. 2021 Jul;35(7):786-803. doi: 10.1177/02698811211021583. Epub 2021 May 28. PMID: 34049452. 

22:  Spindle TR, Cone EJ, Schlienz NJ, Mitchell JM, Bigelow GE, Flegel R, Hayes E, Vandrey R. Acute Effects of Smoked and Vaporized Cannabis in Healthy Adults Who Infrequently Use Cannabis: A Crossover Trial. JAMA Netw Open. 2018 Nov 2;1(7):e184841. doi: 10.1001/jamanetworkopen.2018.4841. Erratum in: JAMA Netw Open. 2018 Dec 7;1(8):e187241. PMID: 30646391; PMCID: PMC6324384.

Vaping and Pulmonary Toxicology:

23:  Meehan-Atrash J, Rahman I. Cannabis Vaping: Existing and Emerging Modalities, Chemistry, and Pulmonary Toxicology. Chem Res Toxicol. 2021 Oct 8. doi: 10.1021/acs.chemrestox.1c00290. Epub ahead of print. PMID: 34622654.

24:  Tehrani MW, Newmeyer MN, Rule AM, Prasse C. Characterizing the Chemical Landscape in Commercial E-Cigarette Liquids and Aerosols by Liquid Chromatography-High-Resolution Mass Spectrometry. Chem Res Toxicol. 2021 Oct 5. doi: 10.1021/acs.chemrestox.1c00253. Epub ahead of print. PMID: 34610237.

25:  McDaniel C, Mallampati SR, Wise A. Metals in Cannabis Vaporizer Aerosols: Sources, Possible Mechanisms, and Exposure Profiles. Chem Res Toxicol. 2021 Oct 27. doi: 10.1021/acs.chemrestox.1c00230. Epub ahead of print. PMID: 34705462.

Epidemiology:

26: Lim CCW, Sun T, Leung J, et al. Prevalence of Adolescent Cannabis Vaping: A Systematic Review and Meta-analysis of US and Canadian Studies. JAMA Pediatr. Published online October 25, 2021. doi:10.1001/jamapediatrics.2021.4102

Prevalence of cannabis vaping by adolescents has recently increased for lifetime use, use in the past 30 days and use in the past year.

Maternal Cannabis Use and Anxiety in Offspring:

Rompala G, Nomura Y, Hurd YL. Maternal cannabis use is associated with suppression of immune gene networks in placenta and increased anxiety phenotypes in offspring. Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2106115118. doi: 10.1073/pnas.2106115118. PMID: 34782458.

LaSalle JM. Placenta keeps the score of maternal cannabis use and child anxiety. Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2118394118. doi: 10.1073/pnas.2118394118. PMID: 34789581.

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