Cannabis Legalization: What Psychiatrists Need to Know

SPECIAL REPORT: SUBSTANCE USE

In the United States, cannabis is a Schedule I drug. However, legislative matters have effectively allowed each state to manage legalized recreational cannabis. This patchwork has led to disparities in state versus federal regulations regarding recreational cannabis that, coupled with myths about its psychological benefits, increase confusion for our patients. This article will summarize changes in cannabis legislation and provide an update for psychiatrists on the evidence both for and against its clinical utility.

Cannabis Legalization: What’s New?

Eighteen states (and Washington, DC, and Guam) have adopted legalized recreational cannabis use, and 37 (plus DC, Guam, Puerto Rico, and the US Virgin Islands) have approved medicinal use. While this patchwork leads to disparities in medical care and arrests across states, it allows for comparisons in mental health trends related to legalization. Longitudinal analysis of 505,796 respondents found an increased diagnosis of cannabis use disorder (CUD) in individuals aged 12 to 17 years (2.2% to 2.7%) and 26 years and over (0.9% to 1.2%) after legalization, which was not mirrored in states where it remains illegal.¹ However, there was no increase in CUD prevalence for respondents aged 18 to 25 years.¹

Evidently, for consumers to make informed choices and to reduce potential harms, legalization alone may be risky and should be coupled with increases in evidence-based education and access to treatment, especially for at-risk groups such as adolescents and individuals with mental illnesses.

Cannabis Use Disorder (CUD)

CUD refers to continuous excessive use, characterized by a loss of control, psychological and social impairments, and risky behavior. The prevalence of CUD (ages 12+) is around 2.9% in the United States,² with males having rates twice that of than females.³ However, in psychiatric patient samples, CUD prevalence reaches ~25%.⁴ Individuals with mental illnesses and other SUDs may be more susceptible to CUD because of shared genetic and environmental factors increasing vulnerability,⁴ or because of overuse in an effort to manage symptoms (ie, coping with negative affect).⁴ There is the popular perception that cannabis is an effective tool in managing anxiety, mood, and eating disorders, but evidence to support self-medication is minimal.⁴

Cannabis and Mental Health: The Facts

The 2 main psychoactive ingredients in cannabis are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is known to produce the characteristic “high” from inhalation of cannabis because of its high-affinity for cannabinoid type 1 (CB1) receptors in the mesolimbic dopamine system; CBD antagonizes these effects, but the exact mechanism is unclear.⁵

THC: The acute effects of THC intoxication, including at higher doses, are outlined in the Table. Cannabis misuse is associated with first-episode psychosis, longer psychotic episodes, more positive symptoms, and poorer psychosocial functioning in individuals with schizophrenia.⁴ Such effects directly correlate with THC dose and potency; evidence suggests a dose-dependent relationship between cannabis use and schizophrenia that cannot be explained by use of other psychoactive substances.⁶ Similarly, in bipolar disorder, cannabis use is associated with earlier onset of depressive, manic, and psychotic episodes and more frequent suicide attempts,⁷ with high THC as the culprit. Moreover, longitudinal studies on bipolar disorder show lower rates of treatment adherence and greater symptom severity, particularly mania and psychosis, in bipolar cannabis users.⁸

Less clear is the interaction between THC and depression. While cannabis prevalence in depression is high,⁴ longitudinal studies have provided modest evidence on whether cannabis use increases depression.⁹ Infrequent use may not be related to depression, whereas heavy use is more likely to increase symptoms.¹⁰ Similarly, evidence on cannabis as a risk factor for anxiety disorders is modest, with some prospective studies showing greater risk of developing anxiety disorders and more anxious symptoms in cannabis users,⁴ while others have failed to replicate such findings.^4,9 These inconsistencies might be explained by genetic differences¹¹ or the dose-dependent nature of THC intoxication, with low doses eliciting feelings of relaxation and euphoria, while higher doses result in dysphoria, panic, and paranoia. Moreover, extensive exposure to THC over time may paradoxically increase anxiety via changes in allostatic load.⁴ Despite claims that cannabis helps reduce depression and anxiety, we found no controlled clinical trials suggesting its effectiveness. In fact, in a recent study of 28 days of cannabis abstinence in people with major depression, there was a significant improvement in depressive and anxiety symptoms, sleep problems, and anhedonia with extended cannabis abstinence, which argues against self-medication of mood symptoms by cannabis use.¹²

CBD: Conversely, CBD does not produce intoxication. Rather, it has been shown to antagonize CB1 and CB2 receptors, thus opposing effects of THC. Preclinical models suggest a range of potential therapeutic benefits of CBD as a function of antipsychotic, neuroprotective, anxiolytic, and sedating properties.¹³ For example, animal models suggest that CBD might produce antidepressant effects via serotonergic neurotransmission, in particular activation of 5-HT1A receptors.¹⁴

Preliminary evidence in human studies is similarly encouraging: CBD may produce antianxiety and antidepressant effects.¹⁵ Interestingly, increased doses are not associated with dysphoria or anxiety as is found with increased THC doses. One study found that administration of CBD produced functional changes in anxiety-related limbic and paralimbic cortical areas that were further associated with a reduction in state anxiety.¹⁶ Moreover, there is evidence that CBD 200 to 1500 mg daily may alleviate psychotic symptoms through inhibition of anandamide metabolism and reduce cognitive impairments through CB1 and CB2 receptor agonism in schizophrenia.^13,17

One case study even found improvements in symptoms of schizophrenia where the individual had previously failed to respond to olanzapine, clozapine, or haloperidol.¹³ Even where findings are null, CBD is well tolerated and does not worsen symptoms.¹⁸ Thus, emerging evidence on anxiolytic, antipsychotic, and antidepressive effects of CBD is promising. Of note, there are a number of drug interactions between CBD and common psychiatric medications that need to be considered when prescribing CBD.¹⁹

In addition, some studies have found support for the use of CBD in treating cannabis-related issues. Specifically, CBD at 40 to 100 mg daily has been shown to improve cannabis withdrawal symptoms,¹³ which may help participants avoid using to alleviate withdrawal. Other open-label studies have found that CBD increased rates of abstinence and reduced the amount of cannabis used by participants.¹³

Unfortunately, trends observed in concentrations of THC and CBD in cannabis in licit and illicit markets have seen the former increasing from an average of 4% to as high as 25% to 30%, and the latter decreasing from 0.28% to less than 0.15% (1995-2014).²⁰ This imbalance precludes the opposing effects of CBD on THC intoxication, increasing the risk of experiencing harms associated with high doses of THC.

Cannabis Legalization and the Opioid Toxicity Crisis

The rapidly increasing rates of opioid-related poisonings has galvanized health care providers, advocates, and governments to find solutions to overprescription of opioids and the toxicity of the illicit opioid market (eg, carfentanil). It has been proposed that legalization of cannabis may play a role in curbing the opioid crisis.

A few studies have attempted to answer this question. Initially, Bachhuber et al²¹ suggested that in states with medical cannabis laws, rates of fatal opioid overdoses were reduced after implementation of these laws. However, more recent studies have suggested the opposite²² and that frequency of cannabis use, in fact, correlates with the severity of opioid use disorder.²³ These studies, although methodologically sound, are not entirely sufficient to answer the question of whether cannabis legalization may curb the opioid crisis—a broad and somewhat vague claim. Examining a few scenarios will help highlight the importance of defining the potential role of cannabis legalization in reducing opioid overdoses.

For those who have not been exposed to opioids, prescription of high-dose opioids long term may increase the risk of developing opioid use disorder²⁴ that may in turn result in transition to use of illicit opioids (eg, heroin, fentanyl).²⁵ In these cases, prescribing cannabis for pain management may, in fact, reduce the chances of introduction to and dependency on opioids.

It has also been suggested that recreational cannabis use may act as a “gateway drug” that encourages transition to use of other drugs, such as opioids. In states where cannabis remains illegal, 1 potential mechanism of this transition (if it occurs) is introduction to the illicit market, criminal networks, and potentially the judicial system if one were arrested. In this instance, legalization of cannabis means individuals could access regulated amounts without having to go through illicit sources.

However, for individuals who already have an opioid use disorder that has arisen from a complex array of biological, psychological, and social circumstances, legalization of cannabis may not affect their use of opioids. Rather, as suggested by Olfson et al,²² we may see that individuals continue to use opioids alone or with cannabis and thus would likely benefit more from a specific and targeted opioid use disorder intervention.

As such, well-controlled longitudinal studies are needed to adequately investigate the clinical and public health relationships between cannabis use and opioid toxicity.

Concluding Thoughts

While there remains a dearth of clinical research on the benefits of cannabis, particularly in individuals with mental illnesses, the evidence suggests they are likely outweighed by the harms of (high-THC) cannabis. However, the question is no longer should cannabis be legalized? The question is how can we effectively promote evidence-based public health messaging around cannabis, regulate available supplies to achieve an appropriate balance of THC and CBD, and increase access to CUD treatment?

Ms Johnstone is a research analyst at the Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada. Dr Hill is an associate professor of psychiatry at Harvard Medical School, and director of addiction psychiatry at Beth Israel Deaconess Medical Center (BIDMC) in Boston, Massachusetts. Dr George is professor of psychiatry, Temerty Faculty of Medicine, at the University of Toronto, and senior physician-scientist at CAMH in Toronto, Ontario, Canada. He is currently deputy editor and incoming coprincipal editor of Neuropsychopharmacology (NPP).

Acknowledgements: This work was funded in part by NIH grant R21-DA-043949 to Dr George.

References

1. Cerdá M, Mauro C, Hamilton A, et al. Association between recreational marijuana legalization in the United States and changes in marijuana use and cannabis use disorder from 2008 to 2016. JAMA Psychiatry. 2020;77(2):165-171.

2. Hasin DS. US epidemiology of cannabis use and associated problems. Neuropsychopharmacology. 2018;43(1):195-212.

3. Kozak K, H Smith P, Lowe DJE, et al. A systematic review and meta-analysis of sex differences in cannabis use disorder amongst people with comorbid mental illness. Am J Drug Alcohol Abuse. 2021;47(5):535-547.

4. Lowe DJE, Sasiadek JD, Coles AS, George TP. Cannabis and mental illness: a review. Eur Arch Psychiatry Clin Neurosci. 2019;269(1):107-120.

5. de Almeida DL, Devi LA. Diversity of molecular targets and signaling pathways for CBD. Pharmacol Res Perspect. 2020;8(6):e00682.

6. D’Souza DC, Pearlson GD, Selloni A, et al. A review of cannabis and cannabinoids in schizophrenia and psychotic disorders. World J Biol Psychiatry; 2022. In press.

7. Polkosnik GL, Sorkhou N, George TP. Effects of cannabis use on psychotic and mood symptoms: a systematic review. Can J Addict. 2021;12(3).

8. van Rossum I, Boomsma M, Tenback D, et al; EMBLEM Advisory Board. Does cannabis use affect treatment outcome in bipolar disorder? A longitudinal analysis. J Nerv Ment Dis. 2009;197(1):35-40.

9. Gobbi G, Atkin T, Zytynski T, et al. Association of cannabis use in adolescence and risk of depression, anxiety, and suicidality in young adulthood: a systematic review and meta-analysis. JAMA Psychiatry. 2019;76(4):426-434.

10. Degenhardt L, Hall W, Lynskey M. Exploring the association between cannabis use and depression. Addiction. 2003;98(11):1493-1504.

11. Otten R, Huizink AC, Monshouwer K, et al. Cannabis use and symptoms of anxiety in adolescence and the moderating effect of the serotonin transporter gene. Addict Biol. 2017;22(4):1081-1089.

12. Lucatch A, Kloiber S, Meyer J, et al. Effects of extended cannabis abstinence in major depressive disorder. Can J Addict. 2020;11:33-41.

13. Khan R, Naveed S, Mian N, et al. The therapeutic role of cannabidiol in mental health: a systematic review. J Cannabis Res. 2020;2(1):2.

14. Silote GP, Sartim A, Sales A, et al. Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms. J Chem Neuroanat. 2019;98:104-116.

15. Zieba J, Sinclair D, Sebree T, et al. Cannabidiol (CBD) reduces anxiety-related behavior in mice via an FMRP-independent mechanism. Pharmacol Biochem Behav. 2019;181:93-100.

16. Crippa JA, Derenusson GN, Ferrari TB, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011;25(1):121-130.

17. Leweke FM, Mueller JK, Lange B, et al. Role of the endocannabinoid system in the pathophysiology of schizophrenia: implications for pharmacological intervention. CNS Drugs. 2018;32(7):605-619.

18. Boggs DL, Surti T, Gupta A, et al. The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. Psychopharmacology (Berl). 2018;235(7):1923-1932.

19. Hill KP, Gold MS, Nemeroff CB, et al. Risks and benefits of cannabis and cannabinoids in psychiatry. Am J Psychiatry. 2022;179(2):98-109.

20. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the last 2 decades (1995-2014): analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613-619.

21. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-1673.

22. Shover CL, Vest NA, Chen D, et al. Association of state policies allowing medical cannabis for opioid use disorder with dispensary marketing for this indication. JAMA Netw Open. 2020;3(7):e2010001.

23. Olfson M, Wall MM, Liu SM, Blanco C. Cannabis use and risk of prescription opioid use disorder in the United States. Am J Psychiatry. 2018;175(1):47-53.

24. Hoffman KA, Ponce Terashima J, McCarty D. Opioid use disorder and treatment: challenges and opportunities. BMC Health Serv Res. 2019;19(1):884.

25. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Phillips JK, Ford MA, Bonnie RJ, et al, eds. Pain Management and the Opioid Epidemic: Balancing Societal and Individual Benefits and Risks of Prescription Opioid Use. National Academies Press (US); 2017. ❒