Real World Evidence and Cannabis Psychosis

 

As readers of this blog know – I am not high on cannabis.  That is based on my experience as an acute care psychiatrist and an addiction psychiatrist. That real world experience was associated with treating hundreds of people for exacerbations of preexisting psychotic disorders as well as seeing psychosis develop in people with no risk factors of family history of psychosis. A significant number of thise people need ongoing treatment for psychosis to stay out of the hospital.  Their course is complicated by cannabis use disorder.  Contrary to the hype – addiction can occur to cannabis with all of the associated problems.

Rhetoric is always a significant factor in the United States, especially when there are large sums of money at stake. Depending on who you read the $38.5B cannabis industry is part of the $1.8T health and wellness industry compared with the total pharmaceutical industry value of $602B.  For twenty years we heard about medical cannabis as though it was a miracle drug.  The first medical application of cannabis may have occurred in the second century AD when a famous Chinese physician mixed it with wine and used it as an analgesic.  The use of cannabis as an intoxicant preceded this medical use by about 800 years (1).  The rise of Taoism, Chinese culture, and the availability of alcohol and opium are thought to have limited its widespread use for that purpose. Hemp was also cultivated as a seed crop but that was supplanted by more effective seed crops much like medical use.  The 20^th century medical rhetoric always ignored that history. I attended many seminars where there was a discussion of the endogenous cannabinoid system as a backdrop to talking about medical applications.  In my home state there was a tortured effort to invent a system parallel to the FDA to approve medical cannabis for certain indications. I use the word tortured because the evidence including collected data was very thin to non-existent.  All of this was an obvious prelude to legalization of cannabis and being able to market it as an intoxicant. The psychiatric side effects and the fact that any intoxicant has major problems associated with it – were minimized. Common minimization rhetoric included the ideas that alcohol was much more dangerous, that cannabis-based crimes were discriminatory, and that the War on Drugs was a failure. There was also the idea that the United States was lagging behind the rest of the world in legalization, when it is only fully legal in 9 countries in the world.

That brings me to a recent paper characterizing the real-world evidence of antipsychotic use to treat cannabis induced psychosis.  I follow two of the authors of this paper (Tiihonen and Taipale) because they are experts in designing observational studies based on registry data that typically does not exist in the US.  In this case they selected a cohort of 1772 patient with a diagnosis of cannabis induced psychosis (CIP) from Swedish registry and insurance data between January 2006 and December 2021.  Exclusion criteria included any previous diagnosis of substance induced psychosis, schizophrenia, or bipolar disorder.  Medication data was collected according to the Anatomical Therapeutic Chemical (ATC) classification.  Medication exposure to antipsychotic and antimanic medications was based on exposures as prescription refills and less than 5 exposures was not counted as an exposure.  Additional psychiatric medications – antidepressants, medications for ADHD and addictions, benzodiazepines and related drugs were also extracted.  The resulting medication list from the supplementary information is listed below along with the effect on the primary outcome (rehospitalization for CIP) by Hazard Ratio.

	Events	Users	Person-years	aHR (95%CI)
Antipsychotics
No exposure	1892	1754	10617,19	Reference
Levomepromazine	30	131	49,64	0.92 (0.59-1.44)
Perphenazine	NA	NA	NA	NA
Perphenazine LAI	9	26	28,58	0.55 (0.25-1.22)
Haloperidol	35	125	69,09	1.01 (0.66-1.54)
Haloperidol LAI	14	22	18,37	1.14 (0.61-2.15)
Flupentixol	5	22	20,42	0.88 (0.31-2.50)
Flupentixol LAI	NA	NA	NA	NA
Zuclopenthixol	10	41	41,29	0.71 (0.32-1.61)
Zuclopenthixol LAI	26	47	45,7	0.77 (0.47-1.26)
Clozapine	28	54	119,25	0.56 (0.34-0.90)
Olanzapine	404	1013	1031,96	0.82 (0.70-0.96)
Olanzapine LAI	13	57	50,1	0.29 (0.16-0.55)
Quetiapine	91	385	405,41	0.94 (0.69-1.27)
Risperidone	72	261	210,27	0.91 (0.66-1.26)
Risperidone LAI	18	40	45,46	0.55 (0.28-1.10)
Aripiprazole	62	331	283,83	0.61 (0.43-0.88)
Aripiprazole LAI	15	69	83,45	0.26 (0.14-0.49)
Paliperidone LAI 1M	32	74	63,03	0.69 (0.45-1.08)
Paliperidone LAI 3M	6	8	10,39	0.43 (0.09-2.03)
AP Polytherapy	423	675	727,23	0.75 (0.64-0.89)
Cariprazine	5	19	9,32	20.88 (1.99-218.64)
Paliperidone oral	5	42	14,8	1.38 (0.48-3.95)
Other SG oral	NA	NA	NA	NA
Other FG oral	NA	NA	NA	NA
ADHD medications
No exposure	3127	1767	13312,32	Reference
Dexamfetamine	NA	NA	NA	NA
Methylphenidate	30	206	307,89	0.67 (0.41-1.11)
Modafinil	NA	NA	NA	NA
Atomoxetine	16	85	59,31	0.64 (0.32-1.26)
Lisdexamphetamine	27	168	223,14	1.10 (0.61-1.98)
ADHD polytherapy	NA	NA	NA	NA
SUD medications
No exposure	3145	1767	13749,18	Reference
Disulfiram	25	79	41,09	0.94 (0.48-1.82)
Acamprosate	NA	NA	NA	NA
Naltrexone	10	60	36,73	1.39 (0.55-3.50)
Buprenorphine	15	24	55,87	0.83 (0.27-2.56)
Methadone	11	17	68,81	3.05 (0.80-11.69)
Multiple SUD drugs	NA	NA	NA	NA
Antidepressants
No exposure	2704	1742	11565,26	Reference
Clomipramine	5	24	30,15	0.57 (0.15-2.12)
Amitriptyline	NA	NA	NA	NA
Nortriptyline	NA	NA	NA	NA
Fluoxetine	22	118	164,43	0.75 (0.41-1.34)
Citalopram	15	109	114,94	0.56 (0.29-1.10)
Paroxetine	12	30	50,26	1.60 (0.67-3.77)
Sertraline	104	447	538,89	0.75 (0.56-1.00)
Fluvoxamine	NA	NA	NA	NA
Escitalopram	60	249	277,43	1.03 (0.71-1.49)
Moclobemide	NA	NA	NA	NA
Mianserin	NA	NA	NA	NA
Mirtazapine	122	449	387,9	0.89 (0.69-1.15)
Bupropion	13	155	86,75	0.94 (0.48-1.82)
Venlafaxine	48	170	217,67	1.15 (0.75-1.76)
Reboxetine	NA	NA	NA	NA
Duloxetine	25	91	101,98	1.30 (0.75-2.27)
Agomelatine	<5	20	9,38	5.28 (0.41-67.42)
Vortioxetine	6	48	36,58	0.67 (0.26-1.73)
Rare antidepressants	NA	NA	NA	NA
Antidepressant polytherapy	65	364	364,42	0.93 (0.62-1.39)
Benzodiazepines and related drugs
No exposure	2817	1755	12756,76	Reference
Any benzodiazepine or related drug	390	732	1231,3	1.19 (1.01-1.40)
Mood stabilizers
No exposure	3020	1768	13280,77	Reference
Carbamazepine	11	41	42,23	0.93 (0.44-1.99)
Valproic acid	89	168	206,7	0.93 (0.70-1.25)
Lamotrigine	15	115	159,81	0.68 (0.34-1.37)
Topiramate	NA	NA	NA	NA
Lithium	60	107	217,85	0.98 (0.67-1.43)
Mood stabilizer polytherapy	8	66	64,51	0.46 (0.20-1.07)

 

The data was analyzed using a stratified Cox regression model.  The advantage to this model is that the assumption that hazard ratios are constant over time are restricted to the stratum occupied by each individual so that hazard ratios between strata may differ based on genetics, age and other factors but they are constant in each stratum.

Of the final sample 84.7% were men and the mean age of onset of the first diagnosis was 26.6 (± 8) years.  About half of the sample had work income at baseline but 5.4% had 90 days sick leave from work in the year before the study and 6.9% were on disability pensions.  

In terms of the primary rehospitalization endpoint – any antipsychotic use was associated with a decreased risk of readmission (aHR 0.75; 95%CI 0.67–0.84).  Some of the antipsychotics associated with less risk like aripiprazole, aripriprazole LAI, olanzapine, olanzapine LAI, and clozapine clozapine,  Any antipsychotic use also reduced the risk of secondary endpoints including hospitalization due to a medical problem (aHR 0.58; 95% CI 0.38–0.89) and hospital admission caused by a substance use disorder (aHR 0.78; 95% CI 0.71–0.87).

The authors include a Forest plot of antipsychotic medications and risk of relapse (see Fig 1.)  The SGA drugs olanzapine, clozapine, and aripiprazole had the best results in both LAI and oral short acting forms.  FGA drugs (pooled) and paliperidone, risperidone, and quetiapine (all SGAs) did not have a statistically significant result.

The authors conclude that AP drugs – especially the LAI version may be effective in preventing rehospitalization following an episode of cannabis induced psychosis – a condition that as a high risk of relapse.  The reduction in risk was about 72%.  Medication effectiveness mirrored effectiveness noted in psychotic disorders for clozapine.  FGA were less effective than noted in studies of first episode psychosis without cannabis use and this may be due to the small numbers being treated with these medications.  They speculate that the effectiveness of aripiprazole may be due to partial dopamine agonist activity with improved cognition and less craving.  They cite one of their previous papers suggesting that the combination of clozapine and aripiprazole may be the best to prevent relapse prevention in schizophrenia and substance use (3).     

In terms of limitations, the authors cite the small subject numbers in some of the studied groups.  They also lacked data on ongoing cannabis use if rehospitalization did not occur. It is always interesting to consider what an ideal randomized controlled clinical trial of this problem would look like.  At the minimum it would involve structured interviews for psychiatric diagnoses, detailed structured interviews on substance use, and possible toxicology screens and measures of medication adherence for oral medications (typically pill counts).  That may be a fundable grant at some point – but the current political atmosphere in the US suggests otherwise. This is a significant strength of the studies from this group.  As I noted in a recent post it also reflects the clinical experience of acute care psychiatrists in the US where substance use is a significant complication of care.   

 This is an excellent observational study of how cannabis use and cannabis use disorder complicates the lives of people. Obviously not everyone who uses cannabis is at risk for these complications – but if they occur and result in hospitalization and the prescription of medications for treating an ongoing psychosis that results in major life disruption and disability.  The less obvious disruption is how both psychosis and cannabis in can impair the insight of the affected individual. Psychosis generally leads to a conscious state where the affected individual cannot accurately assess how they are doing in the environment and take corrective action. With a cannabis use disorder, an individual can experience reinforced use by the biological properties of THC, and continue to use the substance despite negative consequences.  People with those impairments have a much harder time stopping cannabis use often despite very negative consequences.  That pattern of behavior is always a good reason to avoid intoxicants of any kind.  

George Dawson, MD, DFAPA

 

References:

1:  Booth M.  Cannabis – A History. New York. Picador, 2003: 23.

2:  Mustonen A, Taipale H, Denissoff A, Ellilä V, Di Forti M, Tanskanen A, Mittendorfer-Rutz E, Tiihonen J, Niemelä S. Real-world effectiveness of antipsychotic medication in relapse prevention after cannabis-induced psychosis. Br J Psychiatry. 2025 May 6:1-7. doi: 10.1192/bjp.2025.72. Epub ahead of print. PMID: 40326094.

3:  Tiihonen J, Taipale H, Mehtälä J, Vattulainen P, Correll CU, Tanskanen A. Association of Antipsychotic Polypharmacy vs Monotherapy With Psychiatric Rehospitalization Among Adults With Schizophrenia. JAMA Psychiatry. 2019 May 1;76(5):499-507. doi: 10.1001/jamapsychiatry.2018.4320. PMID: 30785608; PMCID: PMC6495354.

Graphic Credit:

The table and figure used in the above post is taken directly from the authors Supplementary data and original paper per the CC license (reference 2):

Open Access article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited.