The Impact of Cannabis Use on Medication Adherence: A Particular Focus in Psychosis

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Case Vignette

“Mr Brown,” a patient in his early 20s, has been readmitted to the psychiatric inpatient unit. Since his first presentation with a psychotic episode about 2 years ago, this is his third admission to the unit. All these hospital admissions have been involuntary in nature. There is a history of cannabis use since his teenage years, initially off and on but more regularly over the past 2 to 3 years. Mr Brown smokes about 20 cigarettes a day, drinks occasionally, and tried lysergic acid diethylamide (LSD) many years ago. He improved with treatment with second-generation antipsychotic medications in each of the previous admissions and remained well for a while in the community. However, he seems to become irregular in terms of taking medications and returns to using cannabis soon after discharge.

In each of the past 2 admissions, Mr Brown stopped coming for follow-up and stopped picking up his prescriptions a few months before the hospital admission. On further enquiry, it seems that Mr Brown started smoking marijuana initially with friends and still does so occasionally, but often uses it on his own nowadays. He finds that it helps him relax and sleep better, and he uses most days of the week when he has money. When asked about medication, Mr Brown expresses some concerns about putting something that is not natural into his body.

Presenting the Problem: Cannabis Use and Nonadherence

Medication nonadherence is a major challenge that affects every medical specialty. Estimates from the early 21st century indicate that the cost of nonadherence is around $100 billion per year in the Unites States alone.¹ Although adherence may be described as the extent to which an individual changes their health behavior to comply with medical advice, deviations from that, termed nonadherence, may either be partial or complete. Partial nonadherence may include taking medication at incorrect doses or times, while complete nonadherence involves discontinuation of the medicine altogether.

In the context of psychiatric disorders, it is estimated that 75% of patients will discontinue taking their prescribed medications over the course of 1 year.² Psychiatric treatment regimens are usually complex and costly, and can run for long, sometimes indefinite periods.

Additionally, illness features, such as lack of insight and cognitive deficit in certain psychiatric conditions, may play a role in nonadherence.³ Other consistently reported risk factors of nonadherence include medication adverse effects, illness beliefs, the doctor-patient relationship, illness attitudes, and substance misuse, including cannabis misuse.⁴ Nonadherence to treatment may increase the risk of relapse for most serious mental illnesses as well as the risk of suicide, violence, and all-cause mortality.⁵ Additionally, nonadherence may increase the financial strain on health care systems through increased hospital admissions and emergency room visits.¹

Given the substantial impact of nonadherence, it is particularly important to focus on its modifiable risk factors. In the context of severe mental illnesses such as psychotic disorders, antipsychotic medications are the mainstay of treatment, but poor adherence often affects their effectiveness.⁶ Although a number of factors affecting adherence to medication treatment has been described in those with psychosis, they are not always amenable to intervention. In particular, illness-related factors such as poor insight and cognitive deficit may be inextricably linked to nonadherence in a way that is difficult to disentangle and intervene.⁷

On the other hand, meta-analytic evidence—from 15 studies reporting on more than 3000 patients—suggests that substance misuse, specifically cannabis misuse, may be one of the most consistently reported risk factors for nonadherence that may arguably also be modifiable.⁸ A subsequent prospective study investigating individuals with first-episode psychosis suggested that the effect on medication nonadherence was most pronounced for cannabis, while the use of nicotine, alcohol, and other illicit drugs did not seem to have a substantial independent effect.⁹

As cannabis is the most frequently used illicit substance worldwide, with up to two-thirds of individuals experiencing a first episode of psychosis reporting its use, cannabis use is a particularly important therapeutic target to address the challenge of medication nonadherence in psychosis. The relationship between cannabis misuse and treatment adherence has also been studied to a lesser extent in bipolar disorder and other diagnoses.

In a recent nationwide study in the United States of patients with bipolar disorder, the risk of nonadherence in patients with cannabis use disorder was nearly one-and-a-half times that in those without cannabis use.¹⁰ Cannabis use has also been found to be associated with medication nonadherence across a range of conditions in adolescents.¹¹

In this article, we will focus mainly on the effect of cannabis use on adherence to medications in those with psychosis—the condition with most of the reported evidence.

Although the association between cannabis use and nonadherence in those with psychosis seems clear, why must practicing clinicians bother? We know that in those with psychosis, cannabis use is associated with an increased risk of relapse¹² and a worse disease course.¹³ Growing evidence now suggests that 1 potential pathway through which cannabis use may increase the risk of poor outcome in those with psychosis may be by increasing nonadherence to medication treatment.¹⁴

Indeed, in a prospective observational study of 245 patients with first-episode psychosis, up to a third of the detrimental effects of cannabis use on outcome in psychosis was shown to be mediated through its effect on nonadherence with medication treatment.¹⁴ Consistent with this, in an independent sample of more than 2000 patients with first-episode psychosis, up to 50% of the harmful effects of cannabis use on hospital admission were found to be mediated by cannabis use contributing to failure of antipsychotic treatment.¹³

Although this study did not disentangle failure of treatment with antipsychotics as a result of nonresponse from that due to nonadherence, collectively these studies indicate that cannabis use may contribute to poor outcome in psychosis by adversely affecting adherence to antipsychotic medications and by making them less effective.

Approaches to Mitigating the Effects of Cannabis Use on Nonadherence and Outcomes in Psychosis

A typical patient may present with a history of psychotic illness associated with cannabis use, as described in the vignette. Here we summarize some of the key aspects of assessment and treatment planning that may be useful in such a scenario.

Assessment

At the risk of stating the obvious, it is worth reiterating that the key to formulating an effective management strategy is a good understanding of the circumstances around cannabis use behaviors as well as a detailed history of medication treatment. Understanding from the patient’s perspective how effective the medications might have been and their reasons for discontinuation or irregular use, including any adverse effects experienced, is particularly important, as is their understanding of the nature and expected course of treatment for their condition. Do they have any specific concerns regarding medications? Do they sometimes forget to take them, or are they unsure why they need to continue medications even after they start feeling better?

Limited insight and acceptance of having an illness and need for treatment are more commonplace in this context and challenging to intervene. However, they may be accompanied by other specific concerns that may be more amenable to intervention. Hence, a specific lookout for such potential intervention targets that may be more readily addressed may be useful.

A strong therapeutic alliance—wherein the doctor-patient relationship is characterized by trust, empathy, acceptance, and a nonjudgmental approach—is really critical to ensuring detailed disclosure of information not just on cannabis use, but on key parameters of use that may serve as intervention targets, such as the amount, frequency, continuity, type of cannabis used, typical triggers or circumstances of use, as well as any benefits perceived or experienced. For example, does it help initiate sleep, reduce anxiety, or deal with painful emotions or other stress?

It may also be worth inquiring about any withdrawal symptoms or cravings that may play a role in maintaining cannabis use behavior. Depending on the length of illness, as part of eliciting history, it may be useful to construct a longitudinal account of the illness course together with the patient, with the aim of demonstrating a repeating sequence of cannabis use behaviors followed by or associated with partial or complete medication nonadherence. One would aim for this to facilitate a shared understanding of how such a course of events leads to a repeating cycle of relapse of psychosis and hospitalization with or without restriction of their liberty and/or other traumatic consequences. Where applicable and practicable, assay of plasma level of antipsychotics may further inform treatment-planning, particularly where nonadherence may be a consideration.

The main purpose of this endeavor really is to prepare the ground for subsequent discussions on the need to address cannabis use behaviors and find alternative strategies that may serve the same purpose as cannabis use (eg, alleviate difficulties in sleep initiation) or may help overcome factors (eg, cravings, withdrawal symptoms) that may maintain its use. Often, this may not be feasible in the immediate aftermath of admission, when the focus may need to be on stabilizing the mental state so that the patient is able to engage meaningfully with the above.

Treatment Planning

What might one do with such information as above? The Figure summarizes the key intervention targets, objectives, and strategies in a graphical format.

Figure. Key Intervention Targets, Objectives, and Strategies

Working toward complete abstinence from cannabis may be ideal and perhaps should be the eventual goal, as there is evidence that discontinuation of use may be associated with a risk of medication nonadherence or relapse of psychosis that is comparable to patients who have never used cannabis.^7,12

However, there is also some evidence that the harms of cannabis use on medication adherence and outcomes in psychosis are most prominent in those using high-potency forms of cannabis on a regular basis, in particular daily users,^8,9 and those using less potent forms of cannabis or using less frequently and less regularly may have comparable risk of relapse to those who have stopped using cannabis altogether.⁸ Therefore, a less than perfect objective of changing from more potent to less potent forms of cannabis or less frequent and less regular use may still be a worthwhile pursuit in an individual patient.

How does one choose the right antipsychotic for patients with psychosis with ongoing comorbid cannabis use? There is not a lot of evidence to inform decision-making in this regard,¹⁵ although a recent review of available evidence points toward potential advantages with clozapine compared to any other antipsychotic in terms of cannabis use, and risperidone compared to olanzapine for craving.¹⁶

However, one needs to be mindful of the modest evidence base in this area and exercise clinical judgement. One may also be guided by whether there is actual treatment nonresponse or partial response, as opposed to partial or complete nonadherence contributing to suboptimum outcomes. This may inform strategies to switch medications or those focused on improving adherence.¹⁷

An important underpinning approach in treatment planning may be to aim for a simplified treatment regime that provides an optimum balance of adverse effects and desired response for the patient in order to promote the best adherence. Given that medication adherence may be a key challenge, long-acting injectable preparations may be considered, although the evidence in support is also modest.¹⁸ Other strategies to improve adherence may also be worth considering,¹⁷ including electronic reminders¹⁹ as well as customized adherence enhancement strategies used in conjunction with long-acting injections.²⁰

Where feasible, medication-focused approaches may also be supported by psychosocial approaches directed at cannabis use behaviors in general. Although there is some indication that some of these approaches may be useful in reducing symptom severity and cannabis use behaviors in the shorter term, there is less clear evidence of their impact on longer-term outcomes of psychosis or cannabis use.²¹

Concluding Thoughts

Cannabis use is an important and preventable risk factor for medication nonadherence in psychiatric patients. A strong therapeutic alliance and focused history taking is essential to address this. In addition to intervention approaches recommended for individuals with psychosis and comorbid substance use, certain specific strategies that may be considered include a focus in the short term in helping patients switch to lower-potency cannabis and encouraging less frequent use, complemented with strategies to augment medication adherence through the use of digital reminders, long-acting antipsychotics, and rationalizing medications to provide an optimum balance of efficacy and tolerability that is acceptable to the patient.

Dr Bhattacharyya is a professor of translational neuroscience and psychiatry in the Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, at King’s College London. Dr Zalzale is affiliated with the Institute of Psychiatry, Psychology and Neuroscience at King’s College London.

Bhattacharyya is supported by grants from the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation scheme, the NIHR Mental Health Biomedical Research Centre at South London and Maudsley National Health Service (NHS) Foundation Trust and King’s College London, and Parkinson’s UK.

The views expressed are those of the author(s), and not necessarily those of the NHS, the NIHR, or the Department of Health.

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