Managing Respiratory Depression Risk: Exploring CB1 Receptors and Safe Co-Prescribing in Pain, Anxiety, and Palliative Care

Published: July 2025

Medical cannabis has gained increasing attention as a therapeutic option for managing pain, anxiety, and symptoms in palliative care. Respiratory depression—particularly associated with opioids and some anxiolytics—remains a significant safety consideration in these settings.^1,2 Unlike these medications, cannabinoids do not significantly affect brain stem respiratory centres, due to the low density of CB1 receptors in those areas.^3,4 This article explores the mechanisms behind this effect and considers the implications for co-prescribing medical cannabis alongside other agents used in symptom management.

Understanding CB1 receptor distribution

Cannabinoids exert their effects primarily through two receptors: CB1 and CB2.^3,4 CB1 receptors are abundant in brain regions involved in mood, memory, pain, and motor control, while CB2 receptors are more prominent in organs and in the immune system.^3,4 However, a key finding in neuropharmacology demonstrated that CB1 receptors are only minimally present in the brain stem, the part of the brain that regulates vital functions such as breathing and heart rate.^3,4

In contrast, opioid receptors are densely concentrated in the brain stem.¹ When opioids bind to these receptors, they can depress the respiratory centres, reducing the drive to breathe and leading to potentially fatal respiratory depression.¹

Due to the lack of significant CB1 receptors in the brain stem, cannabinoids such as tetrahydrocannabinol (THC) do not suppress respiratory function in the way opioids do.⁵

This fundamental difference means:

• Medical cannabis use is not associated with respiratory depression.⁵
• Unlike opioids and benzodiazepines, medical cannabis does not pose the same risk of fatal overdose via respiratory failure.⁵

Simplified diagram demonstrating CB1 receptor distribution in the brain.
Figure adapted from Kayser et al. 2019⁶

This safety profile is supported by clinical and preclinical studies showing that medical cannabis, even when used in combination with other medications, does not increase the risk of respiratory suppression that is seen with some other central nervous system (CNS) depressants.^5,7,8,9

Implications for pain management

Opioid medications form the mainstay of pain management in severe and some chronic pain conditions. They carry a well recognised risk of respiratory depression, overdose and dependence.^1,9 Medical cannabis offers several potential benefits in this context:

• Opioid-sparing effect: Medical cannabis can reduce opioid dosage requirements by providing complementary analgesic effects via different mechanisms.^5,7,8,9
• Reduced respiratory risk: Lower opioid doses decrease the likelihood of respiratory depression, making the overall pain management regimen safer.⁸
• Multimodal pain relief: Medical cannabis can alleviate different types of pain (e.g. neuropathic, inflammatory) via multiple complementary mechanisms, potentially improving pain control when combined with opioids.^10,11

Despite these benefits, co-prescribing medical cannabis and opioids should be undertaken with careful medical supervision and opioid dose adjustment to avoid amplification of common opioid side effects, such as sedation and constipation.¹¹

Considerations for anxiety

Anxiety disorders are commonly treated with benzodiazepines and other anxiolytic medications, which also carry risks of sedation and respiratory depression.^2,12 Medical cannabis could serve as an either adjunctive or alternative treatment in some patients due to:

• Anxiolytic effects in certain medical cannabis strains or formulations, especially those higher in cannabidiol (CBD).¹³
• The risk of respiratory depression from benzodiazepines, especially with higher doses.²
• The potential to lower benzodiazepine dosages, reducing the risk of developing side effects and/or dependence.⁷

Due to inter-patient variability in response to CNS medications and medical cannabis, a personalised approach with close monitoring is advised.

High-THC products (>10%) may exacerbate anxiety or cause psychoactive effects in some patients.¹³ CBD is thought to mitigate THC-induced anxiety, highlighting the importance of selecting products with an appropriate THC:CBD ratio, particularly in patients with a history of anxiety.¹³

Additionally, cannabinoids may inhibit CYP450 enzymes, potentially affecting the metabolism of concurrent medications, including anxiolytics.¹¹ Prescribers should assess drug interactions to minimise the risk of adverse effects such as excess sedation.

The role of medical cannabis in palliative care

Palliative care patients commonly present with complex symptoms requiring multidrug regimens, including opioids for pain, benzodiazepines or other sedatives for anxiety and agitation, antiemetics for nausea, steroids, and other supportive therapies.¹⁴

While clinical evidence on the efficacy of medical cannabis in palliative symptom management remains inconclusive, preclinical studies and case reports suggest potential benefits in managing:

• Pain relief without increasing respiratory depression risk⁸, especially in patients with chronic pain.¹⁵
• Anxiety and insomnia, which are common concerns in palliative care and are frequently reported as having a negative impact on patients’ quality of life.¹⁵
• Nausea and poor appetite, thereby reducing the risk of malnutrition and cachexia.^14,15

Co-prescribing medical cannabis with opioids and other CNS depressants in palliative care requires careful dosing and patient monitoring but could offer a viable adjunctive therapeutic approach in this patient group.¹⁶

Broader safety considerations for medical cannabis

While medical cannabis has a low risk of respiratory depression⁵, potential cognitive impairment, psychoactive effects, and possible interactions with other prescribed drugs should all be taken into account when co-prescribing medical cannabis.¹⁷

More rigorous clinical trials are needed to develop standardised guidelines for medical cannabis use in combination with other medications, particularly in complex conditions such as those found in palliative care.

Summary

The low density of CB1 receptors in the brain stem is thought to underlie the lack of respiratory depression associated with cannabinoid use^3,4, in contrast to opioids and benzodiazepines which have a strong association with respiratory sequelae.^1,2

Given its distinct pharmacological profile, medical cannabis may be considered as an adjunct in pain management, anxiety treatment, and palliative care, particularly where minimising respiratory depressant effects is a clinical priority.

Whilst careful co-prescribing and patient-specific considerations remain essential, medical cannabis has the potential to improve therapeutic outcomes while minimising the risk of one of the most significant side effects associated with conventional medications for these conditions.

Job code: MONT-SGD-2025-0001 | Date of preparation: July 2025