Can you take CBD with antidepressants? Interactions with SSRIs, SNRIs, tricyclics and MAOIs

Using CBD oil alongside other medications is one of the most common questions among people undergoing treatment for depression. The underlying question is always the same: can you take CBD with antidepressants safely?

Today on the Cannactiva blog we review the possible interactions between CBD and antidepressants —SSRIs, SNRIs, tricyclics and MAOIs—, the role the liver plays in that interaction and the precautions worth keeping in mind before combining them.

If what you are after is a general overview of how CBD interacts with all kinds of drugs, we recommend reading our guide first: CBD and drugs: what are the interactions.

Does CBD interact with antidepressants?

The compound cannabidiol (CBD) is one of the main compounds in hemp and, unlike THC, does not produce psychoactive effects. Research continues to study its potential benefits in areas such as anxiety, chronic pain, stress and sleep, situations that often overlap with antidepressant treatment.

At the same time, millions of patients take SSRI, SNRI, tricyclic (TCA) or MAOI antidepressants. These medications include fluoxetine (Prozac), sertraline (Zoloft), escitalopram (Lexapro), paroxetine (Paxil/Seroxat), citalopram (Celexa), venlafaxine (Effexor), duloxetine (Cymbalta) and amitriptyline, among some of the most widely prescribed antidepressants.

CBD acts on the endocannabinoid system —involved in mood, sleep and the stress response— and indirectly influences serotonin 5-HT1A receptors, which helps explain its potential anxiolytic effect (1).

But the most relevant possible interaction between CBD and antidepressants does not happen in the brain, but in the liver. There, CBD can inhibit cytochrome P450 enzymes (CYP2C19, CYP3A4, CYP2D6) (2), the very ones the body uses to metabolise many antidepressants. If those enzymes work more slowly, the antidepressant stays in the bloodstream for longer, which can raise its concentration and, with it, the risk of side effects.

This does not mean the combination is always dangerous, but it does mean each case should be assessed with a healthcare professional. Below we look at it family by family.

Types of antidepressants: SSRIs, SNRIs, tricyclics and MAOIs

Antidepressants regulate neurotransmitters such as serotonin and noradrenaline. They fall into four broad families, and not all of them interact with CBD in the same way (3, 4):

• SSRIs: selective serotonin reuptake inhibitors (sertraline, fluoxetine, escitalopram). The most commonly prescribed in Spain.
• SNRIs: serotonin and noradrenaline reuptake inhibitors (venlafaxine, duloxetine).
• Tricyclics (TCAs): amitriptyline, imipramine, nortriptyline. A narrower therapeutic margin.
• MAOIs: monoamine oxidase inhibitors (tranylcypromine, phenelzine). Rarely used today, but with a high potential for interaction.

All of these antidepressant medications are metabolised, to a greater or lesser extent, by the same liver pathway that CBD can slow down.

CBD and fluoxetine, sertraline, escitalopram and other SSRIs: is there an interaction?

Like SSRI antidepressants, CBD also influences the serotonergic system (5), so it could add to the effect of the drug. In an animal model of post-traumatic stress, combining sertraline and CBD enhanced the results on memory and anxiety compared with using them separately (6).

The point to watch is the liver: CBD can slow the metabolism of some SSRIs (7), so that the drug builds up. This can translate into more nausea, dizziness or drowsiness and, in rare cases, a higher risk of serotonin syndrome (a dangerous excess of serotonin). That is why the combination requires medical supervision.

CBD with venlafaxine, duloxetine and other SNRIs: a greater risk?

Combining CBD and SNRIs can produce an additive effect similar to that of SSRIs (8). In addition, CBD inhibits the enzyme responsible for clearing several SNRIs (9), which could increase sedation, fatigue or difficulty concentrating, especially at high doses.

CBD with amitriptyline and other tricyclic antidepressants

Tricyclics are metabolised by several liver enzymes, and CBD inhibits several of them. In studies, combining desipramine with CBD enhanced its effects even at low doses (10). Because their safety margin is narrow, this combination calls for special caution due to the possible increase in drowsiness, anticholinergic effects or cardiovascular risk (11).

CBD with tranylcypromine, phenelzine and other MAOIs

MAOIs (monoamine oxidase inhibitors) are the oldest class of antidepressants and include drugs such as tranylcypromine or phenelzine. They are rarely prescribed today because they have many interactions, including with certain foods. CBD may slow their elimination and prolong their presence in the blood (12), which could intensify effects such as low blood pressure or dizziness. Given their already complex profile, this combination should be assessed on a case-by-case basis.

Can CBD increase the side effects of antidepressants?

Yes. By slowing the liver metabolism we saw earlier, CBD can intensify effects such as drowsiness, dizziness, fatigue or digestive discomfort (12). It is not that it reduces the antidepressant's effectiveness: rather, it can raise its concentration in the bloodstream. The intensity depends on the dose, the type of antidepressant and each person's metabolism.

What about serotonin syndrome?

It is an uncommon but serious reaction caused by an excess of serotonin (a neurotransmitter), with symptoms such as agitation or a racing heartbeat. It can appear when several drugs or substances that raise serotonin are combined (for example, two antidepressants at once, or an antidepressant with another serotonergic substance).

To date it has been described with the use of marijuana (high in THC), not specifically with CBD products (13, 14, 15). The theoretical risk would increase with high doses of CBD, high doses of the antidepressant, or with the combination of several serotonergic drugs at the same time.

Warning signs: agitation, confusion, excessive sweating or a racing heartbeat; if they appear, see a doctor immediately.

A common question: does separating the doses help? Spacing them out does not avoid the interaction, because CBD's effect on the liver lasts several hours. What does reduce the risk is starting with low doses and keeping your doctor informed.

Should you replace antidepressants with CBD?

CBD is not approved as a treatment for depression in Spain or the European Union. Although there are promising preliminary studies, it should not be introduced or used to replace any prescribed drug without medical supervision. If you are interested in what the research says about CBD and mood, we explore it in our guide CBD and depression: current research.

Conclusion: is it safe to combine CBD and antidepressants?

Combining CBD and antidepressants is not automatically contraindicated, but neither is it something that should be done without judgement. The main point to watch is the liver pathway (cytochrome P450), which can raise the levels of the antidepressant in the bloodstream and increase the likelihood of adverse effects from the antidepressant.

The specific risk depends on the type of antidepressant, the dose, individual metabolism, the presence of other medications and individual conditions such as age or underlying illnesses. The recommendation, as always, is to consult a healthcare professional before combining CBD and antidepressants.

Editorial notice

This article is for informational purposes only and does not constitute medical advice. The information provided here may complement, but never replace, the diagnosis or treatment of a healthcare professional. If you live with depression or take antidepressants, consult your doctor before adding CBD to your routine. Cannactiva products are neither food supplements nor medicines: in the European Union, over-the-counter CBD oils are marketed for external use while their approval as a novel food is being resolved. Research on CBD continues to evolve and new evidence may have emerged since the date of publication.

References

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