CBD and Zoloft: Cannabidiol and SSRIs (Selective serotonin reuptake inhibitors) Drugs

Many people are using CBD to deal with issues of depression, anxiety, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD) and other depression or anxiety related disorders—and many are also using Zoloft (sertraline). Is that a good idea? Bad idea? Good under some circumstances? Why or why not? Read on to learn and find out more about Zoloft and this whole class of drugs known as SSRIs.
Written by 
Zora Degrandpre, MS, ND.
|Last Updated:
CBD and Zoloft

How SSRIs Work

SSRIs work by preventing the re-circulation (inhibit the re-uptake) of serotonin, leaving higher levels of serotonin in the brain. Serotonin is a neurotransmitter and functions by regulating mood, reward centers, memory, and learning. It also helps regulate digestion, nausea/vomiting responses and sleep. Low levels of serotonin can be associated with depression, anxiety, OCD and other behavioral disorders while high levels can cause nausea, vomiting, mental confusion, restlessness, diarrhea, high blood pressure, irregular heartbeat and seizures—these can occur with SSRI use, and—importantly—is one of the reasons to be cautious when taking both CBD and an SSRI such as Zoloft.

There are several SSRIs in common use—the most common are:

  • Sertraline (Zoloft)
  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac)
  • Paroxetine (Paxil, Pexeva)

SSRIs are generally safe to use but can cause problems when combined with nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, warfarin and other blood thinners. Stopping SSRIs suddenly can also cause withdrawal symptoms—these can include nausea, dizziness, a general feeling of unease, lethargy and flu-like aches and pains.

Sertraline (Zoloft) and other SSRIs can have side effects. These can include:

  • Nausea and vomiting
  • Diarrhea or constipation
  • Difficulty in falling or staying asleep
  • Dry mouth
  • Loss of appetite
  • Fatigue
  • Tremors
  • Changes in libido/sex drive
  • Sweating
  • Headache

How CBD Works

CBD is a non-intoxicating cannabinoid and has a wide range of actions, binding with a relatively low activity to both known cannabinoid receptors, CB1 and CB2. CBD also binds to some types of serotonin receptors throughout the body. [1] In animal studies, CBD has been shown to have antidepressive and anti-anxiety effects—but the anti-anxiety effects DO seem to be mediated through the CB1 receptors and not, as expected, the serotonin receptors. The antidepressive effects, on the other hand, appear to be mediated through the serotonin receptors.

Clinical studies on CBD and depression are still relatively few, with one due to be released in 2022. Currently, most of the evidence supporting the use of CBD for depression or anxiety is by word of mouth—and while this is important information, we really need more studies to determine if some forms of depression or anxiety respond better to CBD than others.

While CBD is usually very well tolerated, it can cause side effects in some people—these include some of the side effects seen with SSRIs:

  • Dry mouth
  • Diarrhea
  • Loss of appetite
  • Fatigue
  • Drowsiness

How CBD and Zoloft (Sertraline) May Interact

Most substances taken by mouth—food, drugs, or supplements—have to pass through the liver before passing through the whole body. The liver, being the major organ of detoxification, can biochemically alter most substances. During this process—called First Pass Metabolism—lots of food components, drugs and supplements can get metabolized (changed, broken down etc) by a family of enzymes known as the cytochrome P450 (CYTP450) family.

The CYTP450 family of enzymes can also be affected by some food components, drugs and supplements. If some substance inhibits one of the enzymes, something else—a drug for example—that is normally metabolized by that enzyme will be at higher blood levels than expected and last longer than expected. This can lead to side effects and the drug not working as it is supposed to.

If, on the other hand, if some substance enhances the enzyme, something else that is normally metabolized by that enzyme will be at lower levels than expected and last for shorter periods of time.

Both CBD and Zoloft (sertraline) can interact with the CYTP450 enzymes. The end result is that if CBD is taken together with Zoloft, it can increase the risk of potentially dangerous side effects because there ends up being more Zoloft in your system. Specifically, there is an increased risk of drowsiness, confusion, difficulty concentrating or focusing and difficulty with motor coordination if you take CBD along with Zoloft.[2],[3]

What does that really mean? It means that if you want to use both CBD and sertraline, you can get drowsier, more confused and get clumsier than you might with either of these on their own.

CBD and Other Antidepressants

CBD will interact in the same essential ways with any SSRI—including citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac) and Paroxetine (Paxil, Pexeva).

Can other antidepressant medications such as Serotonin-norepinephrine reuptake inhibitors (SNRIs), Tricyclic antidepressants (TCAs), Monoamine oxidase inhibitors (MAOIs) be taken with CBD?

Serotonin-norepinephrine reuptake inhibitors (SNRIs)

CBD can have moderate interactions with SNRIs—meaning there is some increased risk of experiencing side effects like dizziness, drowsiness and difficulty concentrating. The SNRIs include:

  • Atomoxetine (Strattera)
  • Desvenlafaxine (Pristiq, Khedezla)
  • Duloxetine (Cymbalta, Irenka)
  • Levomilnacipran (Fetzima)
  • Milnacipran (Savella)
  • Venlafaxine (Effexor XR)

Monoamine oxidase inhibitors (MAOIs)

MAOIs are effective antidepressants and include:

  • Isocarboxazid (Marplan)
  • Phenelzine (Nardil)
  • Selegiline (Emsam)
  • Tranylcypromine (Parnate)

Common side effects include a dry mouth, nausea, diarrhea or constipation, headache, drowsiness, sleep problems and dizziness.

These interactions are moderate but can increase the side effects significantly.

Tricyclic antidepressants (TCAs)

This is an older family of antidepressants and includes:

  • Amitriptyline.
  • Amoxapine.
  • Desipramine (Norpramin)
  • Doxepin.
  • Imipramine (Tofranil)

The interactions are considered moderate—and you run the risk of increasing side effects such as dizziness, drowsiness and difficulty concentrating.

The Short Answer to “Can I use ANY antidepressant with CBD?”

The short answer to this question is that you run a risk of increasing side effects if you try and combine CBD with any currently used antidepressant.

Can CBD replace Zoloft?

You should know that CBD may not be as effective as any antidepressant medication, or it may work better in some people than in others. Most medications are designed to address any disorder in a very specific way while we are probably just very lucky that the cannabis plant developed all its cannabinoids.

First, talk to your doctor or other trusted healthcare provider. They should be able to guide you through a process where you slowly decrease your use of Zoloft while increasing the amount of CBD you take. This process will take a while, depending on the amount of Zoloft you may be currently prescribed. But—you should never just stop taking your medication on your own—Zoloft and other antidepressants can be unsafe to quit “cold turkey”. And remember—whenever you take CBD…Start Low and Go Slow.


[1] García-Gutiérrez MS, Navarrete F, Gasparyan A, Austrich-Olivares A, Sala F, Manzanares J. Cannabidiol: a potential new alternative for the treatment of anxiety, depression, and psychotic disorders. Biomolecules. 2020 Nov;10(11):1575.


[2] Zendulka O, Dovrtělová G, Nosková K, Turjap M, Šulcová A, Hanuš L, Juřica J. Cannabinoids and Cytochrome P450 Interactions. Curr Drug Metab. 2016;17(3):206-26. doi: 10.2174/1389200217666151210142051. PMID: 26651971. https://pubmed.ncbi.nlm.nih.gov/26651971/

[3] Brown JD, Winterstein AG. Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use. Journal of clinical medicine. 2019 Jul;8(7):989.


Dr. Zora DeGrandpre practices naturopathic medicine (home visits) in rural Washington and is a professional medical and scientific writer and editor, specializing in naturopathic, functional, botanical and integrative medicine. Dr. DeGrandpre has degrees in drug design, immunology and natural medicine and has extensive research experience in cancer and molecular immunology. In her practice, Dr DeGrandpre has found the use of CBD with elderly patients and others to be safe and clinically effective. She brings to all her writing a straightforward approach that is accurate, clear and authentic.

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