Psychedelics and Depression: How do They Interact?

Psychedelics and Depression: The Use of Psychedelics to Treat Depression

Depression, and more specifically, treatment-resistant depression, can be incredibly difficult to live with. The tenacity this disorder can exhibit prevents over 40% of patients with major depressive disorder from finding relief with conventional treatments, such as antidepressants, as they continue contending with the condition’s severe symptoms. As a result, studies regarding this issue have begun to focus on psychedelics and depression, paving the way to what many researchers are referring to as a mental health game-changer.

Psychedelics and depression

Psychedelics: A Basic Definition

A drug that causes hallucinations, or experiences of “expanded consciousness” (experiences that go beyond the concrete, accepted rules of reality) can be considered a psychedelic. Mescaline, ayahuasca, LSD, and ecstasy are among the most popular and well-known psychedelic drugs. Psychedelics are commonly used to achieve an “out-of-body” experience. Cultures such as certain Indigenous American tribes incorporate psychedelic substances (specifically, the locally produced ayahuasca) into traditional, shamanistic rituals, and believe they can offer a connection to nature and additional spiritual plains.

Psychedelic Medications: Types and Effects

Psychedelic mental health research has focused on three types of medications: ketamine, MDMA, and psilocybin. All three are typically incorporated into psychotherapy (or talk therapy) treatment. This allows the patient to access and begin to unpack deeply stored traumas, which are raised to their consciousness via psychedelics within a safe therapeutic setting. This combination of (albeit experimental) drugs with psychotherapy has been shown to be particularly effective among patients with depression.

It should be stressed that all three psychedelic options are in the initial stages of research. For this reason, they are not (currently) considered first-line depression treatment options, such as serotonin-focused medication or psychotherapy. Any and all psychedelic drug treatments should be conducted in a safe setting and be administered by mental health professionals trained in this specific area and form of therapy.


Ketamine was originally used as an anesthesia, until lower doses of the medication were shown to quickly alleviate symptoms of depression: whereas more traditional antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) take weeks to become effective, ketamine can begin to alleviate depressive symptoms within hours.

Though ketamine does produce some psychedelic effects due to its action as a glutamate antagonist, it has mainly received attention for its proven safety. It has been shown to be particularly effective when taken in tandem with a traditional type of antidepressant.

It still remains unclear how, exactly, ketamine works to combat depression. One leading theory suggests that ketamine binds with the brain’s NMDA receptors, prolonging the activity of the aforementioned glutamate. A neurotransmitter shown to assist with mood, thoughts and cognitive patterns, glutamate reuptake is considered to be a possible contributor to the appearance of depression. This makes ketamine’s blocking of its reuptake a leading theory in the drug’s fast-acting alleviation of depressive symptoms.

Ketamine is typically administered via infusion or nasal spray. Among its possible side effects are high blood pressure, vomiting, nausea, perceptual disturbances, and (rarely) experiences of dissociation. Ketamine nasal spray alone has been FDA-approved to treat depression.

Similarly to opioids, ketamine can be addictive. As such, individuals with a history of drug or alcohol abuse in particular should take its addictive qualities into consideration and raise this issue with their doctor.

Psychedelics for Depression and Anxiety


Methylenedioxymethamphetamine (or MDMA), also known as ecstasy or molly, has long been considered a “party drug” for its hallucinogenic effect. More recently, though, its mental health benefits in battling depression, anxiety, and post-traumatic stress disorder (PTSD) have been receiving attention.

In addition to its hallucinogenic traits, MDMA is also a stimulant, working similarly to amphetamines. Overall, MDMA affects three types of neurotransmitters:

  • Serotonin, which affects one’s mood, behavior, thoughts, sleep patterns, and other bodily functions.
  • Dopamine, which affects one’s mood, energy levels, and movement.
  • Norepinephrine, which affects one’s heart rate and blood pressure.

All three of the above neurotransmitters have been shown to have some involvement in mood or emotional regulation, explaining MDMA’s possible effect in alleviating symptoms of depression.

MDMA has been shown to take effect within 45 minutes and up to six hours. Its pace of activation is considered much faster than current first-line depression treatment options, namely SSRIs.

Reported MDMA side effects include clouded thinking, nausea, jaw clenching, high blood pressure, spatial awareness issues, and chills. Certain studies have also shown that MDMA changes the chemistry of the brain, lowering its serotonin production (effectively setting one’s mood to a new, lower average). As such a reaction would go against depression symptom alleviation, it further highlights the importance of receiving licensed supervision when undergoing psychedelic treatment within a professional, controlled environment.


Commonly known as “magic mushrooms,” psilocybin is a substance found in different species of mushrooms. Similarly to SSRIs, psilocybin is believed to alleviate symptoms of depression by affecting serotonergic pathways in the brain. Patients who received a micro dosage of psilocybin reported increased optimism and a greater quality of life.

Unlike SSRIs, whose main purpose is to stabilize and elevate one’s mood, psilocybin may cause feelings of euphoria, altered consciousness and hallucinations, and spiritual or highly introspective experiences.

Combining psilocybin therapy with psychotherapy aims to help the patient recognize the themes and imagery that are brought to the fore during their psychedelic treatment as a way to better understand their internal turmoil and the issues that sustain their depression. Together, patient and therapist are then hopefully able to process them and see how the patient’s current condition and life in general are shaped by past events. Studies have also noted its “recalibrating” effect, with patients describing how psilocybin helped rapidly alleviate their depressive symptoms and did not “dull the edges” of their emotions, compared to certain reports on SSRIs.

Possible and concerning side effects of psilocybin include panic, paranoia, nausea, drowsiness, and bouts of anxiety or psychosis, otherwise known as a “bad trip.” To balance such an occurrence, it is once again recommended to undergo psilocybin treatment in a calm and relaxing environment and under the supervision of a licensed professional. Those with a history of mania, bipolar disorder, or psychosis should not attempt this treatment.