Advising Patients About Ketamine Use in Clinical Practice

The psychedelic drug ketamine has received much media attention lately. But how much do integrative practitioners know about this medication? And how does its use compare to psilocybin, a natural psychedelic substance? 

Regarding ketamine, a recent systematic review and meta-analysis of 49 randomized clinical trials published in The Lancet found ketamine to be effective at treating depression, especially severe depression. In particular, the analysis found a moderate to high response within 24 hours of treatment, with more frequent, higher doses outperforming single, lower-dose treatments.

“Importantly, ketamine rapidly treats suicidality, which is a crucial offering in the United States where suicide rates have been increasing,” explained physician, mental health expert, and researcher Emily Whinkin, ND, MS. 

Whinkin also describes other benefits of ketamine, especially when comparing it to selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), etc.:

• It is available through many routes of administration across a large dosing spectrum, allowing for more individualized, responsive care.
• It has few medical contraindications or deleterious medication interactions.
• It has few side effects, and most are short-term.
• It can be utilized specifically to facilitate a psychedelic journey, which offers an opportunity for psychospiritual insight.
• It has been shown to offer relief for many comorbidities of depression, such as anxiety, post-traumatic stress disorder (PTSD), substance use, and trauma.

In 2019, esketamine nasal spray was approved by the U.S. Food and Drug Administration (FDA) as an adjuvant for treatment-resistant depression in adults. Esketamine is made from ketamine, which is an anesthetic drug. A 2022 review published in Discover Mental Health concluded that both ketamine and esketamine are viable treatment options for treatment-resistant depression and provide rapid symptom relief.

Ketamine Versus Psilocybin

The biggest factor when comparing ketamine to psilocybin is availability. While ketamine is more easily accessible, psilocybin is currently only legally available in Oregon and Colorado.

“In a world where both are readily available and financially accessible, both have their advantages,” said Whinkin, who is an expert in the field of psychedelic medicine with the Advanced Integrative Medicine Science Institute. “Once research can be performed comparing psilocybin-assisted psychotherapy to ketamine-assisted psychotherapy at various doses, including micro-dosing in humans, we’ll have the scientific data to more clearly understand the different niches each has from a clinical standpoint.”

Both substances positively influence neuroplasticity, and while both provide similar rapid symptom relief, in vivo, research demonstrates that psilocybin’s effects may last longer on average after a single dose—six months with psilocybin compared to about two weeks with ketamine.

“Regarding how long each substance lasts after a single administration, it’s important to note that the animal research used much higher doses than those that are discussed in the literature for depression in humans,” explained Whinkin.

Based on her clinical experience, Whinkin said that anecdotally, the two molecules provide a different type of “psychedelic journey.”

“Ketamine is a dissociative anesthetic that can facilitate an out-of-body experience with loss of connection to existing roles and identities associated with our consensus reality life,” she explained. For example, if a person struggles with dissociation, they may benefit more from the grounding activity of psilocybin versus ketamine. 

"The fact that one is a plant medicine, psilocybin, and one is a synthesized compound, ketamine, can also impact a person's expectation of their journey or relationship to the compound, which may also play a role in the journey experience,” explained Whinkin.

No matter which substance is chosen, the clinical experience is highly influenced by other important factors. 

“With psychedelics, variables that can contribute to outcomes always include trust and relationship with their facilitator, comfort with the setting, quality of the preparation, and quality of the integration experience after the treatment,” said Whinkin.

Contraindications and Interactions

According to a 2021 review published in Molecules, psilocybin has the most favorable safety profile of all the psychedelic substances; however, there is concern that a person could have a "bad trip," which can cause extreme distress, traumatic flashbacks, and paranoia potentially followed by nausea, vomiting, headache, chills, and/or drowsiness. Within the psychedelic community, this is often referred to as a "challenging experience" rather than a bad trip, as healing can still take place with the support from an experienced facilitator.

“Sometimes healing comes from facing distress and finding resources, internally and externally, to somehow move forward, accept, or let go of the fear,” said Whinkin. “But ample safety has to be established for this to be possible.”

Psilocybin has been used across the globe by indigenous communities and in different cultural practices since time immemorial, which may help illustrate its safety profile. 

“From a research perspective, we know more about ketamine’s safety and interaction profile with other medications and conditions because we’ve been able to study it legally since its inception and use in anesthesia,” explained Whinkin.

StatPearls reports that common side effects of ketamine include nausea, vomiting, dizziness, double vision, drowsiness, dysphoria, and confusion, with hallucinations being rare. 

There are some cardiovascular concerns with both substances because they can temporarily increase blood pressure.

Research demonstrates that psilocybin should not be used with lithium carbonate as it may increase the risk of seizures. Ketamine does not appear to have this effect.

“Other psychiatric medications seem to blunt the effects of both ketamine and psilocybin,” said Whinkin. "I have yet to see research comparing the extent of this effect, which would be clinically informative if given a choice between the two for a patient on an SSRI, for example."

Whinkin reminded clinicians that psychedelic compounds such as ketamine and psilocybin may worsen mania or psychosis in individuals with bipolar disorder and psychotic spectrum disorders, so caution and careful medical surveillance are required.

For more information about psilocybin, you can find an article featuring information from Whinkin here and a podcast here.