Ketamine and CBD: The Valuable Interaction

Ketamine could be useful as an antidepressant due to its rapid-acting properties, but it brings on side effects that may stand in the way of its therapeutic use. Adding CBD to ketamine might reduce some of these side effects, the scientists find in a new study.

Research published in September in Neuropharmacology found that co-administration of CBD and ketamine induces antidepressant-like effects devoided from hyperlocomotor side-effects.

Ketamine as an antidepressant

Ketamine was primarily developed and used as an anesthetic. Later it was found that, at lower doses, it produces an antidepressant effect. Most interestingly, this antidepressant effect proved to be rapid and sustained. For that reason, ketamine represents one of the most attractive discoveries in the field of psychiatry over the past decade.

According to the World Health Organization estimations, depression will be the worldwide leading cause of disability by 2030. The scientists hope that ketamine could be efficient in the treatment of the major depressive disorder (MDD), a chronic and recurrent mental disorder causing reduced quality of life, medical morbidity, mortality, and social-economic losses. The diagnosis of MDD is based on a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. Most clinically available antidepressants have two significant limitations – delayed onset of the therapeutic effect (2–4 weeks) and no satisfactory response in a considerable number of patients.

A sub-anesthetic dose (0.5 mg kg−1) of ketamine has demonstrated a rapid antidepressant benefit in depressed patients, including treatment-resistant depression and treatment-resistant bipolar depression. It prompts its rapid antidepressant effect within a couple of hours, and the effect can be sustained for up to two weeks. Crucially, ketamine is found to successfully induce its rapid effects against suicidal ideas.

In 2019, the Federal Drug Administration (FDA) approved the use of S-ketamine (esketamine) in patients with treatment-resistant depression. Esketamine is more active than ketamine, with four times higher potency on N-methyl-D-aspartate (NMDA) receptors. Those brain receptors have an important role in learning and memory, and are crucial for spatial memory, enabling space orientation.

Despite its obvious effectiveness, the broader use of S-ketamine is limited by some undesired side effects, such as psychotic symptoms and increased liability for abuse and dependence.

Ketamine side-effects

A 2013 study on 73 patients found that the most common adverse events with ketamine were dizziness, blurred vision, headache, nausea or vomiting, dry mouth, poor coordination, poor concentration, and restlessness. Significant dissociative symptoms occurred in 17% of the patients. The type of events reported was feeling outside of one’s body or perceiving that time is moving more slowly or more quickly than normal immediately after the infusion. These symptoms resolved in two hours.

The side effects of ketamine can be distressing, particularly in children; with recorded nightmares, delirium, and hallucinations. In adults, the most commonly reported psychotic side-effects are „elevator effect” or dissociative feeling, somnolence or insomnia, and sensory changes, i.e. taste disturbance or somatic sensations. When ketamine is given in large doses, patients quickly become unresponsive.

One of ketamine’s side effects is hyperlocomotion, investigated in this new study. Hyperlocomotion is incessant locomotion, usually appearing as a result of excessive stimulation of the nervous system. The hyperlocomotion, as a behavioral performance, is used for psychosis modeling and evaluation of the antipsychotic potential of molecules. Sometimes studies result in contradictory findings. The opposite results are usually explained by different protocols used. One previous research has shown that CBD at high doses could facilitate the hyperlocomotion induced by ketamine.

The new study

In this study, mice were administrated with 3, 10, and 30 mg/kg of CBD. As a result, co-administration of CBD (10 mg/kg) and S-ketamine (10 and 30 mg/kg) reduced the immobility time in the forced swimming test. In the open field test, pre-administration of CBD (10 mg/kg) prevented the hyperlocomotion induced by S-ketamine (30 mg/kg). CBD alone did not induce any significant effects on locomotion, nor did the combination drugs in smaller doses.

These results suggest that co-administration of CBD and S-ketamine could be an attractive therapeutic strategy in treating depression, by promoting antidepressant effects while preventing the psychostimulant side-effect of S-ketamine.

The findings are in line with the previous research that found that CBD inhibits the hyperlocomotion induced by dextroamphetamine or ketamine. In the newest study, however, the scientist went one step forward in the understanding of the mechanisms involved in this process. They found that there could be a potential common instrument of action for CBD and S-ketamine. For the first time, the results show that the antidepressant-like effect of CBD, similar to ketamine, depends on the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors.

CBD and mental health

There is already some scientific evidence that CBD could help with mental health. A study on 42 patients with schizophrenia found that starting with 200 mg per day and increasing stepwise by 200 mg per day to a daily dose of 200 mg four times daily help fight the symptoms. Also, CBD is efficient with anxiety in public speaking. As for depression, one of the major reasons people use CBD, we still lack clinical evidence. However, preclinical studies have shown the effectiveness of CBD with depression and chronic stress. Furthermore, it has been shown that ineffective doses of CBD (7 mg/kg), when coadministered with ineffective doses of antidepressants already in use for the treatment of depression, like fluoxetine (5 mg/kg) or desipramine (2.5 mg/kg), produced significant antidepressant-like effects. The newest study expresses a need for clinical research that would investigate if CBD could attenuate the psychotomimetic effects associated with S-ketamine administration in depressed individuals.

Ketamine-induced schizophrenia reversed to normal with CBD

Another brand new study published in October in Frontiers in Pharmacology evaluated the effects of CBD on the ketamine-induced expression of NMDA and AMPA receptors in rats with schizophrenia-like symptoms. Ketamine was used to provoke an experimental model of schizophrenia. After seven days of administration of 30 mg/kg of ketamine per day, the rats showed an increase in spontaneous and habituated motor activity. These behavioral changes were reversed to normal by subsequent chronic CBD treatment.

Here, the scientist found a phenomenon – CBD administration per se increased the expression of specific NMDA and AMPA receptor subunits in the prefrontal cortex of the brain. CBD attenuated the ketamine-induced effects although it induced specific effects in the same direction as compared to ketamine. Further research in this field is expected.

Reviewed by Sasha Bajilo, founder of ILESOL Pharmaceuticals, an industrial scale producer of CBD products and formulations. Expert on Hemp/Cannabis policy, member of the Croatian Ministry of Health regulatory commission for medical cannabis.