MDD Treatment Alternatives Explore Potential of Cannabis, Psychedelics


Stemming from recent data on a potential link between major depressive disorder (MDD) and inflammation, research is starting to turn toward alternatives that can treat the disease through anti-inflammatory effects, including ketamine, cannabinoids, and psychedelics.

With a need for more effective treatments for major depressive disorder (MDD), researchers of a new paper published in Brain, Behavior, & Immunity Health have outlined potential alternatives that target the pathophysiology of the disease.

Stemming from recent data on a potential link between MDD and inflammation, research is starting to turn toward alternatives that can treat the disease through anti-inflammatory effects, including ketamine, cannabinoids, and psychedelics, the study authors noted.

“Common treatment for MDD can be effective for some, while not being effective for others. This discrepancy in effectiveness has provided the motivation to find new alternative drug treatments that can be more effective than common treatment and provide long-term relief,” wrote the researchers. “The proposed alternatives provide a promising future for the treatment of MDD by potentially influencing an inflammatory resolution mechanism.”

With anti-inflammatory aspects, ketamine has been explored as a possible treatment for MDD based on a demonstrated ability to quickly relieve depressive symptoms and incite plastic changes and improvements in mood; research also indicates the treatment produces antidepressant effects 30 minutes after administration. Findings from a 2018 study showed that a single-dose of ketamine alone was effective in treating MDD and rapidly reducing suicidal thoughts, the authors wrote.

They noted that ketamine offers infrequent administration and can likely be maintained long term, a positive sign for treatment adherence; one study showed that a single dose of ketamine showed antidepressant effects for up to 7 days.

The researchers also outlined the potential of cannabis in MDD, noting that previous data suggest that cannabis is associated with worsening or initiating the onset of MDD. More recently, research has started to gauge whether there is an inverse relationship between the cannabis and MDD. The group pointed to 2 components of cannabis that have continuously shown antidepressant and anti-inflammatory effects—delta (9)-tetrahydrocannabinol and cannabidiol—and noted that more recently, research has shown anti-inflammatory effects of cannabigerolic acid—another cannabis component—through blocking of the nuclear factor of activated T cells and interleukin-2 production.

In 2016, a group of researchers revealed a connection between the endocannabinoid system, brain-derived neurotrophic factor, and antidepressant and anxiolytic effects. In animal models, the group showed that single and repeated doses of endocannabinoid enhancer drug URB597 resulted in a reduction of symptoms of depression and anxiety during different activities, including a forced swim test.

The impact of psychedelics on MDD has also been explored, as they have been found to mediate inflammation through the 5-HT2A receptor. In 2020, results from a double-blind, placebo-controlled trial showed that treatment-resistant patients with MDD achieved a reduction in C-reactive protein (CRP) and that a greater reduction in CRP was correlated with reduced depression symptoms.

Another recent study of 5-methoxy-N,N-dimethyltryptamine showed that the psychedelic was associated with significantly lower stress and anxiety 7 days after inhalation. Findings from the study also showed correlations between a patient’s rating of the psychedelic experience and the improved affect.

“The quality of a psychedelic experience is important in one’s perception of the experience and thus affects the efficacy of treatment. Indeed, subjective experience and psychological state do affect one’s physiology,” commented the researchers. “Thus, while negative psychological experiences influence inflammation and respective cascading biological events, it is likely that positive psychological experiences provide an opposing effect. It turns out that positive affective traits do in fact predict later lower levels of interleukin-6. This is likely a contributing factor in the efficacy of treatments that also induce positive experiences (eg, psychedelics).”


Richardson B, MacPherson A, Bambico F. Neuroinflammation and neuroprogression in depression: effects of alternative drug treatments. Brain Beha Immun Health. Published online November 8, 2022. doi:10.1016/j.bbih.2022.100554

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