Are we living in a psychedelic drug renaissance? Peruse recent clinical research and you may think that the dancing days of the 60s and 70s are here again, given the upwelling of scientific interest in these mainstays of the counterculture movement.

That interest has perhaps been piqued by the burgeoning US mental health crisis. The pandemic has left the US healthcare system to confront a simultaneous increase in demand for mental healthcare and a shortage of clinicians.

These basic economics, alongside a search for alternative management options, prompt the question of how substances such as marijuana, ketamine, and mushrooms may assist people with depression. Research offers some insight.

 

Medical marijuana efficacy: not so high

But when it comes to marijuana use and depression, clinical research paints a more sober picture.

For example, a 2018 Journal of Affective Disorders study evaluated a group of 307 psychiatric outpatients with depression.

Bahorik AL, Sterling SA, Campbell CI, et al. Medical and non-medical marijuana use in depression: Longitudinal associations with suicidal ideation, everyday functioning, and psychiatry service utilization. J Affect Disord. 2018;241:8–14.

Among this group, 40% used marijuana; in that sub-group, 71.7% used cannabis recreationally and 28.2% used it medicinally. Those who did not use marijuana served as the control.

 

Compared with people who abstained, marijuana users experienced:

• Diminished mental and physical health status

• Higher suicidal ideation (among non-medical users)

• Fewer visits to psychiatrists

• Less improvement in depression symptoms

• Less improvement in suicidal ideation

“Marijuana use, especially non-medical use, among patients with depression may impede depression symptom improvement while lessening the likelihood of psychiatry visits,” the researchers wrote.

Marijuana use and associated barriers to care should receive consideration by depression treatment providers.

 

Ketamine: timing counts

Anesthesiologists: Fork over that ketamine. A 2020 systematic review and meta-analysis of IV ketamine studies, published in the Journal of Affective Disorders, shows that this drug has a case for clinical use for treatment-resistant depression (TRD).

Marcantoni WS, Akoumba BS, Wassef M, et al. A systematic review and meta-analysis of the efficacy of intravenous ketamine infusion for treatment resistant depression: January 2009 – January 2019. J Affect Disord. 2020;277:831–841.

 

The analysis included 28 studies of sub-anesthetic ketamine use for TRD management. Metrics for examination included depression scores, as well as remission and response rates. Ultimately, the analysis revealed some important insights about the timing of ketamine doses and their effects.

Four hours after infusion, participants experienced strong effects that peaked at the 24-hour mark. The effect remained, but in a diminished state, 7 days later. Multiple doses extended and enhanced efficacy, researchers noted.

Results provide support for the use of ketamine in the rapid management of depressive symptoms.

“While ketamine appears promising in the short-term treatment of TRD, more clinical and experimental data is needed with regards to the efficacy, tolerance, and security of long-term administration of ketamine,” the researchers concluded.

 

The magic(?) of mushrooms

Clinical research on psilocybin and its therapeutic properties may prompt physician researchers to contact their faculty mycologists. A 2020 systematic review and meta-analysis published in Biomedicines provides some reasons to be hopeful about the antidepressant properties of “magic” mushrooms.

Vargas AS, Luís Â, Barroso M, et al. Psilocybin as a new approach to treat depression and anxiety in the context of life-threatening diseases—a systematic review and meta-analysis of clinical trials. Biomedicines. 2020;8(9):331.

 

To be included in the review, all studies were required to include a control group and involve patients experiencing depression or anxiety stemming from a life-threatening disease. Researchers looked at psilocybin’s effect on depression and anxiety, measuring its efficacy using the Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI), respectively. In a group of 92 patients, the intervention groups saw greater improvement on the BDI and STAI.

“The obtained results are promising, and emphasize the importance of psilocybin translational research in the management of symptoms of depression and anxiety, since the compound may be effective in reducing symptoms of depression and anxiety in conditions that are either resistant to conventional pharmacotherapy or for which pharmacologic treatment is not yet approved,” the researchers wrote.

They also provided an interesting word of caution. Unlike traditional pharmacotherapy, psychedelic therapies may connect with the mechanisms that define how we make meaning of and evaluate our experiences. Here, clinicians are straying from pharmacotherapy into the realms of cognition, behavior, spirituality, and affect.

 

The acid test

Maybe Timothy Leary and Ken Keesey were onto something, though the doses they made legendary in social experiments like the Acid Tests were likely far greater than those described in this 2020 review published in Therapeutic Advances in Psychopharmacology.

Kuypers KPC. The therapeutic potential of microdosing psychedelics in depression. Ther Adv Psychopharmacol. 2020;10:204512532095056.

 

Whereas so-called “heroic” doses were the order of the day in the Leary-Keesy era of LSD, this review evaluated the efficacy of microdoses (10–20 mcg) across 14 studies of healthy volunteers with depression.

While the experience was pleasant for some participants, others cycled between depressive and euphoric moods.

According to the researchers, the jury is out on whether microdoses of LSD may alleviate depression, but its documented effects could improve cognitive flexibility, which may in turn decrease rumination.

“These preliminary findings warrant the exploration of the safety and therapeutic efficacy of microdosing psychedelics for depression,” study authors wrote, highlighting the need for psychedelic researchers to “keep on truckin’.”