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Frontier mental health research: psychedelics & drug studies

Each month our editorial team sifts through hundreds of papers and curates notable findings—for practitioners and informed readers who want to stay current with the evidence. Subscribe to the monthly Research Digest for expert analysis and concise summaries of key papers.

Health Sciences Lack of energy or motivation Clinical trial

3 papers

Lack of energy or motivation

Based on 24 papers

Researchers are testing many ways to help people who feel low energy or low motivation, often as part of treating depression. The clearest, strongest evidence right now is for ketamine and its close relative esketamine. These drugs can reduce depressive symptoms quickly for some people who did not get better with usual medicines. Regular physical activity, especially walking, also has good evidence for reducing depressive symptoms and may help energy over time. Other approaches look promising but are still early-stage. Psychedelic-assisted psychotherapy (drugs like psilocybin or MDMA given together with careful therapy) shows encouraging results in trials but needs more research and detailed therapy support. Brain-based treatments such as deep brain stimulation (DBS) or combining brain stimulation with ketamine are experimental but may help some people who have not responded to many other treatments. Whole-body hyperthermia (controlled heating) is very preliminary and needs careful testing and safety checks. Across all options, safety, careful preparation, and close follow-up are important because effects and risks vary between people.

Key findings

  • Ketamine and esketamine can reduce depressive symptoms quickly, sometimes within hours to days, and they have the strongest clinical evidence among rapid-acting treatments. 15070 10153 10149 10152
  • Esketamine nasal spray, when added to a newly started oral antidepressant, produced faster and larger drops in depression scores over four weeks in a randomized trial. 12156
  • Ketamine treatments commonly cause short-lived side effects such as dissociation (strange or dream-like feelings) and temporary blood pressure rises, so dosing and monitoring are important. 10159 10149 10153
  • Psychedelic-assisted psychotherapy (for example psilocybin or MDMA given inside a therapy program) shows encouraging results for some people with hard-to-treat depression and PTSD, but the evidence is still early and responses vary a lot between individuals. 15063 15053 15070
  • Good preparation and careful support before and after drug sessions (called 'set and setting' and integration work) are widely considered important for safety and for getting the most benefit in psychedelic-assisted therapy. 15065
  • Regular physical activity, including structured exercise programs and walking, has medium-sized benefits for lowering depressive symptoms and may help energy and motivation over time. 8792 8785 8788
  • Deep brain stimulation produced strong responses in a small trial of people with very treatment-resistant depression, but this evidence comes from a small number of patients and is still experimental. 10166
  • Combining brain stimulation (transcranial magnetic stimulation) with ketamine is a promising idea that might boost and lengthen benefits, but current evidence is preliminary and more trials are needed. 10162
  • Whole-body hyperthermia (controlled heating) can raise protective heat-shock proteins and may improve mitochondrial (cell energy) function, but its use for brain symptoms is experimental and requires precise dosing and careful monitoring. 15128
  • Many standard antidepressants cause weight gain for many people, which can affect health and treatment decisions; bupropion is an antidepressant that is less likely to cause weight gain and is sometimes linked to weight loss. 15114

Treatment‐resistant depression: definition, prevalence, detection, management, and investigational interventions

Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune, Michael Berk, Koen Demyttenaere, Joseph F. Goldberg, et al.
World Psychiatry Summary & key facts 2023 586 citations

Treatment-resistant depression means depression that does not get better after usual treatments. Scientists do not all agree on one clear definition, which makes it hard to know exactly how common it is or which treatments work best. Using the definition that regulators often use, about 30% of people with depression…

Electroconvulsive Therapy Studies Transcranial Magnetic Stimulation Studies Treatment of Major Depression Ketamine

Cingulate dynamics track depression recovery with deep brain stimulation

Sankaraleengam Alagapan, Ki Sueng Choi, Stephen Heisig, Patricio Riva‐Posse, Andrea Crowell, Vineet Tiruvadi, et al.
Nature Summary & key facts 2023 233 citations

Researchers tested deep brain stimulation (DBS) in a small group of people whose depression did not get better with usual treatments. They used an implanted device that both delivered stimulation to the subcallosal cingulate (a brain area linked to mood) and recorded brain electrical signals. Around 9 out of 10…

Functional Brain Connectivity Studies Neurological disorders and treatments Transcranial Magnetic Stimulation Studies

Efficacy and safety of a 4-week course of repeated subcutaneous ketamine injections for treatment-resistant depression (KADS study): randomised double-blind active-controlled trial

Colleen Loo, Nick Glozier, Dávid Barton, Bernhard T. Baune, Natalie Mills, Paul B. Fitzgerald, et al.
The British Journal of Psychiatry Summary & key facts 2023 60 citations

Researchers tested repeated subcutaneous (under-the-skin) injections of racemic ketamine in people whose depression had not improved after at least two antidepressant trials. People got injections twice a week for 4 weeks and neither participants nor the raters knew which drug they were getting. When the study allowed higher, response-guided ketamine…

Mental Health Research Topics Treatment of Major Depression Tryptophan and brain disorders Ketamine
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