This meta-analysis (s=29) examines the effects of psychedelics (including ketamine and MDMA) and two other ‘psychoplastogens’ on peripheral BDNF levels in humans. It finds no significant changes in BDNF levels post-administration (SMD=0.024, p=0.64), regardless of drug, dose, participant age, or psychiatric condition. Studies with better-controlled designs report smaller effect sizes, and later timepoints show minimal increases in BDNF. The authors conclude that peripheral BDNF is likely not a reliable marker of rapid neuroplasticity and recommend neuroimaging or stimulation-based methods for future research.
Abstract of Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans
“Background Peripheral levels of brain-derived neurotrophic factor (BDNF) are often used as a biomarker for the rapid plasticity-promoting effects of ketamine, psychedelics, and other psychoplastogens in humans. However, studies analyzing peripheral BDNF after psychoplastogen exposure show mixed results. In this meta-analysis, we aimed to test whether the rapid upregulation of neuroplasticity seen in preclinical studies is detectable using peripheral BDNF in humans.
Methods This analysis was pre-registered (PROSPERO ID: CRD42022333096) and funded by the University of Fribourg. We systematically searched PubMed, Web of Science, and PsycINFO to meta-analyze the effects of all available psychoplastogens on peripheral BDNF levels in humans, including ketamine, esketamine, LSD, psilocybin, ayahuasca, DMT, MDMA, scopolamine, and rapastinel. Risk of bias was assessed using Cochrane Risk of Bias Tools. Using meta-regressions and mixed effects models, we additionally analyzed the impact of several potential moderators.
Results We included 29 studies and found no evidence that psychoplastogens elevate peripheral BDNF levels in humans (SMD = 0.024, p = 0.64). This result was not affected by drug, dose, blood fraction, participant age, or psychiatric diagnoses. In general, studies with better-controlled designs and fewer missing values reported smaller effect sizes. Later measurement timepoints showed minimally larger effects on BDNF.
Conclusion These data suggest that peripheral BDNF levels do not change after psychoplastogen administration in humans. It is possible that peripheral BDNF is not an informative marker of rapid changes in neuroplasticity, or that preclinical findings on psychoplastogens and neuroplasticity may not translate to human subjects. Limitations of this analysis include the reliability and validity of BDNF measurement and low variation in some potential moderators. More precise methods of measuring rapid changes in neuroplasticity, including neuroimaging and stimulation-based methods, are recommended for future studies attempting to translate preclinical findings to humans.”
Authors: Abigail E. Calder, Adrian Hase & Gregor Hasler
Summary of Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans
In the late 1990s, ketamine’s unexpected antidepressant effects spurred research into its mechanisms, with enhanced structural and functional plasticity emerging as key factors. These neuroplastic effects, particularly evident in the prefrontal cortex, have since been linked to depressive episodes in unipolar and bipolar depression. Classic psychedelics like LSD and psilocybin, as well as MDMA, were later found to exhibit similar rapid and sustained therapeutic effects. Researchers identified dendritic and synaptic growth, as well as increased neurotrophic signalling, as potential mechanisms behind these effects.
The term “psychoplastogen” describes compounds that induce rapid (within 24 hours) and sustained neuroplastic changes, predominantly in the prefrontal cortical circuits. This distinguishes psychoplastogens from slower-acting antidepressants and neuroplasticity-enhancing drugs such as selective serotonin reuptake inhibitors (SSRIs). Notably, psychoplastogens include substances such as LSD, psilocybin, DMT, MDMA, ketamine, and scopolamine.
Preclinical research shows that psychoplastogens promote neuroplasticity by increasing brain-derived neurotrophic factor (BDNF), a neurotrophin crucial for synaptic and dendritic growth, neuronal maturation, and neuroprotection. Although these effects are well-documented in animal models, the ability of psychoplastogens to elevate BDNF in humans remains unclear. Most human studies rely on peripheral BDNF levels, which are more accessible than central BDNF, despite uncertainties regarding their correlation with brain BDNF. However, peripheral BDNF is influenced by various factors such as age, diet, and blood sample handling, complicating its use as a reliable marker.
Methods
Pre-registration and Inclusion Criteria
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https://doi.org/10.1038/s41380-024-02830-z
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Cite this paper (APA)
Calder, A. E., Hase, A., & Hasler, G. (2024). Effects of psychoplastogens on blood levels of brain-derived neurotrophic factor (BDNF) in humans: A systematic review and meta-analysis. Molecular Psychiatry. https://doi.org/10.1038/s41380-024-02830-z
Study details
Compounds studied
DMT
Psilocybin
LSD
MDMA
Ketamine
Ayahuasca
Topics studied
Neuroscience
Study characteristics
Meta-Analysis