1999-aghajanian.pdf: “Serotonin and Hallucinogens”, G.K. Aghajanian, G.J. Marek (1999-08-01):
This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT2A and other 5-HT2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HT2A receptors. Recently, we have observed a novel effect of hallucinogens—a 5-HT2A receptor-mediated enhancement of nonsynchronous, late components of glutamatergic excitatory postsynaptic potentials at apical dendrites of layer V cortical pyramidal cells. We propose that an effect of hallucinogens upon glutamatergic transmission in the cerebral cortex may be responsible for the higher-level cognitive, perceptual, and affective distortions produced by these drugs.
2004-cools.pdf: “Chemistry of the adaptive mind”, Roshan Cools, Trevor W. Robbins (2004-09-20):
A failure to adapt to novel or changing environmental demands is a core feature of a wide variety of neuropsychiatric disorders as well as the normal states of stress and fatigue. We review the neurochemistry of cognitive control, which has been associated primarily with the prefrontal cortex. Many drugs affect the functioning of the prefrontal cortex, but the direction and extent of drug effects vary across individuals and tasks. Apparently paradoxical effects are often observed, where the same medication causes both cognitive enhancement as well as cognitive side effects. We review neurobiological research that is beginning to elucidate the nature of these contrasting effects and the factors underlying the large variability across individuals and behaviours. The work has considerable implications for the understanding of and treatment development for abnormalities such as Parkinson’s disease, attention deficit hyperactivity disorder and drug addiction.
2008-dejongh.pdf: “Botox for the brain: enhancement of cognition, mood and pro-social behavior and blunting of unwanted memories”, Reinoud de Jongh, Ineke Bolt, Maartje Schermer, Berend Olivier (2007-12-17):
It has been suggested that the recent rapid developments in the fields of neuroscience and psychopharmacology have increased the possibilities for pharmacological enhancement of mental functioning. Here, evidence is reviewed which shows that drugs acting on a variety of neurotransmitter systems can indeed enhance cognition, and to a lesser extent mood and pro-social behavior. Moreover, it seems possible to interfere with the (re)consolidation of traumatic memories. There are, however, a number of caveats: first, as cognition-enhancing drugs can simultaneously exert both linear and quadratic (U-shaped) effects, doses most effective in facilitating one behavior could at the same time exert null or even detrimental effects on other cognitive domains. Second, individuals with a ‘low memory span’ might benefit from cognition-enhancing drugs, whereas ‘high span subjects’ are ‘overdosed’. And finally, evidence suggests that a number of trade-offs could occur. For example, increases of cognitive stability might come at the cost of a decreased capacity to flexibly alter behavior. A short overview of ethical issues raised by the use of cognition and mood enhancing drugs demonstrates the tremendous variety in views and opinions regarding the subject.
2008-helland.pdf: “Effect of Supplementing Pregnant and Lactating Mothers With n-3 Very-Long-Chain Fatty Acids on Children's IQ and Body Mass Index at 7 Years of Age”, Ingrid B. Helland, Lars Smith, Birgitta Blomén, Kristin Saarem, Ola D. Saugstad, Christian A. Drevon (2008-08-01):
Objectives: Arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) are essential for brain growth and cognitive development. We have reported that supplementing pregnant and lactating women with n-3 very-long-chain polyunsaturated fatty acids promotes higher IQ scores at 4 years of age as compared with maternal supplementation with n-6 polyunsaturated fatty acids. In our present study, the children were examined at 7 years of age with the same cognitive tests as at 4 years of age. We also examined the relation between plasma fatty acid pattern and BMI in children, because an association between arachidonic acid and adipose tissue size has been suggested.
Methods: The study was randomized and double-blinded. The mothers took 10 mL of cod liver oil or corn oil from week 18 of pregnancy until 3 months after delivery. Their children were tested with the Kaufman Assessment Battery for Children at 7 years of age, and their height and weight were measured.
Results: We did not find any statistically-significant differences in scores on the Kaufman Assessment Battery for Children test at 7 years of age between children whose mothers had taken cod liver oil (n = 82) or corn oil (n = 61). We observed, however, that maternal plasma phospholipid concentrations of α-linolenic acid (18:3n-3) and docosahexaenoic acid during pregnancy were correlated to sequential processing at 7 years of age. We observed no correlation between fatty acid status at birth or during the first 3 months of life and BMI at 7 years of age.
Conclusion: This study suggests that maternal concentration of n-3 very-long-chain polyunsaturated fatty acids during pregnancy might be of importance for later cognitive function, such as sequential processing, although we observed no statistically-significant effect of n-3 fatty acid intervention on global IQs. Neonatal fatty acid status had no influence on BMI at 7 years of age.
2013-rojas.pdf: “Neurological and psychological applications of transcranial lasers and LEDs”, Julio C.Rojas, F.Gonzalez-Lima (2013):
Transcranial brain stimulation with low-level light/
laser therapy (LLLT) is the use of directional low-power and high-fluency monochromatic or quasimonochromatic light from lasers or LEDs in the red-to-near-infrared wavelengths to modulate a neurobiological function or induce a neurotherapeutic effect in a nondestructive and non-thermal manner. The mechanism of action of LLLT is based on photon energy absorption by cytochrome oxidase, the terminal enzyme in the mitochondrial respiratory chain. Cytochrome oxidase has a key role in neuronal physiology, as it serves as an interface between oxidative energy metabolism and cell survival signaling pathways. Cytochrome oxidase is an ideal target for cognitive enhancement, as its expression reflects the changes in metabolic capacity underlying higher-order brain functions. This review provides an update on new findings on the neurotherapeutic applications of LLLT. The photochemical mechanisms supporting its cognitive-enhancing and brain-stimulatory effects in animal models and humans are discussed. LLLT is a potential non-invasive treatment for cognitive impairment and other deficits associated with chronic neurological conditions, such as large vessel and lacunar hypoperfusion or neurodegeneration. Brain photobiomodulation with LLLT is paralleled by pharmacological effects of low-dose USP methylene blue, a non-photic electron donor with the ability to stimulate cytochrome oxidase activity, redox and free radical processes. Both interventions provide neuroprotection and cognitive enhancement by facilitating mitochondrial respiration, with hormetic dose-response effects and brain region activational specificity. This evidence supports enhancement of mitochondrial respiratory function as a generalizable therapeutic principle relevant to highly adaptable systems that are exquisitely sensitive to energy availability such as the nervous system.
2015-hall.pdf: “Genetics and the placebo effect: the placebome”, Kathryn T. Hall, Joseph Loscalzo, Ted J. Kaptchuk (2015-05-01):
- Predisposition to respond to placebo treatment may be in part a stable heritable trait.
- Candidate placebo response pathways may interact with drugs to modify outcomes in both the placebo and drug treatment arms of clinical trials.
- Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.
Placebos are indispensable controls in randomized clinical trials (RCTs), and placebo responses statistically-significantly contribute to routine clinical outcomes. Recent neurophysiological studies reveal neurotransmitter pathways that mediate placebo effects. Evidence that genetic variations in these pathways can modify placebo effects raises the possibility of using genetic screening to identify placebo responders and thereby increase RCT efficacy and improve therapeutic care. Furthermore, the possibility of interaction between placebo and drug molecular pathways warrants consideration in RCT design. The study of genomic effects on placebo response, ‘the placebome’, is in its infancy. Here, we review evidence from placebo studies and RCTs to identify putative genes in the placebome, examine evidence for placebo-drug interactions, and discuss implications for RCTs and clinical care.
2017-carharttharris.pdf: “Serotonin and brain function: a tale of two receptors”, R. L. Carhart-Harris, D. J. Nutt (2017-08-31):
Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/
or relationship to it via 5-HT2AR-mediated plasticity may also be important—and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
2020-okereke.pdf: “Effect of Long-term Vitamin D3 Supplementation vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial”, Olivia I. Okereke, Charles F. Reynolds III, David Mischoulon, Grace Chang, Chirag M. Vyas, Nancy R. Cook, Alison Weinberg, Vadim Bubes, Trisha Copeland, Georgina Friedenberg, I-Min Lee, Julie E. Buring, JoAnn E. Manson (2020-08-04):
Key Points: Question: Can long-term supplementation with vitamin D3 prevent depression in the general adult population?
Findings: In this randomized clinical trial that included 18 353 adults aged 50 years or older without depression or clinically relevant depressive symptoms at baseline, vitamin D3 supplementation compared with placebo did not result in statistically-significant differences in the incidence and recurrence of depression or clinically relevant depressive symptoms (hazard ratio, 0.97) or for change in mood scores over a 5-year treatment period.
Meaning: These findings do not support the use of vitamin D3 in adults to prevent depression.
Abstract: Importance: Low levels of 25-hydroxyvitamin D have been associated with higher risk for depression later in life, but there have been few long-term, high-dose large-scale trials.
Objective: To test the effects of vitamin D3 supplementation on late-life depression risk and mood scores.
Design, Setting, and Participants: There were 18 353 men and women aged 50 years or older in the VITAL-DEP (Vitamin D and Omega-3 Trial-Depression Endpoint Prevention) ancillary study to VITAL, a randomized clinical trial of cardiovascular disease and cancer prevention among 25 871 adults in the US. There were 16 657 at risk for incident depression (ie, no depression history) and 1696 at risk for recurrent depression (ie, depression history but no treatment for depression within the past 2 years). Randomization occurred from November 2011 through March 2014; randomized treatment ended on December 31, 2017, and this was the final date of follow-up.
Intervention: Randomized assignment in a 2 × 2 factorial design to vitamin D3 (2000 IU/
d of cholecalciferol) and fish oil or placebo; 9181 were randomized to vitamin D3 and 9172 were randomized to matching placebo.
Main Outcomes and Measures: The primary outcomes were the risk of depression or clinically relevant depressive symptoms (total of incident and recurrent cases) and the mean difference in mood scores (8-item Patient Health Questionnaire depression scale [PHQ-8]; score range, 0 points [least symptoms] to 24 points [most symptoms]; the minimal clinically important difference for change in scores was 0.5 points).
Results: Among the 18 353 randomized participants (mean age, 67.5 [SD, 7.1] years; 49.2% women), the median treatment duration was 5.3 years and 90.5% completed the trial (93.5% among those alive at the end of the trial). Risk of depression or clinically relevant depressive symptoms was not statistically-significantly different between the vitamin D3 group (609 depression or clinically relevant depressive symptom events; 12.9/
1000 person-years) and the placebo group (625 depression or clinically relevant depressive symptom events; 13.3/ 1000 person-years) (hazard ratio, 0.97 [95% CI, 0.87 to 1.09]; p = 0.62); there were no statistically-significant differences between groups in depression incidence or recurrence. No statistically-significant differences were observed between treatment groups for change in mood scores over time; mean change in PHQ-8 score was not statistically-significantly different from zero (mean difference for change in mood scores, 0.01 points [95% CI, −0.04 to 0.05 points]).
Conclusions and Relevance: Among adults aged 50 years or older without clinically relevant depressive symptoms at baseline, treatment with vitamin D3 compared with placebo did not result in a statistically-significant difference in the incidence and recurrence of depression or clinically relevant depressive symptoms or for change in mood scores over a median follow-up of 5.3 years. These findings do not support the use of vitamin D3 in adults to prevent depression.
Trial Registration: ClinicalTrials.gov Identifiers: NCT01169259 and NCT01696435.
2020-olson.pdf: “Tripping on nothing: placebo psychedelics and contextual factors”, Jay A. Olson, Léah Suissa-Rocheleau, Michael Lifshitz, Amir Raz, Samuel P. L. Veissière (2020-03-07):
Rationale: Is it possible to have a psychedelic experience from a placebo alone? Most psychedelic studies find few effects in the placebo control group, yet these effects may have been obscured by the study design, setting, or analysis decisions.
Objective: We examined individual variation in placebo effects in a naturalistic environment resembling a typical psychedelic party.
Methods: 33 students completed a single-arm study ostensibly examining how a psychedelic drug affects creativity. The 4-h study took place in a group setting with music, paintings, coloured lights, and visual projections. Participants consumed a placebo that we described as a drug resembling psilocybin, which is found in psychedelic mushrooms. To boost expectations, confederates subtly acted out the stated effects of the drug and participants were led to believe that there was no placebo control group. The participants later completed the 5-Dimensional Altered States of Consciousness Rating Scale, which measures changes in conscious experience.
Results: There was considerable individual variation in the placebo effects; many participants reported no changes while others showed effects with magnitudes typically associated with moderate or high doses of psilocybin. In addition, the majority (61%) of participants verbally reported some effect of the drug. Several stated that they saw the paintings on the walls “move” or “reshape” themselves, others felt “heavy…as if gravity [had] a stronger hold”, and one had a “come down” before another “wave” hit her.
Conclusion: Understanding how context and expectations promote psychedelic-like effects, even without the drug, will help researchers to isolate drug effects and clinicians to maximise their therapeutic potential.
…In the second sample, before the debriefing, we asked participants to guess whether they had taken a psychedelic, a placebo, or whether they were uncertain. Overall, 35% reported being certain they had taken a placebo, 12% were certain that they had taken a psychedelic, and the rest (53%) were uncertain. In the first sample, we did not ask this question, but the same number of people spontaneously reported being certain that they had taken a psychedelic drug. During the debriefing, when we revealed the placebo nature of the study, many participants appeared shocked. Several gasped and started laughing. One stated, “It’s very funny!”, and another replied, “It’s sad!” One of the participants who had sat with a group near the paintings throughout the study asked, “So we were all sober and just watching these paintings for 45 minutes‽”
[“This is a remarkable study, and probably the most elaborate placebo ever reported. But how well did the trick work? The authors say that after they revealed the truth, some of the participants expressed shock. However, 35% of them said they were”certain" they had taken a placebo when quizzed just before the debriefing. Only 12% were “certain” that they’d taken a real psychedelic drug, which suggests that the deception was only partially successful.
Some of the participants did report very strong effects on a questionnaire of ‘psychedelic effects’. However, I noticed that the effects reported tended to be the more abstract kind, such as “insight” and “bliss”. In terms of actual hallucinogenic effects like ‘complex imagery’ and ‘elementary imagery’ (i.e. seeing things), no participants reported effects equal to even a low dose of LSD, let alone a stronger dose. See the rather confusing Figure 2 for details." —Neuroskeptic]
2020-westbrook.pdf: “Dopamine promotes cognitive effort by biasing the benefits versus costs of cognitive work”, A. Westbrook, R. van den Bosch, J. I. Määttä, L. Hofmans, D. Papadopetraki, R. Cools, M. J. Frank (2020-03-20):
Stimulants such as methylphenidate are increasingly used for cognitive enhancement but precise mechanisms are unknown. We found that methylphenidate boosts willingness to expend cognitive effort by altering the benefit-to-cost ratio of cognitive work. Willingness to expend effort was greater for participants with higher striatal dopamine synthesis capacity, whereas methylphenidate and sulpiride, a selective D2 receptor antagonist, increased cognitive motivation more for participants with lower synthesis capacity. A sequential sampling model informed by momentary gaze revealed that decisions to expend effort are related to amplification of benefit-versus-cost information attended early in the decision process, whereas the effect of benefits is strengthened with higher synthesis capacity and by methylphenidate. These findings demonstrate that methylphenidate boosts the perceived benefits versus costs of cognitive effort by modulating striatal dopamine signaling.