Friday, May 26, 2023

Foolproof, by Sander van der Linden: a recommendation, review, and analogy with psychotherapy

I strongly recommend a new book by Cambridge psychologist Sander van der Linden, entitled Foolproof: why misinformation infects our minds and how to build immunity.

I have followed van der Linden's research for several years, alongside other experts who are studying the psychology of persuasion, misinformation, and propaganda.    This area has been an interest of mine for many years, after discovering psychologists such as Cialdini and Kahneman.  

This is a subject that everyone needs to learn about!  Persuasive techniques (for good and for bad) have always been with us through history; the power and influence of these techniques will only continue to escalate, thanks to the internet era, and now the era of artificial intelligence (AI).  

I have discussed these issues in other posts, such as:


and 


and 

Garth Kroeker: "GroupThink" (October 6, 2016) 

Van der Linden reviews the history and scope of misinformation.  Among the many current examples are conspiracy theorists impacting public opinion and policy, political influencers attempting to sway elections, propagandists from other countries defending violent or oppressive policies or sowing discord among their opponents, and of course the anti-vaccine community.  

There are a couple of acronyms he introduces: the word CONSPIRE can help us to recognize some of the common features of conspiracy theories:  

C = contradictory.  Most conspiracy theories feature contradictions.  For example, there could be a belief that some awful event is a hoax, but then also a belief that the awful event is real but was caused by evil conspirators.  

O = over-riding suspicion.    A sense of general distrust that goes beyond the topic of the conspiracy theory, particularly a distrust of official or mainstream explanations.  

N = nefarious plot.  A belief that there is a shadowy group of evildoers, such as government officials, corporations, or (at worst) a particular racial or ethnic group, who behind the scenes have caused some bad thing, perhaps with a motive to advance themselves.  

S = "something's wrong."  The belief that regardless of any acknowledged or corrected fact about an event, there's something going on that isn't right.  

P = persecuted individual.  The belief that someone is being deliberately harmed (most commonly, the believers in the conspiracy theory).  

I = immune to evidence.  Presentations of evidence often have little or no effect to change the opinion of people having conspiracy theory beliefs, in fact evidence could even "backfire" and cause the conspiracy theorist to become even more entrenched, or to believe that you or your sources of evidence are all biased or part of the conspiracy.   Such immunity to evidence is common among people who have limited expertise or knowledge about science, but could also be present in some highly educated people.  A conspiracy theorist who does have more scholarly expertise may understandably deploy statistical or psychological terminology to defend their beliefs; for example, by accusing other scholars of having psychological biases (such as confirmation bias).

Re = reinterpreting randomness.  This is creating a false causal story about random, unrelated events.   Humans in general are prone to doing this.   

It's interesting as a psychiatrist to reflect on the "CONSPIRE" factors above.  They are very often present in frank psychotic states, or in milder variants such as paranoid personality.  The tendency to have paranoid thoughts exists as a trait on a continuum in the population.  This trait has various environmental causes, but also has a high heritability.   It is a typical psychotic symptom to believe that there is a special, often ominous explanation behind pseudorandom events.    

Of course, sometimes there are explanations for events which differ from the mainstream understanding.  Through history there have always been maverick scientists,  who demonstrated something new and important, despite the objections or condemnation of their peers.  One example that has always bothered me was Alfred Wegener, who in 1912 was the first to propose the theory of continental drift; he was ridiculed and dismissed by his peers, who couldn't believe that entire continents could move across the face of the earth; Wegener tragically died before his theory was proved correct.   We have to be open to consider alternative theories.  However, maverick scientists, unlike conspiracy theorists, have clear evidence to support their claims; their reasoning does not contain contradictions; they are not immune to evidence, do not reinterpret randomness, and do not have ominous, over-riding suspicious beliefs about persecution.  

Van der Linden's next acronym is "DEPICT", to help remember features of manipulative communication:
  
D - discrediting.  The manipulative communicator will portray experts who disagree with them (such as scientific leaders, or even entire communities such as leading scientific journals), as biased, poorly qualified, incompetent, or having some nefarious agenda.  It is frustrating to have a scientific debate with someone who is engaging in such discrediting, since any sound evidence you raise with them will be dismissed as invalid.  

E - emotional.  Using strong emotional language to induce fear, anger, or disgust as a persuasive tool.  

P - polarization.  Framing issues, and people who have positions on these issues, in a "black or white" fashion, rather than as shades of grey.  This leads to a false sense of dichotomy, and encourages the formation of teams of opponents holding increasingly extreme positions, and increasing disrespect for those who disagree. 

I - impersonation.  Using fake experts to bolster a claim.   A variant of this is using an actual expert, but whose expertise has nothing to do with the issue at hand.  

C - conspiracy theories.  Encouraging conspiracy theory beliefs. 

T - trolling.  Attacking, insulting, or threatening opponents, usually in an online environment, such as on social media.  Such harassment has at times been so intense that scientists or policy experts (including in public health) have been afraid to speak out, fearing for their safety.  

Van der Linden's work focuses on how we can best deal with misinformation.  He concludes with an analogy:  misinformation must be dealt with by "immunizing" ourselves against it.  

In order to build immunity against an infectious disease, it is necessary to be exposed to a weakened version of the pathogen, in order to train the immune system, such that future doses of pathogens would be dealt with quickly.  

Infectious diseases are much easier to manage, with much less risk of harm or spread, by building immunity, rather than by only relying on treatment after infection.   

Similarly, it is much harder to "treat" misinformation after the fact.  Tactics to "treat" misinformation would be debate, education, and careful review of evidence.  But many people who have fallen into a misinformation "rabbit hole" are difficult to reach or persuade using reasoned debate.  Such debate may even cause the misinformed person to become even more angry or stubbornly adherent to their ideas.    

It is better to prevent people from falling into the rabbit hole in the first place--not by eliminating rabbit holes (which is impossible) but by teaching people how to identify and manage rabbit holes if they encounter them.  

The idea of "vaccination" is presented as an analogy throughout the book.  But beliefs and persuasion are not exactly like the body's immune system.  It's a very good analogy, but not perfect.  Much of the phenomenon van der Linden is talking about is explainable through learning theory:   we learn much better if we actually practice "hands on" with things, rather than just passively absorbing theory.  If you want to learn mathematics, you actually have to work through a lot of problems, not just read about how to do them.  If you want to learn how to ride a bike or drive a car, you have to practice cycling and driving, not just read about those things in a book!  As part of the practice, it is best to face challenging situations, and learn through experience how to overcome them.  

Similarly, to deal with emergencies, it is imperative to do behavioural practice many times as a preparation.  We have to do fire drills to prepare for a potential fire.  Pilots need to practice many times in a simulator how to manage engine failure.  If you only read about something, or learn about something, without practicing, you can't possibly become proficient, especially under pressure.  

To deal with misinformation, we have to practice, hands-on, dealing with misinformation, at first with "easy" examples, then more and more difficult ones.  

Applying these ideas to psychotherapy: CBT (cognitive-behavioural therapy) is very important and useful, but at worst it can be too passive.  Many people engaging in CBT do a lot of passive learning, they do written exercises in a workbook, but do not really practice deliberate exposure to uncomfortable stimuli.  The "vaccine" analogy could be useful to incorporate into CBT for treating depression or anxiety.   This is something that I have advocated for many years, mainly an emphasis on the "B" part of CBT.  To deal with panic attacks, it is most helpful to actually practice having panic attacks, in safe, controlled conditions!   To deal with depressive thoughts, it could be a useful exercise to invent simulated depressive thoughts, at first mild ones, then more challenging ones, to understand the mechanism by which they are created, and to practice facing them without being negatively affected.   This exposure therapy is like van der Linden's "vaccine."  But most therapists don't emphasize this enough, they only try to teach people to relax or cope with symptoms after they have occurred.  One of the purposes of talking about past emotional trauma is to recreate the painful events in the mind, but in a limited, controlled, "virtual" form, within the safe context of a therapy office.  In this way talking therapy has a vaccine-like effect.  

Linden's book is a must-read, not only for those interested in propaganda or misinformation, but also for anyone wanting a better understanding of the mind itself, with ideas that touch upon managing almost any life adversity, including mental illnesses.  

References: 


Linden, S. V. D. (2023). Foolproof: Why Misinformation Infects Our Minds and How to Build Immunity. WW Norton.


Wednesday, February 1, 2023

Why to get your COVID bivalent booster

The COVID vaccines have saved millions of lives, and spared millions more a frightening hospital or intensive care admission.   Many people may not realize that recovery from a COVID hospitalization will often not be complete; tissue damage from COVID pneumonia may not heal completely, also the psychological effect of respiratory failure should not be underestimated.  Severe respiratory failure (a terrifying, suffocating experience) can often be a cause of PTSD that could affect you psychologically for years afterwards.   The vaccines have caused a huge reduction in such episodes of respiratory failure.  

COVID vaccinations are not perfect, and their protective effect does diminish gradually with time, though does not disappear entirely.  There are indeed rare cases of serious adverse effects, much lower than the rate of similar or worse adverse effects from COVID itself.  Also, vaccination reduces the probability of spreading to other people, thereby multiplying the beneficial effects in the whole community.  Vaccination followed by a mild case of COVID a few months later likely adds robust protection compared to vaccination or infection alone.   But the most effective and safe protection is to have an updated bivalent COVID booster, particularly if your last dose of vaccine and any episode of COVID infection has been more than 2-3 months before present.  Unfortunately, fewer people have had their boosters compared to previous vaccine doses, resulting in thousands of needless hospitalizations and deaths.  

Anti-vaccine misinformation is widespread, with testimonial accounts from people claiming that the vaccines are harmful.  It is important to know that a bivalent booster will lead to a large reduction in risk of severe disease, hospitalization, ICU admission, and death.    Evidence to support this is very, very robust, and unfortunately has not been emphasized strongly enough in current public health information campaigns.  

I encourage perusing the references below.  Aside from reading the studies and assessing the evidence for yourself, I encourage you to look up the authors and verify for yourself that these are incredibly experienced, well-educated researchers from major research centers, with no major biases or profit motives affecting their findings.    The research findings are corroborated and consistent with the  experience of ICU and infectious disease physicians, who on a daily basis in the past months have continued to see much more severe COVID disease and dangerously high hospital occupancy among those who are not up-to-date with their booster vaccinations.  


The references below are a preliminary list; I encourage you to continue checking out other references I've included in my previous COVID-related posts.  


References

Watson, O. J., Barnsley, G., Toor, J., Hogan, A. B., Winskill, P., & Ghani, A. C. (2022). Global impact of the first year of COVID-19 vaccination: A mathematical modelling study. The Lancet Infectious Diseases, 22(9), 1293–1302. https://doi.org/10.1016/S1473-3099(22)00320-6

CDC. COVID Data Tracker.  Centers for Disease Control and Prevention. 
https://covid.cdc.gov/covid-data-tracker/#vaccine-effectiveness
https://covid.cdc.gov/covid-data-tracker/#rates-by-vaccine-status

Arbel, R., Peretz, A., Sergienko, R., Friger, M., Beckenstein, T., Yaron, S., Hammerman, A., Bilenko, N., & Netzer, D. (2023). Effectiveness of the Bivalent mRNA Vaccine in Preventing Severe COVID-19 Outcomes: An Observational Cohort Study (SSRN Scholarly Paper No. 4314067). https://doi.org/10.2139/ssrn.4314067

https://www.azdhs.gov/covid19/documents/data/rates-of-cov-19-by-vaccination.pdf?v=2023010

Lin, D.-Y., Xu, Y., Gu, Y., Zeng, D., Wheeler, B., Young, H., Moore, Z., & Sunny, S. K. (2023). Effectiveness of Vaccination and Previous Infection Against Omicron Infection and Severe Outcomes in Children Under 12 Years of Age (p. 2023.01.18.23284739). medRxiv. https://doi.org/10.1101/2023.01.18.23284739

Andersson, N. W., Thiesson, E. M., Baum, U., Pihlström, N., Starrfelt, J., Faksová, K., Poukka, E., Meijerink, H., Ljung, R., & Hviid, A. (2023). Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries (p. 2023.01.19.23284764). medRxiv. https://doi.org/10.1101/2023.01.19.23284764

Davydow, D. S., Gifford, J. M., Desai, S. V., Needham, D. M., & Bienvenu, O. J. (2008). Posttraumatic stress disorder in general intensive care unit survivors: A systematic review. General Hospital Psychiatry, 30(5), 421–434. https://doi.org/10.1016/j.genhosppsych.2008.05.006

Tenforde, M.W. et al. (2022). Early estimates of bivalent mRNA vaccine effectiveness in preventing COVID-19-associated emergency department or urgent care encounters and hospitalizations among immunocompetent adults. VISION Network, nine states, Sep-Nov 2022.  Morbidity and Mortality Weekly Report, 71(5152), 1616-1624. 




Sunday, January 29, 2023

Heavy Metals in Chocolate

 Chocolate is one of my favourite foods, and may even have health benefits.  But of course, we have to be wary of bias about health claims that we would really, really love to be true!  

 A few studies suggest possible positive mood effects from chocolate consumption, but this research looks a little bit preliminary or questionable (Shin et al).   

Other studies suggest that dark chocolate could help reduce blood pressure (see Amoah et al for a meta-analysis).  

But a recent simple RCT showed that 8 weeks of dark chocolate intake (100 mg per day) did not affect cognition (Suominen et al). 

In any case, I think chocolate, like other delicious foods, has a role in a healthy, happy lifestyle, provided of course that we stick to moderation, and that we choose products which are high quality and lower in sugar.  

The big issue in the past few weeks has been concern that chocolate contains high levels of lead and cadmium.  This was alarming to read about.  The December 2022 Consumer Reports article on this showed that many brands of dark chocolate (including my own personal favourite) contain up to  7 micrograms of cadmium and 1 microgram of lead in a typical 1-ounce serving.    They compare these numbers to California's maximum allowable dose levels, which are 4 micrograms of cadmium per day, and 0.5 micrograms of lead.    

But whenever we see a report like this, it would be important always to find out what the baseline levels are in the population, otherwise we may be much more alarmed than we need to be.  Various studies have looked at average lead and cadmium intake in the diet.   In summary, average cadmium intake in the diet ranges from 5 micrograms per day in the U.S.,  to 10-15 micrograms per day in Europe, to 30 micrograms per day in Asia, from sources such as grains, nuts, vegetables, and shellfish.  Average lead intake ranges from 2-5 micrograms per day in the U.S., to 10-30 micrograms per day in Europe and other parts of the world, from sources such as cereals, meat, and fish.  Recommendations from various sources, such as the FDA, conclude a conservative safe limit of about 58 micrograms a day for cadmium and 12.5 micrograms a day for lead, for a typical 70 kg adult, which are numbers much lower than previous recommendations. 

So the 7 micrograms of cadmium and 1 microgram of lead in a serving of chocolate is still way below most recommended safe limits, and in a ballpark comparable to existing average dietary intakes across the world.  

Of course, any amount of lead and cadmium should be reduced or eliminated in the diet.  And I hope that chocolate makers will take steps to bring down these levels.  But in the meantime, moderate daily chocolate intake is very unlikely to push your lead or cadmium levels up very much higher than they would have been otherwise; the enjoyment and possible health benefits very likely exceed the small risks.  

It will continue to be a longer-term global issue to minimize heavy metal contamination and other contaminants in food and water.  While some of this contamination is "natural," other examples are made worse by industrial pollution.  In any case, there is more work to be done to improve food safety in the coming decades.  

References:


Suominen, M. H., Laaksonen, M. M. L., Salmenius-Suominen, H., Kautiainen, H., Hongisto, S.-M., Tuukkanen, K., Jyväkorpi, S. K., & Pitkälä, K. H. (2020). The short-term effect of dark chocolate flavanols on cognition in older adults: A randomized controlled trial (FlaSeCo). Experimental Gerontology, 136, 110933. https://doi.org/10.1016/j.exger.2020.110933

Amoah, I., Lim, J. J., Osei, E. O., Arthur, M., Tawiah, P., Oduro, I. N., Aduama-Larbi, M. S., Lowor, S. T., & Rush, E. (2022). Effect of Cocoa Beverage and Dark Chocolate Consumption on Blood Pressure in Those with Normal and Elevated Blood Pressure: A Systematic Review and Meta-Analysis. Foods, 11(13), Article 13. https://doi.org/10.3390/foods11131962

Shin, J.-H., Kim, C.-S., Cha, L., Kim, S., Lee, S., Chae, S., Chun, W. Y., & Shin, D.-M. (2022). Consumption of 85% cocoa dark chocolate improves mood in association with gut microbial changes in healthy adults: A randomized controlled trial. The Journal of Nutritional Biochemistry, 99, 108854. https://doi.org/10.1016/j.jnutbio.2021.108854

Lead and Cadmium Could Be in Your Dark Chocolate. (2022, December 15). Consumer Reports. https://www.consumerreports.org/health/food-safety/lead-and-cadmium-in-dark-chocolate-a8480295550/

Cadmium and Lead Exposure. (n.d.). Retrieved January 29, 2023, from https://encyclopedia.pub/entry/2829

Koch, W., Czop, M., Iłowiecka, K., Nawrocka, A., & Wiącek, D. (2022). Dietary Intake of Toxic Heavy Metals with Major Groups of Food Products—Results of Analytical Determinations. Nutrients, 14(8), 1626. https://doi.org/10.3390/nu14081626

Friday, December 30, 2022

Supplements for Mental Health, Part 3: Omega-3 Fatty Acids & Vitamin D

Omega-3 supplements and Vitamin D have seemed very promising for years, to help with general health, depressive symptoms, cognition, or bipolar symptoms.  

But there was a very large randomized controlled trial, of over 18 000 people,  with an incredible treatment duration of 5 years.  Amazing study!  Recipients received a typical good dose of omega-3 (about 1 gram total of EPA+DHA), plus 2000 IU daily of vitamin D.   

The study showed no effect of the supplement compared to placebo.  There were no significant differences in depression rating scales, suicides, overall death rate, cancer rates, or heart disease rates.  Other findings from this study suggested some possible benefits from Omega-3 for cardiovascular health particularly for people with low dietary fish intake.  

A limitation would be that the study population comprised healthy adults.  It may be that using omega-3 supplementation in the treatment of people with established illnesses such as major depressive disorder or bipolar disorder would be more useful.  

One recent study suggested that omega-3 supplementation may have small but significant benefit in postpartum depression.  Another recent small meta-analysis suggested some benefit in treating residual depressive symptoms in bipolar disorder.   Yet, another good year-long RCT in bipolar patients showed no benefit.  

In ADHD, recent research also showed no benefit from omega-3 in a year-long study.  

In terms of other general health issues, though, there may be benefits from omega-3 and vitamin D supplementation.   The same large RCT mentioned initially (the VITAL study) showed about a 15-20% reduction in autoimmune diseases in the omega-3 or vitamin-D supplemented groups.  There is other evidence that omega-3 supplements could help in other diseases such as macular degeneration.  

So, in conclusion, omega-3 and vitamin D appear to be quite underwhelming in terms of potential mental health benefits.   But there may be some small general health benefits, for particular categories of disease such as autoimmune conditions, for people who may be at risk for deficiencies, such as those of us without much sun exposure, or for those of us who don't eat very much fish.  

Addendum: another study, published by Lavigne & Gibbons in February 2023, showed strong associations between vitamin D supplementation and a lower risk of suicide, in male U.S. veterans, with a stronger association among those with lower vitamin D levels to begin with.  But this is a retrospective cohort study, always much weaker than an RCT, and subject to potential non-causal associations.   Once again, supplementation with a standard daily dose of vitamin D is reasonable and safe; there is negligible risk of harm, with some suggestive data implying potential benefit in autoimmune conditions and mood symptoms, particularly in those who might have been deficient.   

References:



Okereke, O. I., Vyas, C. M., Mischoulon, D., Chang, G., Cook, N. R., Weinberg, A., Bubes, V., Copeland, T., Friedenberg, G., Lee, I.-M., Buring, J. E., Reynolds, C. F., III, & Manson, J. E. (2021). Effect of Long-term Supplementation With Marine Omega-3 Fatty Acids vs Placebo on Risk of Depression or Clinically Relevant Depressive Symptoms and on Change in Mood Scores: A Randomized Clinical Trial. JAMA, 326(23), 2385–2394. https://doi.org/10.1001/jama.2021.21187

Mocking, R. J. T., Steijn, K., Roos, C., Assies, J., Bergink, V., Ruhé, H. G., & Schene, A. H. (2020). Omega-3 Fatty Acid Supplementation for Perinatal Depression: A Meta-Analysis. The Journal of Clinical Psychiatry81(5), 13281. https://doi.org/10.4088/JCP.19r13106

Kishi, T., Sakuma, K., Okuya, M., Ikeda, M., & Iwata, N. (2021). Omega-3 fatty acids for treating residual depressive symptoms in adult patients with bipolar disorder: A systematic review and meta-analysis of double-blind randomized, placebo-controlled trials. Bipolar Disorders, 23(7), 730–731. https://doi.org/10.1111/bdi.13115

McPhilemy, G., Byrne, F., Waldron, M., Hibbeln, J. R., Davis, J., McDonald, C., & Hallahan, B. (2021). A 52-week prophylactic randomised control trial of omega-3 polyunsaturated fatty acids in bipolar disorder. Bipolar Disorders, 23(7), 697–706. https://doi.org/10.1111/bdi.13037

Abdullah, M., Jowett, B., Whittaker, P. J., & Patterson, L. (2019). The effectiveness of omega-3 supplementation in reducing ADHD associated symptoms in children as measured by the Conners’ rating scales: A systematic review of randomized controlled trials. Journal of Psychiatric Research, 110, 64–73. https://doi.org/10.1016/j.jpsychires.2018.12.002

Prokopiou, K., Kolovos, P., Tsangari, H., Bandello, F., Rossetti, L. M., Mastropasqua, L., Mohand-Said, S., & Georgiou, T. (2022). A prospective, multicentre, randomised, double-blind study designed to assess the potential effects of omega-3 fatty acids supplementation in dry age-related macular degeneration or Stargardt disease. Investigative Ophthalmology & Visual Science, 63(7), 377-F0208.

Lavigne, J. E., & Gibbons, J. B. (2023). The association between vitamin D serum levels, supplementation, and suicide attempts and intentional self-harm. PLOS ONE, 18(2), e0279166. https://doi.org/10.1371/journal.pone.0279166

Wednesday, December 28, 2022

Supplements for Mental Health, Part 2: Zinc

 Zinc is a metallic element, and an essential nutrient.  

It is toxic if ingested in excess, with various side effects such as nausea, headache, and diarrhea.  High-dose supplementation can cause copper deficiency, typically at doses greater than 100 mg/day.  The maximum recommended dose is 40 mg/day, with the standard daily requirement being around 10 mg/day.  

The prevalence of zinc deficiency in North America is about 7.5 %  In cases of deficiency, it is obviously beneficial to use supplements.  But what about supplementation above a baseline, normal dietary intake? 

There are some positive studies, including RCTs, typically using doses of about 25 mg per day.  But a few groups have shown negative results, including a major study of using several nutritional supplements, including zinc, all at once. (Sarris et al, 2019).  This group showed that placebo did considerably better than supplements, for treating depression.   

There is in particular no evidence of benefit from zinc supplementation in the treatment of COVID.  

Overall, the research is variable, often low-quality.  It is clear, once again, that zinc supplementation is very helpful in situations in which there could be nutritional deficiencies.  

But the risk of supplementing with zinc in a 25 mg per day range would be very low.  It could be on a list of things to try, as an adjunct for the treatment of depression or ADHD.  It would best be done on a randomized basis, for example to set up your own personal study to take either zinc or placebo for 6 weeks (with the truth of what you were actually taking unknown to you until the trial was over) then with repeated randomized 6-week trials several times, to assess any consistent change in symptoms between placebo and zinc trials.  




References

Lai, J., Moxey, A., Nowak, G., Vashum, K., Bailey, K., & McEvoy, M. (2012). The efficacy of zinc supplementation in depression: Systematic review of randomised controlled trials. Journal of Affective Disorders, 136(1), e31–e39. https://doi.org/10.1016/j.jad.2011.06.022

Duncan, A., Yacoubian, C., Watson, N., & Morrison, I. (2015). The risk of copper deficiency in patients prescribed zinc supplements. Journal of Clinical Pathology, 68(9), 723–725. https://doi.org/10.1136/jclinpath-2014-202837

Estimating the Global Prevalence of Zinc Deficiency: Results Based on Zinc Availability in National Food Supplies and the Prevalence of Stunting. (2012). PLOS ONE, 7(11), e50568. https://doi.org/10.1371/journal.pone.0050568

Yosaee, S., Clark, C. C. T., Keshtkaran, Z., Ashourpour, M., Keshani, P., & Soltani, S. (2022). Zinc in depression: From development to treatment: A comparative/ dose response meta-analysis of observational studies and randomized controlled trials. General Hospital Psychiatry, 74, 110–117. https://doi.org/10.1016/j.genhosppsych.2020.08.001

Sarris, J., Byrne, G. J., Stough, C., Bousman, C., Mischoulon, D., Murphy, J., Macdonald, P., Adams, L., Nazareth, S., Oliver, G., Cribb, L., Savage, K., Menon, R., Chamoli, S., Berk, M., & Ng, C. H. (2019). Nutraceuticals for major depressive disorder- more is not merrier: An 8-week double-blind, randomised, controlled trial. Journal of Affective Disorders, 245, 1007–1015. https://doi.org/10.1016/j.jad.2018.11.092

Thomas, S., Patel, D., Bittel, B., Wolski, K., Wang, Q., Kumar, A., Il’Giovine, Z. J., Mehra, R., McWilliams, C., Nissen, S. E., & Desai, M. Y. (2021). Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial. JAMA Network Open, 4(2), e210369. https://doi.org/10.1001/jamanetworkopen.2021.036