A guy is a Chad,
Is every celibate man
On the internet.

Every man is Chad,
Angry online celibates:
The internet guys.

That celibate Chad,
So chronically online;
That's right, call him man.

I do very badly in the summer. This has been true for as long as I can remember. It is very hot today and there is a couple fighting in one of the apartments whose windows are adjacent to my courtyard.

The woman is crying, and the crying is making her voice so high pitched it’s hard to believe it’s real. I do not know what they are fighting about because she is crying in French, and the sobs and shrillness of her voice make individual words difficult to discern.

All of the apartments enclosing the courtyard have their windows cracked open and their curtains drawn so there is no way to identify where exactly the voices are coming from either. Only the apartment on the third floor, to the right, I know with certainty is safe—with its wide open windows and no curtains and the man, right in frame, who’s been renovating it for the last few months.

He’s always there, even today that it’s Sunday. He used to wake me up at 9 in the morning, either by drilling into a wall or by talking very loudly on the phone. He was always on the phone with someone. He played music sometimes, too, and I quite liked what he played. A few times I perched by my own open window and stuck my phone out to Shazam whatever song he was listening to, hoping he wouldn’t notice.

But all that seems to be over now. He’s been very quiet, lately. I wonder if the renovations are almost done, and he’s going to live there after, or if he’s going to leave the apartment he’s spent countless hours in and let someone else, maybe a happy French family, take his place.

I wonder if I’ll miss him. He is, after all, the only neighbor I’ve really known, more than just a shadow behind a curtain or an angry voice with no identifiable source or target. I hope he gets to stay.

A man walks out of the bathroom in an Upper East Side café. He has no drink in hand; I know from experience this is one of the few spots in the area that’ll let you piss without buying anything. As he walks out, he turns to me for a split second. “Give me 30 minutes and you’ll see.” I don’t know what the hell he’s talking about and I have no time to ask — in a flash, he’s out the door. Was it a threat? A warning? A neutral premonition? I didn’t even think about chasing after him to find out. I paid 6 goddamn dollars for this cappuccino, after all.

Let’s cure depression!

In 1965, Schildkraut was the first to set forth the hypothesis that depression was associated with low levels of norepinephrine and serotonin. This notion is intrinsically tied to the medical model of mental illness: a patient displays a set of symptoms, the patient is diagnosed on the basis of these symptoms, and finally the patient is cured once the disease and its cause are known. This designation of mental disorders on the basis of biological pathways absolutely revolutionized understandings in psychopathology and set the foundation for the development of drugs targeting the biological mechanisms of depression.

Antidepressants—drugs with the objective of targeting depression or low moods—were first introduced in the 1950s. The first classes of antidepressants were monoamine-oxidase inhibitors and tricyclic antidepressants, though these were for the most part gradually phased out due to their undesirable side effects and elevated risk for toxic overdoses. In 1987, fluoxetine (also known as Prozac) was the first Selective Serotonin Reuptake Inhibitor (SSRI) to hit the market, ushering in a new wave of SSRI drugs and quickly becoming the most widely prescribed antidepressant ever marketed. Despite an increase in reports in the early 1990s of unusual violent and suicidal reactions, shortly after the drug’s release, the sales of Prozac and other SSRIs continued unquestioned. 

Antidepressants all share the same mechanisms of action: they modulate monoaminergic neurotransmission at a synaptic level. What this means is that they prevent the transportation of a specified neurotransmitter from the synapse (a tiny gap between neurons) back into the presynaptic neuron, hence increasing its availability and activity. Usually, serotonin or norepinephrine are the neurotransmitters of focus but more recent antidepressants are expanding to target dopamine as well. These antidepressants act on the premise that monoamine neurotransmitters regulate the basis of mood, and that depression or other mental health disorders are related to a deficiency of serotonin, norepinephrine, or dopamine and can be treated by increasing their availability.

Today, the medical model guides much of current thinking about behavioral disorders. Specifically, the idea that depression is caused by a lack of serotonin or other neurotransmitters has become the 21st century’s ‘dominant cultural story of depression aetiology’. After all, if SSRIs and other psychoactive drugs can normalize and treat individuals’ behaviors, this must mean that the original problem lies in a chemical deficiency in the brain. And if a deficiency or abundance in a certain chemical can so severely impact our state of being, then it makes sense to rethink ourselves as ‘neurochemical selves’, ultimately run by our biology. 

With the launch of SSRIs, the pharmaceutical industry certainly employed itself to further embed this possibility into the professional (psychiatric) and popular psyche. Throughout the 1990s, millions of dollars were spent on advertising campaigns, promoting SSRIs as miracle drugs able to reverse the brain’s underlying abnormalities.                  

It wasn’t just pharmaceutical companies trying to market their own products, though. The American Psychiatric Association (APA), the leading authority on basically all psychiatry-related matters in the US, echoed the rhetoric that depression was due to a chemical imbalance, and that antidepressants worked to correct it. For the decades that followed, the vast majority of psychiatric and psychopharmacological literature and publications endorsed the serotonin (or just generally biochemical) hypothesis. And all of the hype around this new serendipitous theory and the astounding effects of SSRIs worked; between the 1980s and mid 2000s, antidepressant prescriptions in the US increased over 4x, and are still on the rise. It’s even more impressive when you consider that 73% of Americans who are prescribed antidepressants (which, by the way, are often prescribed by non-psychiatrists, including primary care doctors) were never even diagnosed with depression. 

Mental disorders: you probably aren’t born with them

Despite all the razzmatazz on the advancements of psychiatric theories, the portrayal of depression and other mood disorders as intrinsic, biologically-embedded diseases (rather than as potentially understandable reactions to one’s conditions of existence) is actually quite problematic.

First off, behaviors that indicate a certain disorder are varied and often have different, unknown causes; diagnosing a mental disorder solely on the basis of behavioral symptoms (as is currently the standard) is usually not very effective. Take the Diagnostic and Statistical Manual (DSM), considered the gold standard for diagnosing mental health problems and their symptoms. In the DSM V, its latest version, the definitions and symptoms defining schizophrenia, bipolar disorder, depressive disorders, anxiety disorders, and trauma-related disorders all overlap significantly and all lead back to the role of trauma and adverse events. These categories are so general and conflated that some researchers have gone so far as to claim that “psychiatric diagnoses are scientifically worthless as tools to identify discrete mental health disorders”, ultimately not providing any real insight into what each individual is experiencing nor optimal approaches to treatment. Furthermore, these categories frequently serve as tools to individualize symptoms of societal issues (such as oppression, poverty, and inequality), instead passing them off as symptoms of isolated cases of mental illness. It’s just you, I swear! Besides the lack of clinical utility of many psychiatric classifications, the DSM itself has an extremely troublesome history. Just as one example (of many), homosexuality was defined as a mental disorder in the DSM until 1974, then replaced with “sexual orientation disturbance” until its complete removal from the manual in 2013. 

Second, the idea that there are distinct, underlying biological causes to each of these sets of symptoms (and so mental disorders) is actually completely unfounded. This boils down to genetic and neuro essentialism, reducing mental disorders to immutable deficiencies or chemical imbalances rooted in DNA which distinguish each individual, neglecting the impact of the environment and personal agency over one’s thoughts and feelings. Neurobiology and genetics contradict such essentialist accounts. Neuroplasticity—the brain’s ability to reorganize and form new synaptic connections—continues throughout adulthood, enabling us to change both physically and behaviorally throughout our entire lives. Although it is possible for mental disorders to be inherited, there are no identifiable genes for any such disorder; epigenetics points to the much more crucial role of the environment in modulating or exhibiting these effects.

Finally, despite extensive research, no association has ever been established between serotonin levels and depression. The activation or blockage of serotonin receptors (increasing or decreasing its availability) has improved and worsened depressive symptoms in a manner that is completely unpredictable, and depressed people have not been found to have reduced serotonin activity compared to non-depressed people. Recent evidence actually suggests that antidepressants long-term may actually reduce serotonin concentrations due to our body’s ability to compensate for external interventions and maintain homeostasis. So if we’re going off the (albeit incorrect) premise that depression is caused by a lack of serotonin, antidepressants should over time actually make it worse.

Hmm, something definitely seems a little off. Keep in mind that, according to survey data, around 80% of the general population now believes that depression is caused by a chemical imbalance. So how can we explain all of the speeches and publications and pamphlets flaunting the chemical mechanisms behind depression and SSRIs if it is actually pretty well established that the hypothesis these explanations are based on is not true?

Well, if you ask Wayne Goodman—an academic psychiatrist and also chair of the FDA’s psychopharmacological committee—, despite the lack of evidence for a neurochemical deficiency in depression, it still makes sense to describe it that way because it is a ‘useful metaphor’. Others, such as Ronald Pies—a renowned psychiatrist, and former editor-in-chief of the Psychiatric Times—instead professed that most well-informed psychiatrists do know the theory is not true, but bring it up anyway to make their patients feel better and save time when explaining their diagnoses to them. Sounds very professional. Similarly, the National Alliance on Mental Illness portrayed depression as “a chronic medical illness”, running with the assumption that characterizing depression in biomedical terms reduces stigma by removing accountability from the individual for their psychological state.

Unfortunately, this appears to not even be true. Despite the fact that many patients now present with self-described chemical imbalances, public endorsements of the chemical imbalance explanation have not bettered societal attitudes towards depressed people, and have actually been shown to worsen stereotypes of dangerousness and unpredictability. It also doesn’t actually make the ones getting these diagnoses feel any better; causal attributions to chemical imbalances made people (wrongly) feel that they did not have a say in regulating their own moods.

Regardless, it shouldn’t be too big of a deal. After all, antidepressants are one of the most well researched categories of drugs; before hitting the market, they underwent over a thousand randomized trials investigating their effectiveness and demonstrating a positive statistically significant effect. These strict regulations surely mean that even if psychiatrists (and nonpsychiatrists) are increasingly diagnosing antidepressants to depressed (and nondepressed) individuals, there’s probably no harm done. A preventative measure, one could call it.

Antidepressants: one of the most evidence-backed drugs out there

Let’s take a look at these studies, though, just to make sure. Yes, all one thousand of them—generally, I promise. There’s a lot to unpack here so I’m just going to run us through a few important questions when it comes to evaluating research:

1. Who is funding the research (and why)?

The answer to the first question is pretty obvious. If a company needs their drug to be well-researched for it to be approved and marketed, it is very well in their best interest to make sure researchers are incentivized to carry out this work. Not only do they want their drugs out on the market, they want to get them there fast. Delays in the drugs’ approvals or indications for further investigations into specific adverse effects are equivalent to millions of dollars lost in potential revenue. Pharmaceutical companies are motivated to ensure the research demonstrates consistent profiles for their drugs, so the regulatory process can run smoothly. Indeed, somewhere between ⅔ and ¾ of all trials published in major journals (such as the Annals of Internal Medicine, JAMA, Lancet, New England Journal of Medicine) are funded by pharmaceutical companies.

Despite the pharmaceutical industry being one of the most profitable sectors for decades, it has recently been undergoing a crisis due to patent expirations, poor pipelines of new drugs, and pressure on prices. What this means, really, is that since there are fewer products being researched and developed, it is even more important that these pass through regulatory processes intact. It is worth noting here that only about 1.3% of pharmaceutical company spending goes towards actual research for new medications. 

2. Who is actually carrying out the study?

This one is a little trickier. Ghost management is basically standard practice in pharmaceutical roll-out; the drug manufacturers pay medical communication companies to write scientific articles (on the basis of industry-designed and -funded studies), which are then published in a variety of medical journals under the name of renowned academics in the field. Indeed, the pharmaceutical industry spends about 70-75% of their clinical trial budget on contract research organizations (CROs), maintaining complete control over the study’s design, organization, and analysis. That means that for every independent researcher given a grant to carry out their own study, there are way more CROs manufacturing manuscripts according to their pharmaceutical sponsors' publication plans. In 2020, CROs had a total combined revenue of around $50 billion, mostly thanks to pharmaceutical clinical trials.

Okay, so does it really matter if it’s a CRO or an independent researcher doing the work as long as the studies actually get done?

It sure seems so! Ghost management conveniently provides pharmaceutical companies with plenty of opportunities to intervene to manipulate the data presentation, omit adverse events, and affect the duration and conducting of the trials themselves. It just so happens that industry-sponsored trials are much more likely to report positive results than independent studies, and these positive trials are then over-represented in medical journals (compared to studies with negative results, which are often simply not published). It’s important to note here that when dealing with CROs, the sponsor (aka whichever company is developing the drug) has access to all of the data being collected, and a pretty massive conflict of interest. Big pharma companies, who in 2021 gained approximately $610 billion through the sale of prescription drugs alone, also obviously have access to a much vaster array of resources than the typical meager independent researcher. They also have good reasons to want their very positive research to infiltrate the public domain as deeply as possible; industry trials are cited in medical journals much more frequently than non-industry trials, and thousands of “key opinion leaders” are hired to discuss positive clinical trials to physicians across the country.

These mechanisms work to give the impression, by looking at the academic literature, that the evidence for antidepressants is much more robust than it actually is. By slapping the name of (paid) scientists and researchers onto substantially pre-written papers, pharmaceutical companies get to make their work seem a lot more legitimate than it actually is, integrating it smoothly into the field of medical science.

3. What are the methods employed to determine the drug’s efficacy?

Regardless of whose name you’re publishing it under, bad research is obviously bad research. After all, there are regulations, and the FDA (and the EMA–European Medicines Agency) do require the submission of methods and raw data, so if the studies were really wonky, surely someone would notice. Maybe these companies are just toying around with authorship to ensure their information reaches enough people, which doesn’t sound too bad.

The gold standard in research for assessing efficacy is the randomized controlled trial (RCT): patients are assigned to either a placebo (a sugar pill with no active pharmacology) or the active-drug group in a double-blind manner (meaning neither the researchers nor the patients are aware of which group they are in). In theory, this method enables the assessment of the effects of the active drug vs the placebo while minimizing expectations and bias. Industry and non-industry sponsored research appear to not differ on their standard methodological quality (including sequence generation, allocation concealment, follow-ups, selective outcome reporting, and blinding procedures). Seeing as meta-analyses of RCTs typically report antidepressants as 20-30% more effective than placebo, this actually bodes pretty well.

Of course, though, it’s never that easy. Meta-analyses, such as the one mentioned above, are usually limited to data that is publicly available. Unfortunately, pharmaceutical companies derive a significant chunk of their profits from their intellectual property rights (IPRs). What this means is that most of the data (including that generated during premarket safety and efficacy evaluations) is patented and legally protected as trade secrets. Even when lawsuits are filed (and won) against drug manufacturers, this data and other industry documents usually remain sealed by the court unless explicitly dictated otherwise in the settlement. So it’s actually really difficult to get your hands on the nitty gritty of what’s going on in these clinical trials. But surely no one’s got anything to hide?

Nonetheless, the companies are obliged to register all of their trials and (stated) method protocols with the FDA, alongside the raw collected data. This allows the FDA statisticians to double check the company-run analyses and make sure there is no data-tweaking going on to make their product seem more favorable. 

Yet, there are quite a few issues that can occur with RCTs; these are occasionally and occasionally not reported. Antidepressant trials are typically quite short; most only follow up on participants for 6-8 weeks, and some trials last for as short as 3-4 weeks. This means that there is very little evidence indicating the efficacy and any potential side effects of antidepressants in the long term (past 8 weeks, really), despite the reality that most people on antidepressants tend to stay on them for a while. Another big issue is unblinding: when either the researcher or participant (or both) realize which test group they are assigned to. Unblinding happens frequently in antidepressant studies because of the drugs’ various side effects, which make it easy to distinguish who is actually taking the medication from who isn’t. In these circumstances, the outcome becomes primarily influenced not by the true therapeutic effect of the drug but by the expectations associated with taking an active medication. 

Another common methodological issue is the scale employed to measure depression outcomes. A very popular one is the Hamilton Depression Rating Scale (HDRS), which contains various items nonspecific to depression; a substantial portion of the scale is dedicated to sleep. Consequently, improvements on the HDRS may not actually be reflective of a reduction of depressive symptoms, but may at least in part be due to other effects, such as a response to the sedative effects of antidepressants. 

Finally, RCTs for antidepressants typically have very stringent criteria for participant eligibility. Anyone who has low severity symptoms, comorbid anxiety or any other psychiatric or medical comorbidity, substantial suicidal ideation, prior non-response to treatment, or has shown a strong response to placebo in earlier stages of testing is excluded from Phase III clinical trials. Basically, most people who realistically would represent the average depressed person are excluded from testing, prioritizing instead patients who have the greatest likelihood of demonstrating drug-placebo differences.

These little methodological tweaks not only make it difficult to effectively determine the risk:benefit ratio of antidepressants, they also act to inflate the semblance of a positive impact of antidepressants on mood.

Oh, and one more thing worth mentioning. RCTs don’t really test or assess for adverse events. So most claims on the safety and tolerability of drugs are not at all well supported; if you just choose not to seek out any potential health risks, surely they’ll never materialize!

4. Which results are being published (and where)?

Results from RCTs for the development of new drugs are published in a variety of medical journals; before publication, all submitted studies are peer reviewed. Although peer review can definitely be effective in minimizing biases and catching potential oversights, it is also a process that has been demonstrated to be prone to partiality and abuse. This is particularly true as many journal editors face a financial conflict; as editors are increasingly responsible for journal budgets, publishing trials (which is extremely profitable) is generally in their best interest. Furthermore, it is commonplace for journal editors to have significant commercial ties to the manufacturers of the product being studied; these ties go beyond just research funding and often include being employees of the company, participating on their advisory boards, and receiving consulting monies or honoraria.

Another prevalent issue is selective publishing, wherein only positive trials are published in journals and those that had inconclusive or negative results are swept under the rug. Staying on top of this practice is complicated by the unavailability of the data from unpublished trials. Yet, researchers are able to evaluate the validity of results from published trials by comparing the information found in author surveys, registries, institutional review boards, and funding agencies. 

One study took it upon themselves to conduct a meta-analysis on all of the data from 74 FDA-registered trials for the 12 antidepressant drugs that were approved between 1987 and 2004: Bupropion SR (Wellbutrin SR), citalopram (Celexa), duloxetine (Cymbalta), escitalopram (Lexapro), fluoxetine (Prozac), mirtazapine (Remeron), nefazodone (Serzone), paroxetine (Paxil CR), sertraline (Zoloft), venlafaxine (Effexor), and venlafaxine XR (Effexor XR). They found that of the 74 trials, 38 of them demonstrated statistically significant benefits from antidepressants; of these 38, 37 were published in journals. The remaining 36 trials demonstrated a negative or lack of effect from antidepressants; 3 of these were accurately published with negative results, 11 were published with rhetoric that misrepresented the data to give the semblance of a positive effect, and 22 were never published at all. 

Not only do pharmaceutical researchers cherry-pick which studies to publish to overplay the favorable impact of the drugs tested, the studies that were actually published still conveyed an effect size that was almost ⅓ greater than that derived from the data registered with the FDA, embellishing even further. These studies also often include abstracts and conclusions that overstate the benefit, using phrases such as “efficacious and well-tolerated”, without really addressing the small magnitude of effects, methodological limitations, patient selection, withdrawals and adverse events, or the short-term duration of the trial.

Briefly, I’d like to go over the case of Forest Laboratories, a pharmaceutical company that in 2009 faced a class action lawsuit for misrepresenting the safety and efficacy of Celexa and Lexapro by promoting the drugs for pediatric use, off-label. A settlement was reached in 2014 and, as a result, the company’s unpublished data and internal communications were opened up to the public. Forest failed to disclose trials in which citalopram had no significant difference in symptom reduction compared to the placebo, and actually increased suicidality in children and adolescents. They also omitted in the published study that the only reason they were able to demonstrate citalopram’s positive effect was because they included data from 8 participants who had been unblinded to the drug (due to a packaging error). They also did not disclose that various participants withdrew from the study due to experiencing potentially dangerous states of over-arousal, none of which occurred with the placebo.

An honest mistake? Maybe, but not likely. 

In 2002, Dr. William Heydorn, senior Forest Laboratories study director, wrote:

“The publications committee discussed target journals, and recommended that the paper be submitted to the American Journal of Psychiatry as a Brief Report. The rationale for this was the following: ... As a Brief Report, we feel we can avoid mentioning the lack of statistically significant positive effects at week 8 or study termination for secondary endpoints” 

A few months prior, Dr. Heydorn also wrote:

“Given what I have seen of the data, I believe that we should maintain control, which means either writing in house or having an outside group (like Weber Shandwick [BSMG] or a CRO) draft the manuscript”

As you can imagine, Forest had to expend quite a few big bucks to settle the lawsuit.

Maybe they’re just one bad apple, that’s true, but given the prevalence of ghostwriting, industry funding, selective publishing, effect size inflation, and lack of transparency regarding unpublished data, it feels a little hard to believe. And it certainly isn’t an isolated incident! Between 1999 and 2016 alone, the pharmaceutical industry has dispensed over $33 billion dollars in settlements for falsifying study results, providing doctors with bribes in exchange for prescribing their drugs, misleading marketing, and knowingly shipping out contaminated products.

So, do antidepressants actually work?

At the end of the day, antidepressants definitely can be effective and substantially beneficial (at least in the short term); completely dismissing them or casting them aside would be harmful to those they do help. Despite the fact that the specific biological mechanism they are targeting is not at the root of depression, mind-altering drugs (including antidepressants) do obviously still impact mood and mental perceptions.

Nonetheless, antidepressants are widely over-used, and there are serious issues with the way they are researched, developed, marketed, and prescribed that need to be addressed. 

One of these issues is the reality of withdrawal, or discontinuation syndrome. Various studies have demonstrated that after discontinuing antidepressants (when compared to a placebo), many individuals report relapsing into depression. Yet, this is most likely not a sign of antidepressants’ efficacy; depressive-like withdrawal symptoms are misdiagnosed as relapsing, further reinforced by nocebo effects, wherein negative expectations associated with being taken off medication can induce physical illness. And these withdrawal symptoms are very well documented, accompanying both abrupt and gradual discontinuations of both SSRIs and SNRIs; clinical effects are general, visual, cardiovascular, gastrointestinal, sensory, neuromuscular, vasomotor, cognitive, affective, psychotic, sleep, and behavioral. For a lot of people, belief in an intrinsic chemical imbalance and a difficult withdrawal period may lead to a lifelong dependence on antidepressant drugs (which themselves carry a lot of adverse health risks). Keep in mind that there is no controlled data on whether antidepressants are safe in the long-term (despite over 1/4 of individuals on antidepressants have been taking them for over a decade), and the data that does exist is at the very least concerning.

Furthermore, despite psychiatrists’ and physicians’ best intentions—due to lack of access to all drug trial data and alternative analyses—it is difficult to make an evidence-based, unbiased decision when recommending a specific drug. It also certainly doesn’t help that pharmaceutical companies often give personal financial payments (from cash to gifts) to physicians; between 2015 and 2017, 67% of all US physicians received such a payment. These payments obviously have an impact on physician prescribing practices, notably by increasing the prescription of less effective, less safe, and more expensive drugs. After all, they aren’t small gifts—industry payments to US physicians in 2018 alone totaled $2.18 billion in value. It’s no wonder then, too, that one of the biggest obstacles to reform are the physicians themselves, who think industry gift-giving is a very appropriate practice that should be continued.

Another factor to keep in mind is that although antidepressants are effective, there is a very good chance a majority of their positive effects have nothing to do with the actual drug and everything to do with placebo. The efficacy of SSRIs is highly dependent on psychological factors (such as having positive outcome expectations); whether the SSRI was administered overtly or covertly resulted in significantly different neural changes in brain regions associated with emotion-cognition interactions, suggesting a biopsychological (not biomedical) explanation for antidepressant effects. Furthermore, various studies have demonstrated that taking an active placebo is just as effective as taking antidepressant medication, and actually involves lower risks of relapse. For certain disorders, placebos actually outperform medication. Even when patients are aware they are being prescribed placebos (and not active medications), they still hold incredible benefits so long as there is an accompanying explanation that they’ve been demonstrated to efficiently treat their particular condition—pointing once more to the understated role of positive expectancies. 

Again, the fact that antidepressants were approved by various regulatory agencies does obviously mean that they have demonstrated a significant result in some trials and some scales, and so can be beneficial to at least certain groups of individuals (particularly those with severe symptoms who have been non-responsive to other treatments, and those who have already been on antidepressants). Yet, for the vast majority, there are much safer (and cheaper) alternatives that are demonstrated to be as, and usually more, effective than antidepressants. Open-label placebo interventions in most cases offer the same results without any health risks at all, alongside psychotherapy, physical exercise, acupuncture, omega-3, homeopathy, tai chi, qigong, and yoga. 

At the very least, though, people should be accurately informed of the real effectiveness and safety profile of the medications they are being prescribed, of the biases present in the medical literature informing their physicians (and their potential financial incentives), and of other successful alternatives so they can actually be recommended the safest and most appropriate treatment.

At the end of the day, it’s good to have a think about what we’re putting in our bodies. And when the treatments are equally effective, recommend the safest; when they are equally safe, let each individual make their own, well-informed decision! <3

P.S. Just in case you’re curious, here’s a short list of a few major journals & their commercial ties:

1. International Clinical Psychopharmacology

   1. Journal editor received consulting fees + honoraria from AstraZeneca, Bionevia, Bristol-Myers Squibb, GlaxoSmithKline, J&J, Hundbeck, Merck & Co, M’s Science, Merz Pharmaceuticals, Nurim Pharmaceuticals, Ostuka, Pfizer, Pierre Fabre, Roche Pharm, Sanofi-Aventis, Sepracor, Servier Labs, Synopsis, Takeda, Xytis, Wyeth, Theracos

2. Journal of Clinical Psychiatry

   1. Journal editor 1: 

      1. Is a major stock owner of Healthcare Technology Systems

      2. Consults to Dey Pharma, PGxHealth, Myriad Genetics, Zynx Health

      3. Principal investigator on grant from Pfizer Pharmaceuticals

   2. Journal editor 2:

      1. Consultant for Eli Lilly, Pfizer, Best Practice Project Management, AstraZeneca, Wyeth, Cyberonics, Novartis, Forest, GlaxoSmithKline, ZARS, Jazz, Lundbeck, Takeda

      2. Major stock ownerships of HealthCare Tech Systems

3. International Journal of Neuropsychopharmacology

   1. Editor-in chief of journal serves on advisory board for Lundbeck 

   2. Official journal of CINP (which maintains partnership + cooperation w worldwide pharmaceutical industry)

4. Journal of Psychopharmacology

   1. First joint journal editor:

      1. Has received honoraria from Jannsenn + Lilly

      2. Acted as consultant to Lundbeck + D&A Pharma

   2. Second joint journal editor:

      1. Has received grants + honoraria from AstraZeneca, Biovail, Bristol Myers Squibb, Eli Lilly, Jannsen, Labopharm, Lundbeck/Takeda, Schering-Plough/Merck, Sepracor, Servier, Wyeth

5. European Neuropsychopharmacology

   1. Journal editor holds stocks in TGD + BiolineRx

      1. Also received support + money from J&J, Pfizer, Lundbeck, BioLineRx, Eli Lilly, Sanofi-Aventis, Roche, GSK, Servier, Envivo, Novartis

Since 2001, though, glyphosate has become the most widely used pesticide in the United States and worldwide. This dramatic surge in glyphosate’s use took place thanks to Monsanto’s introduction of Roundup Ready crops in 1996—transgenic plants modified specifically to survive the direct application of glyphosate. Now not only did Roundup® flaunt a fantastic safety profile, the pesticide also significantly lightened farmers’ workload (eliminating the need for tilling or plowing fields) and weaned them off of more harmful, traditional pesticides.

Pretty swanky, right?

Yet, in 2018, a Californian man named Dewayne Anthony Lee Johnson sued Monsanto; he claimed to have developed terminal non-Hodgkin lymphoma, a form of cancer, due to his chronic exposure to Roundup® as a school groundskeeper. The Superior Court of California for the County of San Francisco unanimously agreed with his claim, compensating him with $78 million dollars. This case set a precedent for thousands of others who felt personally victimized by Monsanto; as of December 2022, Monsanto has settled over 100,000 lawsuits against Roundup®, with 30,000 still pending. Since Monsanto’s merger with Bayer, another giant in the chemical industry, in 2018, Bayer has decided to set aside another $4.5 billion to cover any future Roundup® cancer litigations. 

But as Henry Kater (2020) once commented: “The truth is David that everyone in your family including you will eventually have health problems. Its called life, nothing to do with roundup. People just want to blame an easy target and the thieving lawyers allow them to get away with it.”

And is he wrong?

After all, glyphosate-based products have been not only approved for use but deemed completely safe by the U.S. Environmental Protection Agency (EPA), European Food Safety Authority (EFSA), European Chemicals Agency (ECHA), and leading health authorities in Germany, Australia, Canada, Korea, New Zealand, Japan, and elsewhere. Despite a recent pending revision of glyphosate’s ecological impact, the EPA remains steadfast in their declaration that there is “no risk of concern to human health when glyphosate is used in accordance with its current label”, presumably since “glyphosate is unlikely to be a human carcinogen.”

That’s great news, considering the CDC found detectable levels of glyphosate in over 80% of urine samples collected from adults and children across the United States. 

It seems that Mr. Kater may be entirely correct. After all, over the last few decades we’ve been witnessing a drastic upswing in anxiety and depression, early on-set cancer diagnoses, and deaths due to neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and related dementias. In fact, deaths caused by Alzheimer’s have jumped 71% between 2000 and 2013, and the number of individuals diagnosed with this disease are expected to double every 20 years, from 47 million in 2015 to 76 million in 2030 to 145 million in 2050. It really does seem that we (and everyone in our families) probably will eventually have health problems. That’s just life, though, right?

There are obviously an infinitude of complex, interrelated variables at play in the development of these illnesses, ranging from genetics to the environment. But, just for the sake of it, let’s take a look at some graphs.

Again, there are obviously a lot of different factors at play here. I don’t want to be reductive and let’s not forget that correlation does not equal causation. 

We already know that exposure to pesticides may cause acute and delayed health effects, including but not limited to: irritation of the skin, chronic and long term severe damage to the nervous system, mild cognitive dysfunction, cognitive and psychomotor dysfunction, minor psychiatric morbidity, depression, neurodegenerative diseases, neurodevelopmental effects, and altered reproductive functions. 

But the whole point of glyphosate (and Roundup® specifically), the reason it's used by millions of farmers worldwide, is that it’s way safer than most other pesticides. Apparently, it’s even safer than common household items like vinegar and table salt.

Yet, in 2015, the International Agency for Research on Cancer (IARC), a subgroup of the World Health Organization, ruled that glyphosate should be classified as a 2A substance, meaning it is “probably carcinogenic to humans.” So let’s take a closer look at the effects of this herbicide on our organism. 

Glyphosate has been shown to not only cross the blood-brain barrier but actually accumulate in the brain in a dose-dependent manner. Furthermore, exposure to glyphosate spikes levels of TNFα (an inflammatory cytokine) in the blood. An increase in TNFα was observed particularly in the hippocampus and the cortex, 2 brain regions closely associated with memory and cognition and crucial in the progression of neurodegenerative diseases. By increasing cytotoxicity, glyphosate is implicated in damaging neurons and reducing cell viability, as well as altering gene expression, particularly of oligodendrocytes (cells essential for learning and memory). These factors have led researchers Winstone et al. (2022) to conclude that “glyphosate exposure may lead to an earlier onset or an accelerated progression of AD [Alzheimer’s Disease] pathology”, providing causative support to the correlation between the rise of glyphosate use and deaths related to neurodegenerative disease. 

Research also indicates that low and environmentally relevant concentrations of glyphosate act as endocrine disruptors, inducing the growth of human breast cancer cells, and that glyphosate induces DNA damage and methylation (linked to genetic instability and tumor development). Exposure to glyphosate also enhances levels of oxidative stress in the brain and liver, incurring damage to the substantia nigra, a brain region notably linked to the development of Parkinson’s. Going back to Dewayne Johnson, a study found that high exposure to glyphosate-based herbicides increased the risk of developing non-Hodgkin lymphoma by 41%.

Samsel & Seneff (2015) focused instead on the impact of glyphosate on the dysregulation of Manganese (Mn), one of the 14 essential trace elements. They explain that glyphosate induces Mn deficiency, which has been tied to celiac disease, autism, Alzheimer’s, anxiety, IBS, osteoporosis, and infertility. Okay, so maybe you’re thinking, ‘I can just take a Manganese supplement—easy fix! ’ Apparently not. If an adequate amount of Mn is incorporated into the diet to compensate for this deficiency, then glyphosate (through its disruption of bile acid homeostasis) ironically promotes the toxic accumulation of Mn in the brainstem. Lovely.

Okay, so maybe glyphosate is just a little neurotoxic. But Roundup® and most pesticide formulations are only about 36-48% glyphosate, with the rest being a mixture of water, salts, and adjuvants. Unfortunately, the adjuvants and surfactants added to most formulations are actually more toxic and can even enhance the harmful mechanisms of glyphosate itself. What’s more, glyphosate can actually increase the body’s absorption of other toxic substances (including aluminum and arsenic), promoting neurotoxicity and damage to the pineal gland, which supports the neuroendocrine and immune systems. 

So far, glyphosate actually sounds pretty unsafe. Thankfully, the National Pesticide Information Center (NPIC) asserts that glyphosate quickly passes through the body without breaking down, and so does not pose a significant risk. Yet, animal and human studies show that glyphosate does bioaccumulate, with residues found in urine but also in bodily tissues such as the kidney, lung, liver, spleen, muscles, and intestines. This indicates that it indeed does not just pass through without any impact on the organism. As we’ve already noted that this bioaccumulation is also dose-dependent, it checks out that in areas where people were permanently exposed to pesticides, the rates of neurological diseases were unusually high.

If all this is true, though, why are all these oh-so-very-trustworthy institutions claiming otherwise?

It’s pretty obvious why Monsanto (now Bayer) would want to cover up all the risks and disease associated with glyphosate, considering the billions they are making by selling this herbicide and controlling a quasi-monopoly on the only GMO seeds (patented, of course) that could withstand said herbicide. But what about the EPA, European Food Safety Authority (EFSA), and all those other leading authorities which should have the peoples’ best interests at heart?

In the 1970s, the company that Monsanto employed to test the safety of Roundup® and other pesticides, Industrial Bio-Test Laboratories, was involved in a scandal; they were doctoring toxicology reports. In 1991, it happened again. Craven Laboratories, a company which Monsanto used for their many studies on glyphosate, was caught committing fraud and falsifying test results on the effects of pesticides. Monsanto claims they have repeatedly and unknowingly been victims of fraud. In the 1990s, the EPA ruled Roundup® as safe. 

Following the 2015 IARC ruling that glyphosate actually probably did cause cancer, the EPA decided to reconsider their initial safety approval. Then CropLife America stepped in, a lobby group funded by various agrochemical companies (including Monsanto, now Bayer). They intervened to remove dissenting voices from the EPA’s review panel; the EPA inspector general ended up having to investigate the agency for collusion with Monsanto. Their decision maintained that Roundup® was safe for use.

A majority of the studies which Monsanto reports as backing up their claims of glyphosate’s safety have been extensively criticized for their flawed methodologies and their authors’ undeclared conflicts of interest. These studies disregarded potential toxic effects by only carrying out short-term testing (under 3 months), disregarding exposures that are higher than estimates of residues found in food, examining the effects of pure glyphosate without the interactions of adjuvants in pesticide formulations, and often testing on too few subjects to achieve statistical significance. 

Apparently, regulatory processes completely diverged from sound scientific evidence. In 2019, the European Food Safety Authority renewed the authorization for the safe consumption of NK603, a genetically modified corn resistant to Roundup®, and other GMOs, across the EU. They specifically cited a study by Steinberg et al. as the basis for their decision, in which he concluded that no other long-term studies are needed due to the lack of adverse effects in rats from the consumption of NK603 or other GM products heavily exposed to glyphosate. Pablo Steinberg declared no conflicts of interests in this paper. 

It turns out, though, that Steinberg is actually an expert of the International Life Science Institute (ILSI), a food industry lobby group which has been chaired by Monsanto and has actively worked to weaken testing and regulations on GMO products. He has also been an adviser at the Danone Institute since 2005, whose molecular biology laboratories produce genetically modified microorganisms for yogurts and other products, and so whose interests lie with the unregulated legalization of GMOs. 

Today, there is still no label on Roundup® warning of any serious risks. Their only listed potential hazard to humans and domestic animals is that it may cause “moderate eye irritation.”

These are just a few of a multitude of examples. The ties between policy regulators, lobbyists, agro-chemical companies, and scientific reviewers run deep. Read the Monsanto Papers, if you’d like. Hell, take a look at what Monsanto did with Agent Orange, or PCB, or DDT.

For now, my advice is to take a deep breath, try your best, and maybe do a sudoku or a crossword every now and then, if you feel like it.

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