DEPRESSION, CHEMICAL IMBALANCES CONVENIENT AND OTHERWISE

The Defence agrees with Peter C Gøtzsche, of the Institute for Scientific Freedom, who writes:

"Psychotropic drugs were developed based on rat experiments and selected if they disrupt the rat’s normally functioning brain. The pills don’t cure us, they simply change us by causing a wide array of effects in people, like all brain active substances do, including street drugs. And they are not in any way targeted. There is nothing particularly selective about selective serotonin reuptake inhibitors (SSRIs). This term was invented by SmithKline Beecham to give paroxetine an advantage over other drugs, but it was adopted by all companies. There are serotonin receptors throughout the body, and the drugs have many other effects than increasing serotonin, e.g. they can affect dopamine and noradrenaline transmission and can have anticholinergic effects."

And lo and behold, the powers-that-be have taken control of the language again:

"Psychiatric drugs work...either by suppressing emotional reactions so that people get numbed and pay less attention to significant disruptions in their lives or by stimulating them.

"I shall therefore avoid the conventional nomenclature for drugs. It is misleading to call pills used for depression antidepressants and pills used for psychosis antipsychotics.

"These drugs are not “anti” some disease. The 'anti' also gives an association to antibiotics, which save lives, but psychiatric drugs do not save lives; they take many lives. Furthermore, unlike antibiotics, they do not have disease specific properties.

"I therefore talk about depression pills and psychosis pills, which do not give any false promises. "
https://www.scientificfreedom.dk/wp-content/uploads/2023/05/Gotzsche-Critical-Psychiatry-Textbook.pdf [3021]

The dispensation of depression pills has increased dramatically since the introduction of SSRIs, on the back of a surge of advertising based on the notion of chemical imbalance. Since the 1990s, the number of depressed people with these chemical imbalances has supposedly gone through the roof.

The idea that depression is a disease has proved very popular. It's also politically expedient, as approximately half of the UKs 6m unemployed people of the 1980s stopped being unemployed and were reclassified as ill instead. Their illness was defined as depression, and how was their depression defined? By being prescribed depression pills. Simply being on Prozac, Seroxat or some other SSRI defines you as a victim of "depression".

Yet it turned out there was no evidence of such a chemical imbalance.

Nowadays, the mental health industry has taken to claiming they never said people who need pills have a chemical imbalance, per the serotonin hypothesis. Have you heard this? Did you assume it was a fact because it came from "on high"? Have you heard any opposing theories?

Ten times psychiatry promoted the chemical imbalance to the public:
https://x.com/dsowens17/status/1881812105378033897 [3950]

According to a widely reported review by Moncrieff et al (2022):

"The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT1A receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT1A receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration."
https://www.nature.com/articles/s41380-022-01661-0 [2673]

Following this, the serotonin hypothesis claimed to have made a comeback, but the extent of this amounted to one person.
https://www.sciencedirect.com/science/article/abs/pii/S0006322322017048 [4080]

madintheuk.com dissects the conclusions of Erritzoe et al:

"The researchers had three hypotheses:

"People with depression would have lower serotonin at baseline than healthy controls.
People with major depressive disorder would have smaller change in serotonin levels after being dosed with an amphetamine.
Both baseline serotonin and change in serotonin levels after amphetamine dosing would be related to the severity of depression.

"Hypothesis 1
This first hypothesis is the one most relevant to the bottom-line question: do people with depression have lower serotonin levels than people without depression?

"To test this, the researchers conducted a PET scan on the brains of people with depression and healthy controls. They determined that both the depression group and the control groups had similar serotonin levels, and both groups were consistent with 'healthy' levels, which is what previous studies had found. The authors wrote:

"'The regional [serotonin] distribution for both groups was consistent with previous reports for healthy individuals with high binding across cortical areas.'
The researchers then ran a bunch of additional statistical tests on this same data (tests to include other factors, such as age, and then breaking the data down into specific regions and re-running the tests—a controversial statistical process known as p-hacking because it increases the likelihood of finding a statistically significant result by chance). Even after all this, the researchers found that the depression group and the healthy control group continued to have serotonin levels which were no different, except for one slight average difference in one brain region (the temporal cortex). Even in this area, the data shows an almost complete overlap between the two groups.

"Conclusion number one: There was no difference in serotonin levels between those with depression and those without. Their first hypothesis was demonstrated to be false.

"Hypothesis 2
The second element of the study was a test to see whether a dose of amphetamine, which is known to trigger the release of serotonin, would produce less of a response in depressed patients than in the controls.

"The researchers dosed all participants with 0.5 mg/kg of d-amphetamine, and measured how much, on average, each group’s levels of serotonin changed. This was done by measuring serotonin binding potential in the frontal cortex, to estimate serotonin release capacity.

"They found a statistically significant effect: on average, the healthy control group’s serotonin levels changed more than the serotonin levels of those with a diagnosis of major depression after being dosed with an amphetamine. This was the result that prompted the researchers to write that their study 'provides clear evidence for dysfunctional serotonergic neurotransmission in depression by demonstrating a reduced 5-HT release capacity in patients undergoing a major depressive episode.'

"There was in fact a wide variation in serotonin release in both the depressed patients and the controls. And if the serotonin response for each of the individuals is plotted out on a graph, as was done in the paper, it immediately becomes apparent that the 'statistically significant' effect arises from two individuals: one in the depressed group without Parkinson’s, and one in the depressed group with Parkinson’s.

"In the chart below (from the study publication, red bars added), the depression group scores are on the left, while the control group scores are on the right. The black boxes in the depression group are for those without Parkinson’s; the white boxes for those with Parkinson’s.

"As can be seen, there are two outliers (one black box and one white box), and except for those two, every depressed person’s score, detailing how much their serotonin levels changed, overlaps with a healthy person’s score.



"Since Parkinson’s disease is an obvious confounder, there is only one outlier in the depressed group, out of 11.

"The researchers, as they reported their results, ignored this fact. Instead, they calculated the mean change in serotonin release scores for the 20 healthy controls and 16 depressed patients, and concluded that there was a slight 'statistically significant' difference (p value = .041). Without the one outlier, this statistically significant finding would have vanished.

"Such is the data related to hypothesis number two. And here is the relevant conclusion to draw: In 10 of 11 depressed patients without Parkinson’s, their serotonin release scores overlapped with those of the healthy controls, and thus were in a normal range. Four out of five in the Parkinson’s group were within this same normal range.

"Hypothesis 3
To test their third hypothesis, the researchers ran an analysis to test whether serotonin levels were related to the severity of depression, measured by the Hamilton Depression Rating Scale (HAM-D), in both those with depression and those with depression and Parkinson’s disease). They found that severity of depression across both groups was not related at all to levels of serotonin.

"Then they ran a similar analysis to test whether the change in serotonin levels in response to the amphetamine dosing was related to the severity of depression. They found that severity of depression was not related to the change in levels of serotonin either."

"'There was no significant correlation between HAM-D depression scores and baseline [serotonin],' the researchers wrote. They added, 'There were no statistically significant associations between HAM-D depression scores and [change in serotonin].'

"Thus, their third hypothesis—that serotonin levels or change in serotonin would be related to depression severity—was also proven false.

"They write, 'We found no relationship between the severity of depression (as assessed by a HAM-D scale) and the magnitude of induced 5-HT release. At this stage we have no explanation for the lack of such relationship.'"
https://www.madintheuk.com/2022/11/serotonin-depression-myth/?utm_source=ReviveOldPost&utm_medium=social&utm_campaign=ReviveOldPost [4083]

This represents a split in thinking between the disease-based model of depression and a rather different philosophy of life which might be described as psychiatry-skeptic. Important criticisms of this psychiatric world-view took shape with Thomas Szasz and his 1960 book "The Myth Of Mental Illness" and the Goldenhan experiment - the latter described as the research from which psychiatry never fully recovered.

Around the same time the use of psychedelics became popular, and then illegal. People took them to alter their mood, and it wasn't intended to make them depressed.

Despite this, the connection was not made, in the public imagination, between LSD and depression. Serotonergic psychedelics were marched off into a fantastical "narcotics" category.

Instead the disease-based, and therefore drug-based, model of mental illnesses - for the major categories of which, schizophrenia, psychosis, depression, no consistent evidence of any metabolic or biochemical marker has ever been shown - persisted and remained dominant into the era of SSRIs and continues to be supported by, of course, the pharmaceutical manufacturers right up to the present. There was every reason to hope, of course, that finding chemical pathways to alter would lead to cure. But ever since the era of haloperidol and benzodiazepam, the truth was that "drugs that diminish people's responsiveness to their environment in general can cause people who are in a psychotic state to lose interest in their delusional preoccupations" (Deniker, 1960, in The past and future of psychiatry and its drugs - Moncrieff, J. (2020) BPS Psychotherapy Section Review, No. 65, Winter 2020, 77-83). Psychiatry was having trouble maintaining its respectability and professional self-respect, and it was having trouble keeping up with other, more successful branches of medicine, which did indeed find plausible and effective mechanisms of drug action in scientifically demonstrable metabolic dysfunctions (Moncrieff, ibid.)
https://discovery.ucl.ac.uk/id/eprint/10137711/3/Moncrieff_The%20past%20and%20future%20of%20psychiatry%20and%20its%20drugs.pdf [1368]

"She argues that, given how little we know about the biology of mental illness, there are no targeted, disease-specific drugs; antidepressants are closer in nature to alcohol. They do not rectify an underlying brain malfunction, but rather change how you think or feel. 'Those changes are superimposed onto whatever someone is thinking and feeling at the time. We even have an expression for this with alcohol: we talk about "drowning your sorrows"' Moncrieff said, when we met in her spartan shared office at King’s College. 'If you recognise that’s what the drugs are doing, then it immediately becomes obvious they are not going to be a long-term solution and they might be harmful.'"

and

"'The pharmaceutical industry and the medical profession have coached the population for decades that there is a medical solution to various crises in life – and I think we need to uncage people because that’s simply not true,' Moncrieff said. 'We need to find more non-medical ways of supporting people through crises.' Rather than viewing depression as an illness, she wants people to see it as a 'mood state': 'Mood states are related to emotions, and moods and emotions are the way that human beings, which are complex, intelligent organisms, respond to events in their environment. Depression is by definition a reaction to a state that someone doesn’t want to be in, to something that’s gone wrong in someone’s life, or a stressful situation.'"
https://web.archive.org/web/20230422110709/https://www.newstatesman.com/the-weekend-interview/2023/04/joanna-moncrieff-im-not-convinced-antidepressants-have-any-use [2455]

"Moncrieff is clear there is no shame in suffering from mental illness. But she believes the best approach to tackling it is through talking therapies, exercise and a willingness to make appropriate changes in one’s life. 'But a very neuro-reductionist view of mental health problems and life in general is particularly gaining traction among young people. It trumps everything else. Why have marital therapy if your brain is the problem?'"
https://archive.ph/2025.01.12-003252/https://www.thetimes.com/uk/society/article/do-antidepressants-work-british-professor-depression-medication-ld28kgvj5#selection-3603.0-3603.437 [3898]

Various critics with ties to pharmaceutical companies lined up to criticise her debunking of the serotonin hypothesis.



"Responding to the criticism, Prof Moncrieff said the aim of the study was not to argue that antidepressants don’t work but to question whether the pills should be prescribed in the first place.

"'People are told the reason they feel depressed is that there is something wrong with the chemistry in their brain and antidepressants could put it right. But if there’s no evidence there’s anything wrong with the brain’s chemistry, then that doesn’t sound like a sensible solution. This profession has misled people for so long about the need for antidepressants and now doctors don’t want to admit they got it wrong.’"
https://www.dailymail.co.uk/health/article-11042143/Joanne-Moncrieff-University-College-London-disproves-link-low-serotonin-depression.html [4194]

The problem was elucidated in 2016 by Robin M Murray, Professor of Psychiatric Research at the Institute of Psychiatry, King’s College London (KCL) and a Fellow of the Royal Society, who discusses his journey in "Mistakes I Have Made in My Research Career", under such headings as "The Unrewarding Search for the Causes of the Brain Changes Underlying Schizophrenia", "The Runaway Rise of the Neurodevelopmental Hypothesis", "I Ignored Social Factors for 20 Years", and "Dopamine Supersensitivity; Another Old Idea I Dismissed for too Long",

"If I had the chance to have a second career, I would try harder not to follow of the fashion of the herd. The mistakes I have made, at least those into which I have insight, have usually resulted from adhering excessively to the prevailing orthodoxy. Fortunately, I have often been rescued from this by the arrival of a brilliant young research fellow who has proposed a novel approach; I have usually resisted her/his idea initially before eventually come round to its merits. Sadly, this reliance on the corrective influences of younger colleagues has its limits. For example, David Marsden was already a famous professor when I met him; he must have been too senior for me to take seriously his insightful comments on the effects of antipsychotics on the brain! Consequently, I sailed on, believing the same false dogma for several decades.

"It is curious that as I grow older, I find myself increasingly asked to give my predictions for future directions in psychiatry. This is likely to be as productive as asking Mick Jagger to comment on likely new trends in Hip-Hop. I shall therefore confine myself to saying that if I was starting afresh, I would throw myself into examining gene × environment interactions and epigenetics, as ways of elucidating the mechanistic pathways through which the environment contributes to the onset of psychosis. However, one has to be very good at statistics to succeed in this area. So if I wasn’t clever enough, I would instead go into neurochemical imaging; it is true that the maths is still complicated but at least the pictures of the brain are pretty.

"I expect to see the end of the concept of schizophrenia soon. Already the evidence that it is a discrete entity rather than just the severe end of psychosis has been fatally undermined. Furthermore, the syndrome is already beginning to breakdown, for example, into those cases caused by copy number variations, drug abuse, social adversity, etc. Presumably this process will accelerate, and the term schizophrenia will be confined to history, like 'dropsy.'"
https://academic.oup.com/schizophreniabulletin/article/43/2/253/2730504?login=false [4327]

Let's take a moment to look at one widely-touted cure-all, benzodiazepines.

"'It's more difficult to withdraw people from benzodiazepines than it is from heroin – it just seems that the dependence is so ingrained and the withdrawal symptoms you get are so intolerable that people have a great deal of problem coming off. The other aspect is that with heroin usually the withdrawal is over within a week or so. With benzodiazepines a proportion of patients go on to long-term withdrawal and they have very unpleasant symptoms for month after month and I get letters from people saying that it can go on for 2 years or more. Some of the tranquilliser groups can document people who still have symptoms 10 years after stopping.' (Source: Professor Malcolm Lader, BBC Radio 4, Face the Facts, broadcast on March 16, 1999)."

“'All the benzodiazepines are non-selective and act on all types of GABA/benzodiazepine receptors. Valium acts on exactly the same receptors as Klonopin etc. The main reason that benzodiazepines have somewhat different structures is not so much that they act on different receptors (they don't) but so that the drug companies can call them different drugs.'"
http://www.benzo-case-japan.com/addiction-english.php [1766]

Maust et al (2023) at the University of Michigan at Ann Arbor reported in JAMA that ceasing benzodiazepine use was associated with an increased risk of dying. Among people who weren't simultaneously taking an opioid, the adjusted cumulative incidence of death over 1 year was 5.5% for those who stopped benzodiazepine treatment compared with 3.5% for those who didn't.

Discontinuation was defined as having no benzodiazepine prescription for 31 consecutive days during a 6-month period after baseline. Patients were followed for about 1 year after baseline benzodiazepine prescriptions.

The researchers also found the risks of secondary outcomes including nonfatal overdose, suicidal ideation, and emergency department use were higher among those who stopped benzodiazepines, whether or not they also used opioids (relative risk 1.2, 1.4, and 1.2, respectively).
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2813161?utm_campaign=articlePDF&utm_medium=articlePDFlink&utm_source=articlePDF&utm_content=jamanetworkopen.2023.48557 [4278]

Prisoners force-fed Librium in 1961 became addicted after two months, says Professor Malcolm Lader.

Says Professor Heather Ashton:

"We had people who'd been told they had multiple sclerosis, and when we got them of the benzos their symptoms disappeared."

"It was very difficult to get compensation because nobody realized it was a real illness."

Both Lader and Ashton put research proposals to the Medical Research Council and the Wellcome Trust, with a sample of 300 long-studied participants, MRI, EEG and magnetoencephalography, but they never got the money for it.

In 2014, drug poisonings with benzodiazepines reached 15385 in England, more than all illegal drugs combined. Heroin: 2450, cocaine: 2306, and by some classification somehow, cannabis 739. Deaths (England and Wales) were heroin: 952, methadone 394, benzodiazepines 372, and diazepam/valium 258.
https://www.youtube.com/watch?v=MVoFlGR7Lhs [1767]

In Scotland

"In 93% of all drug misuse deaths, more than one drug was found to be present in the body.

"Of all drug misuse deaths in 2021, 84% involved opiates or opioids (such as heroin, morphine and methadone). 69% involved benzodiazepines (such as diazepam and etizolam).

"In recent years there has been a large increase in the number of drug misuse deaths involving benzodiazepines. In 2015 there were 191 of these deaths and in 2021 there were 918; almost five times as many. This increase has mostly been driven by street benzodiazepines rather than those which are prescribed.

"In 2020 (the most recent year available for the rest of the UK) Scotland’s drug misuse rate was 3.7 times that for the UK as a whole, and higher than that of any European country."

and

"The proportion of drug misuse deaths where gabapentin and/or pregabalin were implicated has increased from <1% in 2008 to 36% in 2021. These are drugs used to treat epilepsy and nerve pain. The proportion where cocaine was implicated has also increased from 6% in 2008 to 30% in 2021. The number of drug misuse deaths where alcohol was implicated (in addition to a controlled drug) has remained fairly similar, although the proportion has fallen from 29% in 2008 to 12% in 2021."

The report, "Drug-related deaths in Scotland in 2021" does not mention cannabis, marijuana, psychedelics, LSD, psilocybin or mushrooms.
https://web.archive.org/web/20240323190516/https://www.nrscotland.gov.uk/files/statistics/drug-related-deaths/21/drug-related-deaths-21-report.pdf [2607]

Benzos have even spawned their own disease syndrome:

"Benzodiazepine-induced neurological dysfunction (BIND) has been proposed as a term to describe symptoms and associated adverse life consequences that may emerge during benzodiazepine use, tapering, and continue after benzodiazepine discontinuation."

Ritvo et al's Table 1 of their "Long-term consequences of benzodiazepine-induced neurological dysfunction: A survey" (2023) shows the symptoms reported, which occurred across all respondents, regardless of taper status and cause for original prescription of the benzodiazepine.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0285584 [2821]

Eventually the late Professor Ashton, realizing that the patients knew better what was going on than their doctors, published an online manual on how to withdraw from benzodiazepines. The manual is available in twelve languages and Slovene is not one of them.
https://benzo.org.uk/manual/contents.htm [1768]

Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.

Despite having been withdrawn in other countries, clozapine is still in the Slovenian pharmacopoeia.
http://www.cbz.si/cbz/bazazdr2.nsf/o/26D48494772FCCCCC12586880005AB9A?opendocument [4349]

Szkultecka-Debek et al have some information on drug choices in schizophrenia in CEE countries:



Clozapine was the most reported medication for refractory patients. No clozapine deaths had been recorded in Slovenia as of 2016.
https://www.psychiatria-danubina.com/UserDocsImages/pdf/dnb_vol28_no3/dnb_vol28_no3_234.pdf [4351]

Describing clozapine as an "outstanding drug", a newer study, "An expert review of clozapine in Eastern European countries: Use, regulations and pharmacovigilance", a newer study, by Sagud et al (2023) found wide disparities:

"Clozapine prescription among antipsychotics in 2021 varied six-fold across countries, from 2.8 % in the Czech Republic to 15.8 % in Montenegro. The utilization of antipsychotics in both 2016 and 2021 was highest in Croatia, and lowest in Serbia in 2016, and Montenegro in 2021, which had half the defined daily dose (DDD)/1000/day compared to the Croatian data. From 2016 to 2021, the prevalence of antipsychotic use increased in almost all countries; the proportion of clozapine use mainly remained unchanged. Differences were detected in hematological monitoring requirements and clozapine approved indications. Only a few national schizophrenia guidelines mention clozapine-induced myocarditis or individual titration schemes. The VigiBase search indicated major underreporting regarding clozapine and its fatal outcomes. By comparison, the United Kingdom had less than half the population of these Eastern European countries but reported to VigiBase more clozapine ADRs by 89-fold and clozapine fatal outcomes by almost 300-fold."
https://www.sciencedirect.com/science/article/abs/pii/S0920996423003122?via%3Dihub [4352]

Then, according to a January 2024 report in the Times, it was reported "this outstanding drug" has been

"linked to 7,000 deaths since it was approved.

"The Times found that the drug is linked to almost eight times as many reported deaths as any other high-risk medicine.

and

"The Times’ analysis shows an average of more than 400 clozapine-linked deaths have been reported to the Medicines and Healthcare products Regulatory Agency each year for the past decade.

"The medicines watchdog’s yellow card reporting scheme also gets around 2,400 notifications a year of 'suspected serious reactions' to the drug."

and the side-effects are

"Blood disorders: signs of problems include flu-like symptoms such as sore throat and temperature.

"Seizures.

"Heart disease: signs of a problem include chest pain, palpitations, or a rapid pulse.

"Diabetes: a third of people taking clozapine may develop diabetes after five years of treatment, the majority of these cases happen within the first six months.

"Bowel obstruction: clozapine can cause slowing of bowel movement resulting in constipation, blockage and a 'paralytic ileus', which may be fatal.

"Skin reactions: people taking antipsychotics may be more sensitive to sunlight. You should consider how to protect people’s skin from direct sunlight."
https://www.standard.co.uk/news/health/what-clozapine-prescription-drug-dangerous-side-effects-b1131180.html [4348]



The month prior saw the publication of "Revealing the reporting disparity: VigiBase highlights underreporting of clozapine in other Western European countries compared to the UK" by De las Cuevas et al (2023) wherein:

"VigiBase reports from clozapine's introduction to December 31, 2022, were studied for ADRs and the top 10 causes of fatal outcomes. The UK was compared with 11 other top reporting Western countries (Germany, Denmark, France, Finland, Ireland, Italy, Netherlands, Norway, Spain, Sweden and Switzerland). Nine countries (except Ireland and Switzerland) were compared after controlling for population and clozapine prescriptions.

"Results
The UK accounted for 29 % of worldwide clozapine-related fatal outcomes, Germany 2 % and <1 % in each of the other countries. The nonspecific label “death” was the top cause in the world (46 %) and in the UK (33 %). “Pneumonia” was second in the world (8 %), the UK (12 %), Ireland (8 %) and Finland (14 %). Assuming that our corrections for population and clozapine use are correct, other countries underreported only 1–10 % of the UK clozapine fatal outcome number.

"Conclusions
Different Western European countries consistently underreport to VigiBase compared to the UK, but have different reporting/publishing styles for clozapine-related ADRs/fatal outcomes. Three Scandinavian registries suggest lives are saved as clozapine use increases, but this cannot be studied in pharmacovigilance databases."
https://www.sciencedirect.com/science/article/pii/S092099642300422X?via%3Dihub [4350]

But it seems this bad news about clozapine wasn't really news at all, according to psychiatric patient Zekria Ibrahimi, in response to the BMJ article "Coroners warn health secretary of clozapine deaths" (2019):

"Clozapine was first produced in 1958. It was marketed from 1970. It began killing patients. After multiple deaths in Finland, it was banned there, and then across Europe. The major problem was 'agranulocytosis'. The BMJ feature mentions agranulocytosis among other side effects, without emphasizing agranulocytosis as the prime key danger.

"Research on clozapine stopped in 1976."

But

"Clozapine reemerged in 1988. Unlike the 'typical' anti-psychotics, it does not appear to cause Tardive Dyskinesia, and it does not seem to raise Prolactin.

"A long-term risk of Clozapine - and other anti-psychotics - is the Metabolic Syndrome - from weight gain to diabetes to cardiovascular damage to premature death.

"The Maudsley Guidelines carry a huge section (pages 62 to 77) on Clozapine side effects - about which a portion of psychiatric nurses seem not to be aware."
https://www.bmj.com/content/363/bmj.k5421/rr-5 [4352]

Clearly, taking a pill cannot objectively make the world less annoying, stop your wife leaving you, increase your income, or make the weather better. If the harvest fails, or your home is destroyed in an earthquake, depression is a problem, but what are the options, since the depressing stimuli cannot simply be magicked away? Isn't depression, after all, a rather rational and realistic response to overwhelming situations?

Many would argue with the statement that no consistent biological markers have been found. For instance tumor necrosis factor alpha is implicated, according to Simen et al at the Department of Psychiatry, Division of Molecular Psychiatry, Yale University, New Haven, Connecticut, who:

"...show that deletion of either TNFR1 or TNFR2 leads to an antidepressant-like response in the forced swim test and that mice lacking TNFR2 demonstrate a hedonic response in a sucrose drinking test compared with wildtype littermates. In addition, deletion of TNFR1 leads to decreased fear conditioning. There were no differences in behavior in anxiety tests for either null mutant."

They conclude:

"These results are consistent with the hypothesis that TNFα can induce depression-like symptoms even in the absence of malaise and demonstrate that both receptor subtypes can be involved in this response."
https://www.sciencedirect.com/science/article/abs/pii/S000632230501366 [1569]

While at the School of Life Sciences at the University of Minho in Portugal IL-10 was found to improve the mood of female mice.
https://repositorium.sdum.uminho.pt/bitstream/1822/8631/1/Mesquita%20JPR.pdf [1568]

The depressed person could be told to pull his or her socks up. They can be hosed down with cold water, given ECT, or have psychosurgery. These became indistinguishable from abuse. Or if they are rich enough and want their emotions to be taken seriously, patients might receive a talking cure or spend time in a sanitorium. None of this, for either reputational or practical or economic reasons, could really compete with the drug-centred model and so psychiatry became increasingly confined to the drug-centred model.

For there to be a psychopharmacological treatment there had to be biochemical mechanisms. But these were slow in coming, and not long after SSRIs arrived, the chemical imbalance theory of their action has become increasingly dubious.

Says Gotzsche:

"In 2003, the huge deception became too much for six psychiatric survivors. They were so angry about the stories they had been told by their psychiatrists that they sent a letter to the American Psychiatric Association and other organisations stating that they would begin a hunger strike unless scientifically valid evidence was provided that the stories the public had been told about mental disorders were true. They asked for evidence that major mental illnesses are biologically-based brain diseases and that any psychiatric drug can correct a chemical imbalance. They also required the organisations to publicly admit if they were unable to provide such evidence.

"The medical director of the American Psychiatric Association tried to get off the hook by saying that, 'The answers to your questions are widely available in the scientific literature.' In his book, The art of always being right, philosopher Arthur Schopenhauer calls this deplorable trick 'Postulate what has to be proven.'

"The hunger strike ended when people started getting health problems, but the Association bluffed. It stated in a press release that it would not 'be distracted by those who would deny that serious mental disorders are real medical conditions that can be diagnosed accurately and treated effectively.'

"Schopenhauer says about this trick: 'If you are being worsted, you can make a diversion - that is, you can suddenly begin to talk of something else, as though it had a bearing on the matter in dispute and afforded an argument against your opponent … it is a piece of impudence if it has nothing to do with the case, and is only brought in by way of attacking your opponent.'

"This is one of many examples that psychiatry is more of a religion than a science. Religious leaders couldn’t have invented a better bluff, if people had required proof that God exists: 'We priests and cardinals will not be distracted by those who would deny that God exists and knows about people’s problems and can treat them effectively.'" [3021]

As far as CaPs are concerned, the propaganda has been the opposite of that applied to psychiatric drugs. They do not induce physical dependence, but have been legally conflated with drugs which do.

On the other hand, plausible mechanisms of action in depression, addiction, OCD and PTSD have been demonstrated. Cannabis can cheer you up and also help one relax. Mushrooms can refresh your interface with the world. Taking these drugs can be revelatory and fun.

Medical psychopharmacology does not recognise fun as a cure for depression. If you want fun, the law says, you should drink alcohol. Alcohol is an addiction-forming depressant. Even its most ardent supporters would not claim they drink because of an alcohol deficiency, or because it rectifies a chemical imbalance.

At the same time, the existence of an endocannabinoid deficiency is taboo. But there are more cannabinoid receptors in the brain than there are for all of the neurotransmitters put together. However there is no time to teach the ECS in medical schools, their curricula are too full already. https://www.leafly.com/news/science-tech/cannabis-endocannabinoid-system-in-medical-school. [505]

Stefan Broselid, Ph.D., Editor-In-Chief of the Aurea Care Science Medical Journal, compared the presence of ECS-related topics in the popular textbook “Guyton and Hall Textbook of Medical Physiology”:



"Undoubtedly, the most striking feature of the table is the complete absence of any mention of the ECS and its components. The ECS is a biological system composed of endogenous lipid-based neurotransmitters that bind to cannabinoid receptors in the central and peripheral nervous system. The ECS is involved in regulating many physiological and cognitive processes, such as pain, mood, memory, appetite, inflammation, and immune responses. It also happens to constitute the main pharmacological targets of the active compounds in cannabis, such as THC and CBD, but this has virtually nothing to do with its role and importance in human physiology."

And

"In a national survey conducted in 2017, medical school curriculum deans from 101 accredited American medical schools in the US reported that close to 90% of their residents and fellows do not feel at all prepared to prescribe medical cannabis and 85% report that they have received no education at all about the ECS or medical cannabis (Evanoff et al. 2017)."

The author suggests the name itself is responsible for the bogeymanisation:

"If it is the unfortunate nomenclature-based connotation to a misunderstood medical plant that is to blame, why not change the name of the endocannabinoid system to better reflect its main functional role rather than its etymological history? After all, if endocannabinoids had been discovered prior to phytocannabinoids, the ECS quite likely would have been known for its main function, perhaps as the homeostatic system? We shouldn’t have to rename it, but I can’t stop thinking about what would happen."
https://aureamedicalsciencejournal.se/the-missing-chapter-how-human-physiology-textbooks-fail-to-include-the-endocannabinoid-system/ [4861]
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC5648595&blobtype=pdf [4862]

According to Schroder et al at McLean Hospital and Harvard Medical School, one problem with a belief in a chemical imbalance requiring antidepressants is that believing in a chemical imbalance is depressing:

"We found that although psychosocial explanations of depression were most popular, biogenetic beliefs, particularly the belief that depression is caused by a chemical imbalance, were prevalent in this sample. Further, the chemical imbalance belief related to poorer treatment expectations. This relationship was moderated by symptoms of depression, with more depressed individuals showing a stronger relationship between chemical imbalance beliefs and lower treatment expectations. Finally, the chemical imbalance belief predicted more depressive symptoms after the treatment program ended for a 2-week measure of depression (but not for a 24-hour measure of depression), controlling for psychiatric symptoms at admission, inpatient hospitalizations, and treatment expectations."
https://www.sciencedirect.com/science/article/abs/pii/S0165032720325064

 [4421]

MDMA is very obviously a useful treatment for PTSD. Serious suicidal ideation (a score of 4 or 5 on the C-SSRS) was minimal during the study and occurred almost entirely in the placebo arm.
https://www.nature.com/articles/s41591-021-01336-3 [506]
https://cssrs.columbia.edu/wp-content/uploads/C-SSRS_Pediatric-SLC_11.14.16.pdf [3022]

In all of this, it is of tantamount importance to psychiatry and the law is that fun and health are not to be connected. Apparently, the important message to keep front and centre is the one about depression, not the one about happiness.

The safety of illegal drugs used in happiness, or amelioration of unwanted states, is not determined by their legality. They do not become safer when they are decriminalised, or less effective when outlawed. When, in 1992, the Vatican decided to admit Galileo was right, the solar system did not abandon a geocentric arrangement and reposition itself into a new legal format. In the event of future legislative changes, a return to geocentricism can be guaranteed

Cannabis has been a medicine for thousands of years https://link.springer.com/article/10.1007/s12231-016-9351-1 [507] and the scourge of humanity for a hundred. Psychedelics have played a part in the development of civilisation, Richard Nixon and the American war effort somewhat less so.

Suicodologists in Quebec found that the devil in the weed was in the detail:

In longitudinal cross-lagged analyses, weekly cannabis use at age 15 was associated with greater odds (OR=2.19, 95% CI=1.04-4.58) of suicidal ideation two years later. However, other substance use (alcohol, tobacco, other drugs) fully explained this association.
https://www.sciencedirect.com/science/article/abs/pii/S0165032720309344?via%3Dihub [508]

Meanwhile, in "Matrix Metalloproteinase-9 as an Important Contributor to the Pathophysiology of Depression" Hongmin Li et al at The Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China

"Among MMP members, the most important may be MMP−9. It is implicated in the remodeling and stabilization of dendritic spines, pre and post-synaptic receptor dynamics, consolidation of long term potentiation, synaptic pruning and myelin formation. MMP-9 is also involved in the sprouting, pathfinding and regeneration of axons."

As for depression:

"The role of MMP-9 in the pathology of depression. MMP-9 is elevated in endothelial cells and neutrophils during inflammation. (A) Excessive MMP-9 is thought to be involved in demyelination associated with depression. (B) MMP-9 disrupts BBB through tight junction proteins or basement membrane degradation, which increases neuroinflammation and may be linked to depression or bipolar disorders with cognitive decline. (C) Activated MMP-9 localizes in part to synapses and is involved in synaptic pruning essential for longterm potentiation (LTP), and attenuation of cortical synaptic LTP-like plasticity; collectively, these are thought to contribute to depression. (D) MMP-9 remodels perineuronal nets that participate in synaptic stabilization and limit synaptic plasticity. Depression may occur when perineuronal net signaling is aberrant."

"Domenici et al. reported that MMP-9 in serum was significantly higher in patients with major depressive disorders (n = 245) vs. controls. Rybakowski et al. performed a study on 54 in-patients with bipolar mood disorder and 29 control subjects. An increase of serum MMP-9 at the early stages of bipolar illness is found to accompany only the depressive episodes and not manic ones."

Among the human highlights

"Alaiyed et al. reported that MMP-9 levels were elevated in prefrontal cortex of antidepressant-treated patients with major depressive disorders."

and

"MMP-9 inhibitors possess potential therapeutic effects for depression."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8971905 [1640]

"As bipolar disorder and marijuana use are individually associated with cognitive impairment, it also remains unclear whether there is an additive effect on cognition when bipolar patients use marijuana. The current study aimed to determine the impact of marijuana on mood in bipolar patients and to examine whether marijuana confers an additional negative impact on cognitive function. Twelve patients with bipolar disorder who smoke marijuana (MJBP), 18 bipolar patients who do not smoke (BP), 23 marijuana smokers without other Axis 1 pathology (MJ), and 21 healthy controls (HC) completed a neuropsychological battery. Further, using ecological momentary assessment, participants rated their mood three times daily as well as after each instance of marijuana use over a four-week period. Results revealed that although the MJ, BP, and MJBP groups each exhibited some degree of cognitive impairment relative to HCs, no significant differences between the BP and MJBP groups were apparent, providing no evidence of an additive negative impact of BPD and MJ use on cognition. Additionally, ecological momentary assessment analyses indicated alleviation of mood symptoms in the MJBP group after marijuana use; MJBP participants experienced a substantial decrease in a composite measure of mood symptoms. Findings suggest that for some bipolar patients, marijuana may result in partial alleviation of clinical symptoms. Moreover, this improvement is not at the expense of additional cognitive impairment."
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157060 [2448]

In astonishing news, science has now discovered that cannabis makes you happy, describing this in the Yale Journal of Biological Medicine (2020) as a "positive side effect".

Li et al (2020) examined "The Effectiveness of Cannabis Flower for Immediate Relief from Symptoms of Depression":

"We observed 1,819 people who completed 5,876 cannabis self-administration sessions using the ReleafApp™ between 06/07/2016 and 07/08/2019, with the goal of measuring real-time effects of consuming Cannabis flower for treating symptoms of depression. Results: On average, 95.8% of users experienced symptom relief following consumption with an average symptom intensity reduction of –3.76 points on a 0-10 visual analogue scale (SD = 2.64, d = 1.71, p <.001). Symptom relief did not differ by labeled plant phenotypes (“C. indica,” “C. sativa,” or “hybrid”) or combustion method. Across cannabinoid levels, tetrahydrocannabinol (THC) levels were the strongest independent predictors of symptom relief, while cannabidiol (CBD) levels, instead, were generally unrelated to real-time changes in symptom intensity levels. Cannabis use was associated with some negative side effects that correspond to increased depression (e.g. feeling unmotivated) in up to 20% of users, as well as positive side effects that correspond to decreased depression (e.g. feeling happy, optimistic, peaceful, or relaxed) in up to 64% of users. Conclusions: The findings suggest that, at least in the short term, the vast majority of patients that use cannabis experience antidepressant effects, although the magnitude of the effect and extent of side effect experiences vary with chemotypic properties of the plant."

and

"One of the most clinically relevant findings from this study was the widely experienced relief from depression within 2 hours or less. Because traditional antidepressants have times-to-effect in weeks, short-term Cannabis use might be a solution to these delays in treatment or could be used to treat acute episodes associated with suicidal behavior and other forms of violence."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309674/ [2447]

In 2024, Specka et al made the same discovery again, in a retrospective longitudinal 18 week study of 59 outpatients with MDD who had previously tried antidepressants - in "Effectiveness of Medical Cannabis for the Treatment of Depression: A Naturalistic Outpatient Study":

"Patients were 20-54 years old; 72.9% were male; one third reported times of regular cannabis consumption within the previous five years. Drop-out rate was 22% after 18 weeks. Mean severity of depression decreased from 6.9 points (SD 1.5) at entry to 3.8 points (2.7) at week 18 (baseline observation carried forward; 95% CI for the mean difference: 2.4 to 3.8; p<0.001). A treatment response (>50% reduction of the initial score) was seen in 50.8% at week 18. One third of patients complained about side effects, none was considered as severe. Concomitant antidepressant medication (31% of patients) was not associated with outcome."
https://pubmed.ncbi.nlm.nih.gov/38211630/ [4366]

And in fact this discovery reoccurs every now and then. In 2009 the Laboratory of Neuroendocrinology, The Rockefeller University, New York researchers Hill et al considered "The therapeutic potential of the endocannabinoid system for the development of a novel class of antidepressants", stating:

"Substantial evidence has accumulated implicating a deficit in endocannabinoid in the etiology of depression; accordingly, pharmacological augmentation of endocannabinoid signaling could be a novel target for the pharmacotherapy of depression. Within preclinical models, facilitation of endocannabinoid neurotransmission evokes both antidepressant and anxiolytic effects. Similar to the actions of conventional antidepressants, enhancement of endocannabinoid signaling can enhance serotonergic and noradrenergic transmission; increase cellular plasticity and neurotrophin expression within the hippocampus; and dampen activity within the neuroendocrine stress axis. Furthermore, limbic endocannabinoid activity is increased by both pharmacological and somatic treatments for depression, and, in turn, appears to contribute to some of the neuroadaptive alterations elicited by these treatments. These preclinical findings support the rationale for the clinical development of agents which inhibit the cellular uptake and/or metabolism of endocannabinoids in the treatment of mood disorders."
https://pubmed.ncbi.nlm.nih.gov/19732971/ [4385]

We await those clinical agents with some skepticism and trepidation and we'll just be ok with weed, thanks.

In a 2023-published longitudinal comparison of mortality rates in bipolar disorder with common causes of mortality Yocum et al at the University of Michigan began by examining deaths and associated variables among 1,128 participants who had volunteered for the program's long-term study of individuals with and without bipolar disorder."

They discovered that the 847 study participants with bipolar disorder accounted for all but two of the 56 fatalities that have occurred since the study's start in 2006. Their analysis, adjusting for statistical differences, reveals that a person with a diagnosis of bipolar disorder was six times more likely to die over a 10-year period than participants in the same study without a bipolar disorder diagnosis.

To see if they could discover the same effect, the researchers then looked to another data source. More than 18,000 patients who receive primary care from Michigan Medicine, the academic medical centre at the University of Michigan, had years' worth of anonymous patient records examined by the researchers. Those in this group who had a history of bipolar disorder had a four-fold higher risk of passing away during the study period than those who did not.

High blood pressure was the only factor in this group of individuals linked to an even higher risk of passing away during the study period. Regardless of bipolar disorder, the risk of death was five times higher for those with hypertension than for those with normal blood pressure. In contrast, regardless of bipolar status, smokers were twice as likely to die in this sample as never-smokers, and those over 60 were three times more likely to die. McInnis, a psychiatry professor at the University of Michigan Medical School, stated, "To our major surprise, in both samples we found that having bipolar disorder is far more of a risk for premature death than smoking."
https://economictimes.indiatimes.com/industry/healthcare/biotech/healthcare/bipolar-disorder-can-make-you-die-early-says-study-key-findings/bipolar-disorder-and-death/slideshow/106638965.cms [4323]
https://www.sciencedirect.com/science/article/abs/pii/S0165178123005516?via%3Dihub [4324]

It is fairly simple - the Defence hopes not simplistic - to infer that the benefits reported in [2448] will ameliorate the tendency to die reported in [4324] via positive effects on both mood and cardiometabolic stress.

Those seeking a more convenient route through the system could go to the pub, where they will at the very least lose some dignity, and at worst kill somebody.

Alternatively they could go and get some cannabis, which according to Li et al [2447] works immediately, altering their perception of the situation by raising their hedonic tone.

But if you insist on banning the one thing that will help without anyone getting their face smashed in, and if you insist on banning something which is impossible to ban - so drunk people in Ptuj can pick and choose enemies upon whom they can unleash their rage - ban depressed people. Not cannabis and psychedelics.

In 2022, Miranda et al found cannabis had "uniquely beneficial effects" in bipolar patients:

"Cannabis use is highly prevalent in people with bipolar disorder (BD), with many reporting using cannabis to ameliorate symptoms. These symptoms include deficits in goal-directed behaviors (i.e., decision-making and hyper-motivation) and cognitive function (i.e., attention and learning). However, chronic cannabis use is also associated with cognitive impairment, thus it is unclear to what degree cannabis is useful in ameliorating symptoms of BD. Here, we determined the effects of chronic cannabis use on goal-directed behavior and cognition that are impaired in people with BD. We recruited BD+ and BD- participants that were either cannabis users (C+) or non-users (C-). We performed a 2X2 ANOVA on interim data using BD and cannabis use as between-subjects factors on the 4 diagnostic groups: BD-/C- (n=25), BD-/C+(n-21), BD+/C- (n=8) and BD+/C+ (n=12). Participants were tested with a cognitive battery measuring risky decision-making (Iowa Gambling Task; IGT), motivation (Progressive Ratio Breakpoint Ratio Task; PRBT), reward learning (Probabilistic Learning Task; PLT) and sustained attention (5-C CPT). Overall, cannabis users were younger than non-users. Using age as a covariate, we observed BD x cannabis interaction effects on the IGT and PRBT. BD+/C+ participants showed less risk-prone behaviors on the IGT (F (1,63), p=.015, ES=.09) and normalized motivation on the PRBT (F (1,61), p=.045, ES=.065). We observed moderate effects of cannabis on punishment sensitivity (F (1,63), p=0.059, ES=0.055) and sustained attention (F (1,48), p=0.056, ES=0.074). Chronic cannabis use was associated with a modest improvement in some cognitive functions. Cannabis use was also associated with a normalization of risky decision making and effortful motivation in people with BD, but not healthy participants. Thus, chronic cannabis use may have uniquely beneficial effects in people with BD. Previous studies suggest that some people with BD have increased dopaminergic activity due to a reduced dopamine transporter expression. Chronic cannabis use has been shown to reduce dopamine release, thus chronic cannabis use may result in a return to dopamine homeostasis in people with BD and consequently normalizing their deficits in goal directed behaviors. We are engaged in additional studies that explore this potential dopaminergic/endocannabinoid mechanism."
https://www.abstractsonline.com/pp8/#!/10619/presentation/84925 [2445]

"To pin down the effects of cannabis on those with bipolar, researchers recruited people with and without the disorder, along with cannabis users and non-users in each group, analyzing each combination. Participants were tested on cognitive battery measuring risky decision-making, reward-learning, and sustained attention.

"Ultimately, researchers confirmed that cannabis indeed could hold some special benefits for those with bipolar, specifically in helping to reduce risky decision-making. Researchers also suggested that cannabis reduces the dopaminergic activity in the brain, which helps suppress symptoms, and found that cannabis had moderate effects on punishment sensitivity and sustained attention.

According to Colizzi et al (2019):

"'Chronic cannabis use was associated with a modest improvement in some cognitive functions,' authors noted. 'Cannabis use was also associated with a normalization of risky decision making and effortful motivation in people with [bipolar disorder], but not healthy participants. Thus, chronic cannabis use may have uniquely beneficial effects in people with [bipolar disorder].'"
https://hightimes.com/health/study-cannabis-has-uniquely-beneficial-effects-on-people-with-bipolar-disorder/ [2446]

This aligns with the metabolic overdrive hypothesis of bipolar: hyperglycolysis and
glutaminolysis in bipolar mania. According to Campbell and Campbell (2024):

"Evidence from diverse areas of research including chronobiology, metabolomics and magnetic resonance spectroscopy indicate that energy dysregulation is a central feature of bipolar disorder pathophysiology. In this paper, we propose that mania represents a condition of heightened cerebral energy metabolism facilitated by hyperglycolysis and glutaminolysis. When oxidative glucose metabolism becomes impaired in the brain, neurons can utilize glutamate as an alternative substrate to generate energy through oxidative phosphorylation. Glycolysis in astrocytes fuels the formation of denovo glutamate, which can be used as a mitochondrial fuel source in neurons via transamination to alpha-ketoglutarate and subsequent reductive carboxylation to replenish tricarboxylic acid cycle intermediates. Upregulation of glycolysis and glutaminolysis in this manner causes the brain to enter a state of heightened metabolism and excitatory activity which we propose to underlie the subjective experience of mania. Under normal conditions, this mechanism serves an adaptive function to transiently upregulate brain metabolism in response to acute energy demand. However, when recruited in the long term to counteract impaired oxidative metabolism it may become a pathological process."
https://www.openread.academy/en/paper/reading?corpusId=50309855 [4761]

"A limited number of studies consistently support the evidence for altered brain glutamate levels as measured by proton magnetic resonance spectroscopy (1H-MRS) in otherwise healthy chronic cannabis users, with all but one of the five studies indicating reduced levels of glutamate-derived metabolites Glutamate (Glu) or Glutamate + Glutamine (Glx) in both cortical and subcortical brain areas."
https://www.nature.com/articles/s41380-019-0374-8 [4760]

In a sample of 297 with a mean age below 30, Beaton et al (2016) found the illegal weed users were more sensible than the legal nicotine addicts:



"Post-hoc comparisons showed that the Control and Marijuana groups were less impulsive than the Marijuana+Nicotine, Nicotine, and Overeating groups (Table 3)."

"Impulsive Sensation Seeking (ImpSS) and Barratt's Impulsivity scales (BIS) Scales were analyzed with a non-parametric factor analytic technique (discriminant correspondence analysis) to identify group-specific traits on 297 individuals from five groups: Marijuana (n = 88), Nicotine (n = 82), Overeaters (n = 27), Marijuauna + Nicotine (n = 63), and CONTROLs (n = 37).

"Results: A significant overall factor structure revealed three components of impulsivity that explained respectively 50.19% (pperm < 0.0005), 24.18% (pperm < 0.0005), and 15.98% (pperm < 0.0005) of the variance. All groups were significantly different from one another. When analyzed together, the BIS and ImpSS produce a multi-factorial structure that identified the impulsivity traits specific to these groups. The group specific traits are (1) CONTROL: low impulse, avoids thrill-seeking behaviors; (2) Marijuana: seeks mild sensation, is focused and attentive; (3) Marijuana + Nicotine: pursues thrill-seeking, lacks focus and attention; (4) Nicotine: lacks focus and planning; (5) Overeating: lacks focus, but plans (short and long term).

"Conclusions: Our results reveal impulsivity traits specific to each group."
https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC4318510&blobtype=pdf [3922]

In similar attention to the same detail, Round et al (2020) found:

"Trait impulsivity was significantly higher in cigarette smokers than non-smokers, irrespective of cannabis use, except for motor impulsivity, where cigarette smoking was only associated with elevated trait impulsivity in non-smokers of cannabis. Dimensions of trait impulsivity were significantly positively related to cigarette smoking frequency and nicotine dependence, but not to cannabis smoking frequency or dependence. Smoking cigarettes or cannabis was associated with significantly impaired reflection impulsivity relative to not smoking either substance. However, no additional increases in reflection impulsivity were observed in those who smoked both cigarettes and cannabis. No group differences in response inhibition were detected."

Trait impulsivity in detail:

"There were significant main effects for cigarette smoking status on BIS-11 total scores (F(1, 220) = 32.76, p < .001, ηp 2 = .13), along with the attention (F(1, 220) = 15.63, p < .001, ηp 2 = .07) and non-planning subscales (F(1, 220) = 27.95, p < .001, ηp 2 = .11), such that individuals who smoked cigarettes scored significantly higher than those who did not smoke cigarettes (Figure 1(a) to (c)). No significant effects of cannabis smoking or interactions were found (all F(1, 220) < 2.27, p ⩾ .101, ηp 2 ⩽ .01). For the BIS-11 motor impulsivity subscale, there was again no significant main effect of cannabis (F < 1, p = .773, ηp 2 < .001), but a significant main effect of cigarette smoking (F(1, 220) = 19.14, p < .001, ηp 2 = .08), this time qualified by a significant cigarette smoking × cannabis smoking interaction (F(1, 220) = 5.92, p = .016, ηp 2 = .03; see Figure 1d). Cigarette smoking was again associated with higher levels of impulsivity, but simple effects analyses showed that this effect was seen in NS (p<.001), but not smokers (p = .178) of cannabis. Motor impulsivity did not differ as a function of cannabis smoking in either cigarette smokers (p = .095) or non-cigarette smokers (p=.078)."
https://journals.sagepub.com/doi/pdf/10.1177/0269881120926674?download=true [3923]

"A Naturalistic Examination of the Acute Effects of High-Potency Cannabis on Emotion Regulation Among Young Adults: A Pilot Study" by Cavalli et al (2024) made the horrifying finding that:

"Participants reported a more positive mood and decreases in anxiety while intoxicated. There was no evidence that acute high-potency cannabis affected participants' implicit or explicit emotion regulation task performance."
https://onlinelibrary.wiley.com/doi/10.1002/hup.2915 [5194]

"Potentiation of GABA by either CBD or 2-AG is selective for the α2 subunit" report Bakas et al (2017).
https://www.sciencedirect.com/science/article/abs/pii/S1043661816311392?via%3Dihub [3926]

Adolescent cannabis users showed lower GABA in a small study of just 39 subjects by Subramaniam et al in Salt Lake City, where sales of tea and coffee are presumably quite low. But:

"Assessment of impulsive behavior demonstrated no significant between-group differences in motor, non-planning, attention, and total impulsivity scores. Additionally, impulsivity measures and tissue-corrected GABA+ or Glx levels were not significantly correlated in either group."
https://www.sciencedirect.com/science/article/abs/pii/S03768716220006317 [3927]

The University of Utah is not affiliated with the LDS, but Mormon attendance is reckoned at 25-50%. Given this venue, it may be that the Mormons are increasing their impulsivity and denying themselves a good night's sleep. Tea accumulates GABA and a special process has been devised to produce high-GABA tea.
https://en.wikipedia.org/wiki/GABA_tea [3924]

Although there has been a debate about whether oral GABA can even cross the blood-brain barrier, collected studies using tea, coffee, rice and other dietary sources, a review by Hepsomali et al (2020) - based in various non-Mormon places from Nottingham to Hokkaido - found mildly convincing evidence for benefits upon stress and sleep.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7527439/ [3925]

Cannabis is not the only influence on GABA. The Defendant wonders on what superstitious or empirical basis cannabis could be held responsible for legal transgressions when alcohol would not.

Compass Pathways plc published some results on psychedelics and depression in 2021:

"In the randomised, controlled, double-blind trial, a single dose of investigational COMP360 psilocybin was given to 233 patients in conjunction with psychological support from specially trained therapists. All patients discontinued antidepressants prior to participation. The trial was powered to compare two active doses of COMP360, 25mg and 10mg, against a comparator 1mg dose. The 25mg group vs the 1mg group showed a -6.6 difference on the MADRS* depression scale at week 3 (p<0.001). The 25mg group demonstrated statistical significance on the MADRS efficacy endpoint on the day after the COMP360 psilocybin administration (p=0.002). The 10mg vs 1mg dose did not show a statistically significant difference at week 3. The MADRS was assessed by independent raters who were remote from the trial site, and blind to intervention and study design, effectively creating a triple blind.

"At least twice the number of patients in the 25mg group showed response and remission* at week 3 and week 12, compared with the 1mg group. The protocol-defined sustained response* up to week 12 was double, with 20.3% of patients in the 25mg group vs 10.1% in the 1mg group. Using a definition of sustained response* that is consistent with other TRD studies, the difference was more than double, with 24.1% of patients in the 25mg group vs 10.1% in the 1mg group."
https://ir.compasspathways.com/news-releases/news-release-details/compass-pathways-announces-positive-topline-results [4310]

Another report that year by Carhart-Harris et al compared psilocybin and escitalopram. Psilocybin worked better. The subjects were tested using the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression.

"A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (P=0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups."
https://www.nejm.org/doi/full/10.1056/NEJMoa2032994 [4311]

"The Montgomery–Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. It was designed in 1979 by British and Swedish researchers (Marie Åsberg) as an adjunct to the Hamilton Rating Scale for Depression (HAMD) which would be more sensitive to the changes brought on by antidepressants and other forms of treatment than the Hamilton Scale was. There is, however, a high degree of statistical correlation between scores on the two measures.

and

"The questionnaire includes questions on ten symptoms:

"Apparent sadness
Reported sadness
Inner tension
Reduced sleep
Reduced appetite
Concentration difficulties
Lassitude
Inability to feel
Pessimistic thoughts
Suicidal thoughts

"Each item yields a score of 0 to 6; the overall score thus ranges from 0 to 60. Higher MADRS score indicates more severe depression. Usual cutoff points are:

"0 to 6: normal/symptom absent
7 to 19: mild depression
20 to 34: moderate depression
35 to 60: severe depression."
https://en.wikipedia.org/wiki/Montgomery%E2%80%93%C3%85sberg_Depression_Rating_Scale [4257]

In 2021 Aaronson et al embarked upon "Single-Dose Synthetic Psilocybin With Psychotherapy for Treatment-Resistant Bipolar Type II Major Depressive Episodes. A Nonrandomized Controlled Trial" (2023)...

"Bipolar II disorder (BDII) is a lifelong condition characterized by recurrent hypomanic and depressive episodes with a lifetime prevalence of at least 0.4% among adults. It causes a level of functional impairment and disability comparable to bipolar I disorder (BDI) Despite treatment, patients with BDII are typically symptomaticmost of the time, primarily experiencing protracted and difficult-to-treat periods of depression. Bipolar disorder has high mortality, as 30% of affected individuals attempt and 5% to 15% commit suicide. Historically, BDII was viewed as the lesser of the bipolar disorders due to the absence of florid mania. However, recent studies document that functional impact and risk of suicide are similar in BDI and BDII."

and

"INTERVENTIONS A single dose of synthetic psilocybin, 25 mg, was administered. Psychotropic medications were discontinued at least 2 weeks prior to dosing. Therapists met with patients for 3 sessions during pretreatment, during the 8-hour dosing day, and for 3 integration sessions posttreatment.

"MAIN OUTCOMES AND MEASURES The primary outcome measure was change in Montgomery-Åsberg Depression Rating scale (MADRS) at 3 weeks posttreatment. Secondary measures included MADRS scores 12 weeks posttreatment, the self-rated Quick Inventory of Depression Symptoms-Self Rating (QIDS-SR), and the self-rated Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF), each completed at baseline and all subsequent visits. Safety measures included the Columbia Suicide Severity Rating Scale (CSSRS) and the Young Mania Rating Scale (YMRS) completed at each visit.

"RESULTS Of the 15 participants in this study (6 male and 9 female; mean [SD] age, 37.8 [11.6] years), all had lower scores at week 3, with a mean (SD) change of −24.00 (9.23) points on the MADRS, (Cohen d = 4.08; 95% CI, −29.11 to −18.89; P < .001). Repeat measures analysis of variance showed lower MADRS scores at all tested posttreatment time points, including the end point (Cohen d = 3.39; 95% CI, −33.19 to −16.95; adjusted P < .001). At week 3, 12 participants met the response criterion (50% decrease in MADRS), and 11 met remission criterion (MADRS score 10). At the study end point, 12 patients met both response and remission criteria. QIDS-SR scores and Q-LES-Q-SF scores demonstrated similar improvements. YMRS and CSSRS scores did not change significantly at posttreatment compared to baseline."
https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2812443 [4256]

In "Psilocybin use in bipolar disorder: A comprehensive review" Do et al (2026) say:

"Two small clinical trials show that psilocybin combined with psychotherapy was safe and effective for the treatment of BDII depression with large treatment effects. No serious adverse events, including treatment-emergent mania/hypomania or increased suicidality, were reported in both trials. However, other studies have raised concerns about the safety of psilocybin in BD patients, including the development or worsening of manic symptoms, sleep disruptions and anxiety. Overall, the majority of BD patients believe that psilocybin could benefit their mental health problems, but their experiences varied depending on several contextual factors, such as polysubstance use, psilocybin dose, solo versus social experiences and pre-psilocybin sleep deprivation."
https://www.sciencedirect.com/science/article/pii/S0165032725019275 [5548]

The psychopharmaceutical upheaval continued in 2023 with a reanalysis of the data that made Prozac great.

"Back in 2003, the NIMH-sponsored Treatment for Adolescents with Depression Study (TADS) included 439 adolescents aged 12-17 who met DSM-IV criteria for depression. There were four treatment arms, including fluoxetine (Prozac) only; cognitive-behavioral therapy (CBT) only; fluoxetine and CBT; and placebo. The psychotherapy groups were not able to be blinded. The randomized trial lasted for 12 weeks, and participants were asked which group they believed they were in at both 6 weeks and 12 weeks. Improvement in depression was measured with the Children’s Depression Rating Scale–Revised (CDRS-R).

"The TADS study is commonly cited as evidence for Prozac’s effectiveness in depression treatment, because the combined drug and CBT group did slightly better than the placebo group. However, the drug group alone did no better than the placebo group in the TADS analysis of the CDRS-R.

"The current analysis was conducted as part of the Restoring Invisible and Abandoned Trials (RIAT) initiative, which allowed the researchers access to the raw data from the TADS study. They obtained information on the fluoxetine group (109 participants) and the placebo group (111 participants), since those were the two blinded groups, in order to directly compare the effects of unblinding.

"In all the groups, more than 60% of the participants and raters correctly guessed whether they received the drug or placebo (a perfectly blinded study would result in 50% guessing correctly).

"The researchers found that the placebo effect was stronger than the actual treatment itself. Those who guessed that they received the treatment were more likely to improve than those who guessed they received the placebo—even if their guess was incorrect. That is, on average, those who believed they received the drug improved, even if they actually received the placebo. Likewise, those who believed they received the placebo were less likely to improve, even if they actually received the drug.

"Those who believed they received the drug, on average, improved by 10 points more on the CDRS-R than those who believed they received the placebo. Those who believed they received the drug improved by 26.98 points, on average. Those who believed they received the placebo improved by 16.65 points, on average.

"Amazingly, the group that did the best was those who believed they received the drug, but actually received the placebo. These patients did better than those who received the drug and knew it!

"'Adolescents who guessed they were on fluoxetine, but were actually allocated to placebo, demonstrated the largest improvement in CDRS-R,' the researchers write.

"Finally, the researchers confirmed the initial finding of TADS: after accounting for the placebo effect (treatment guess), the researchers found that taking Prozac did not improve depression.

"The researchers write, 'Treatment guess had a substantial and statistically significant effect on outcome (Children’s Depression Rating Scale-Revised change mean difference 9.12, p < 0.001), but actual treatment arm did not (1.53, p = 0.489).'

"The researchers conclude that unblinding, which amplifies the placebo effect, may be the reason antidepressants typically beat placebo by a slight margin in clinical trials. They add that future studies need to make sure to assess unblinding in order to provide accurate data on drug efficacy.

"'Our analysis suggests that the effects that are demonstrated in placebo-controlled trials of antidepressants may represent amplified placebo effects that are a result of the differential distribution of expectancy effects caused by unblinding. Since the expectancy effects are substantial, even a small degree of unblinding might produce an apparent difference between an active drug and a placebo. For future research, there is a clear need for more stringent study designs that systematically record and analyse treatment guesses and assess blindness, and do so early on and repeatedly,' they write.

"Moreover, since clinical practice guidelines are based on evidence from studies like TADS, the researchers argue that guideline authors need to reassess the evidence base for their recommendations. Recommending antidepressants on the basis of studies like TADS is poor science."
https://www.madinamerica.com/2023/12/placebo-effect-not-antidepressants-responsible-for-depression-improvement/ [4297]

From tests in mice, Themann et al (2025) feel "Prozac exposure during adolescence increases pain sensitivity in adulthood":

"Preclinical work indicates that early-life exposure to FLX alters neurobehavioral responses as a function of age (Kryst et al., 2022; Olivier et al., 2011). For example, adult rodents with juvenile FLX pre-exposure display increases in anxiety-related behavior (Flores-Ramirez et al., 2021; Iñiguez et al., 2010), altered responses to inescapable stress (Iñiguez et al., 2010; Karpova et al., 2009), impaired spatial memory performance (Flores-Ramirez et al., 2019) and changed preference to commonly abused drugs, like cocaine (Flores-Ramirez et al., 2018; Iñiguez et al., 2015; Warren et al., 2011) and nicotine (Alcantara et al., 2014). Such enduring FLX-induced behavioral changes are accompanied by neurobiological deviations within multiple brain regions including the hippocampus (Iñiguez et al., 2021; Kroeze et al., 2015; Sierra-Fonseca et al., 2021), prefrontal cortex (Themann et al., 2022), ventral tegmental area (Alcantara et al., 2014; Iñiguez et al., 2014), and amygdala (Homberg et al., 2011) – which comprise key brain-circuitry known to impact emotion regulation. Consequently, signifying that early life exposure to FLX, resulting in chronic elevations of serotonin, may predispose individuals to undesired mood-related symptomatology in adulthood.

"Antidepressant medications (Coluzzi and Mattia, 2005; Hache et al., 2011; Trujillo and Iñiguez, 2020), including FLX (Hache et al., 2012), are able to reverse hyperalgesia in animal models for the study of nociception. This is not surprising because there is a correlation between depression symptoms, inflammation, and pain sensitivity (Chan et al., 2019; Hamdy et al., 2018; Humes et al., 2024; Tesic et al., 2023). Because SSRI prescriptions are on the rise in the juvenile population, with such treatment lasting for years, it is possible that adolescent FLX exposure may impact responses to pain perception in later life (Baudat et al., 2022). Indeed, recent clinical evidence suggests that adolescent exposure to FLX increases the levels of the inflammation markers interleukin-6 (IL-6) and interleukin 1-Beta (IL-1β) six months after treatment (Amitai et al., 2020). For this reason, the goal of this preclinical investigation is to examine whether chronic FLX exposure during the juvenile stage of development alters responses to thermal nociception in adulthood, using female mice as a model system."

And...

"The long-term effects of juvenile FLX exposure (PD35-49) on HPT behavioral responses in adult (PD70) female C57BL/6 mice are shown in Fig. 1B. Mean differences in time (s) to lick a hindpaw were noted as a function of juvenile SSRI pre-exposure (n = 10 per group). Specifically, adult female mice with FLX history displayed shorter latency to hindpaw lick when compared to VEH-controls (t18 = 2.22, p = 0.03) – a murine behavioral response indicative of hyperalgesia..."
https://www.sciencedirect.com/science/article/abs/pii/S0022395625002626?via%3Dihub [5030]

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