Feeling Good with Narcotics Now “Evidence” of Opioid Deficiency: The Chemical Imbalance Theory of Depression, Redux


In a curious twist of the reformulation of the chemical imbalance theory of mood disorders – an idea that just won’t die – psychiatrists have turned their attention to depression as the result of a deficiency of endorphins. A recent randomized controlled trial compared the opioid partial agonist buprenorphine to placebo. The supposed success of the treatment in this studies led the authors  to conclude “these results support the hypothesis of a significant role of opioid dysregulation in major depression and the therapeutic potential of opioid modulation.” Put in plain terms, the astonishing conclusion is that people reporting feeling better with narcotics is “proof” that they have an opioid deficiency that justifies “treatment” with narcotics. It does not require a PhD in neuroscience to see why this claim is nonsense.

Backward Logic

The history of psychopharmacology is littered with examples of response to psychotropic drugs taken as evidence of drugs correcting some underlying disease state. In the early days of lithium in the treatment of manic-depressive illness, it was believed that such extreme mood states might be caused by a lithium salt deficiency. When it was discovered that the early antidepressant drugs inhibited the transporters of noradrenaline and serotonin, it was believed that deficiencies in these neurotransmitters might be the cause of depressive states. Similarly, when neuroleptics were discovered to block D2 dopamine receptors, hyperactivity of the dopamine system was hypothesized as the cause of psychosis.

This backward logic of presuming drugs are correcting an underlying disease process, rather than simply suppressing symptoms has been called the “disease-centered model” of drug action by psychiatrist Joanna Moncrieff. In the same way, taking depressed people feeling better with narcotics as supporting “opioid dysregulation” as the cause of their despair, is a remarkable feat of backward logic. It also highlights just how suspect previous claims have been. But this idea is even more pernicious because of the lethality of buprenorphine and the fact we are already in the midst of a prescription opioid epidemic.

The Dangers of Buprenorphine

Buprenorphine is already a blockbuster drug. It is the key ingredient in Suboxone and Subutex, popular office-based substitution therapies for people with opiate addiction. It was marketed as “non-abusable” as it is combined with naloxone, an opioid blocker, preventing users from injecting it. You can get “high” from it despite claims to the contrary, and it has significant abuse potential. People become dependent on it and buprenorphine addiction is real. It is fatal in overdose, especially when combined with alcohol or benzodiazepines. It is one thing to prescribe buprenorphine as opioid substitution and a harm reduction intervention to those already addicted to heroin and prescription narcotics. It is another thing altogether to prescribe it to opiate naïve individuals desperate for relief from emotional distress. Although the recent study found no evidence of withdrawal or dependence emerging, it was only 4 weeks long, which is far too short to identify these problems.

Reformulating Emotional Distress

In my clinical practice I see people who are desperately searching for relief from their pain. Sometimes I feel completely helpless as I bear witness to the intractable suffering that seems recalcitrant to any therapy. From this vantage point, it is easy to see the appeal of a pill that could rapidly lift interminable despair. The problem is we have redefined human emotions as something to be suppressed and eradicated, as lacking purpose and meaning. In my younger patients especially, I notice a trend to see powerful emotions as unacceptable, and to have unrealistic beliefs that we should be happy all the time. In our culture of a pill for every ill, emotions we don’t want can be obliterated on demand. We have lost our ability to tolerate distress, to find meaning in emotion, and purpose in experience. As the sociologist Nikolas Rose has noted, we have recoded our moods in terms of neurochemistry. Emotions no longer have context. They are aberrations in neurochemistry. I’m no longer hurting because I’m lonely, but because I’m running low on endorphins. Buprenorphine for depressive despair reinforces the belief that emotions should be obliterated, and can only be done so through modulating biochemistry.

Does it Even Work?

Although we can see how relief of depression by buprenorphine does not mean depression is caused by opioid dysregulation, let’s consider the actual study results. Much of the improvement seen in the study — as with other antidepressants studies — can be explained by placebo effects, regression to the mean (people feel better eventually anyway), contextual healing, and positive expectancy effects. Some of the difference can also be explained by the unmasking of the active drug vs. placebo by the terrible nausea and vomiting induced by the drug. In fact, those given a whopping 8mg dose (which is what you would start a prescription opioid addict on) did not seem to get the same positive effects as the 2mg group, presumably because they experienced too much dizziness, nausea and vomiting. But if we look at those given 2mg, they did not achieve the 50% reduction in depression scores that is typically defined as “response” in antidepressant studies. In other words, it doesn’t even work very well. Yet somehow the conclusion is: “these results support the hypothesis of a significant role of opioid dysregulation in major depression and the therapeutic potential of opioid modulation.” I think not.


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      • This article points out that combining the antidepressants with the opioids is the second most deadly combination of psychiatric drugs cocktails:


        The adverse effects of Wellbutrin (SNRI) combined with Ultram (synthetic opioid) is what resulted in my “bipolar” misdiagnosis. So I’m positive such drug combinations are highly unwise. And drugs.com does say combining these drugs is not recommended either, as they have a major drug interaction warning:

        “The risk of seizures may be increased during coadministration of tramadol with any substance that can reduce the seizure threshold, such as selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, and theophylline. These agents are often individually epileptogenic and may have additive effects when combined. Many of these agents also exhibit CNS- and/or respiratory-depressant effects, which may be enhanced during their concomitant use with tramadol.”

        And when ignorant or unethical doctors try to treat the adverse effects of a major drug interaction between an antidepressant and an opioid, by adding antipsychotics. The CNS effects can result in the following central symptoms of anticholinergic intoxication syndrome:

        “Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.”

        Symptoms which look exactly like “bipolar” or “schizophrenia” to the medical community. Combining the antidepressants and the synthetic opioids is really stupid medical advice, unless the goal is to make healthy people ungodly sick or kill them, for profit. Which does seem to be the goal of the pharmaceutical industry today. Although, it’s not supposed to be the goal of the medical community, theoretically, but it is profitable for them, too.

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  1. My golly….I wonder whether I have alcohol dysregulation in my brain that leads to my social anxiety in some situations – a glass of red wine seems to fix it. Might go and ask my doc for a script. Or volunteer for a RCT.

    Thanks for another revealing post Vivek.

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  2. There is a buprenorphine-based antidepressant now in clinical trials that was fast tracked by the FDA. Alkermes has designated it as ALKS-5461. Alkermes stock dropped over 40% in value after the announcement. It recently failed in two late-stage clinical trials, but Alkermes isn’t giving up. Here’s a link to a Reuters article on the failures: http://www.reuters.com/article/us-alkermes-study-idUSKCN0UZ1L4. Here’s a link to an article I wrote on ALKS-546, “The coming Depression Apocalypse”: http://faith-seeking-understanding.org/2015/06/17/the-coming-depression-apocalypse/

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  3. The link at the top of your article does not work; it should read like this:


    As for the article itself, thank you and I enjoyed it.

    This study should be a nonstarter because major depression is not a single illness. In this study, they are throwing together a bunch of different people who are feeling depressed for different reasons. Major some were young men who recently lost their girlfriends. Maybe a few were college woman who were stressed by having to work full time and attend school full time. Others might be older socially isolated single women under economic stress. Some might be new mothers stressed by their new children… etc.

    Without the context it’s impossible to tell what is really going on with these people. Saying they “have major depression” is bullshit and explains nothing. As Vivek said, “We have lost our ability to tolerate distress, to find meaning in emotion, and purpose in experience.” Instead the Kafkaesque delusion emerges that some unknown disorder called major depression is causing the problems for these brains out of context.

    Opioid deficiency almost certainly has nothing to do with causing their feelings of depression and could at most be understood as a mild correlation, or neurochemical expression of, their feelings of distress.

    As usual the point is to maintain the lie that life problems are medical illnesses so that drug companies can continue to profit via the pill scam, and so that psychiatrists can continue to advance their careers by spitting trash research serving the interests of their masters, the corporations.

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  4. The supposed rationale for using buprenorphine as an antidepressant is better understood by studying advertising and marketing instead of pharmacology. What customer base is more reliable than that of the strung-out? They’ll always come back for more.

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  5. Its a bit off topic but I am on prescribed pain meds after suffering nerve damage from years of chemo therapy. The way pain meds have been advertised/marketed and sold and the abuse that followed is a huge problem for those of us who need pain meds to regain a quality of life worth living.

    It seems like everyday I am seeing articles about the abuse of prescription pain meds but rarely do you ever see anything that delves into how prescription drug abuse has negatively effected and stigmatized people who need these mediations to live a better life … or live a life at all .

    It’s off topic but something I wanted to put out there for people to consider.

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  6. I have only read the last half dozen blogs or so on “Mad in America”, and I am compelled to write to tell you that most of them outrage me. As someone who has suffered from severe chronic major depression for 35 years, and been treated with antidepressants for 30–a medication which has been, for me, the literal difference between my life and death–the devotion of these blogs to “proving” that antidepressants do not truly work for is offensive and ignorant. (I understand this particular blog is about treating depression w opiates, which I too consider to be dangerous. However, in severe stages of my depression, it has been a last resort.) Most people who are prescribed antidepressants do not even have major depression to begin with–so I agree that they are vastly overprescribed. However, there are some people, like myself, who simply can’t survive w/out medical treatment. I have NEVER found an SSRI or any antidepressant at all to be helpful, except for the MAOI, which is the one I’ve been on most of my life. When it ceases to work for me, every year or so, so that I take a 6 week “drug holiday,” I become so suicidal and depressed during that time that I usually must hospitalize myself or be hospitalized. So there is NO DOUBT in my mind that I would not even be alive if it weren’t for the efficacy of a specific antidepressant—and I know I’m not the only individual for whom this is true. I know several people, mostly online, who have derived huge, life altering reprieve from critically severe depression w medication, and “Mad in America”, in general, seems determined to prove that antidepressants are plain wrong, and completely useless, which is an insult to the people they do actually help. Frankly, I don’t believe they help *many* people–probably, far fewer are helped than not–but that is partially connected to the fact don’t actually have any kind of chemical imbalance or depletion–actual depression–to start with. That a chemical imbalance of some sort is a cause of major and recalcitrant (“treatment resistant”) depression has not yet been *disproven.*
    As for “opiate therapy”–yes, it’s simplistic, and naïve or cynical (can’t decide which) for researchers to conclude that they will make good antidepressants, as they seem to lift people’s moods. They do–for a time–improve mood, but the harm from long term opiate addiction far outweighs their benefit, imo. I have turned to them, w my psychiatrist’s encouragement, at times when I am off my MAO antidepressant, when the depression becomes literally too agonizing to live through. I have never been on them longer than a month, however, and would never plan to be. But there are times when they *have* become the only thing left between myself and suicide. I don’t presume that there are not others like me, who could be temporarily helped by the use of opiates.
    The underlying presumption in “Mad in America”, that there is no such thing as chemical imbalance in depression and that, therefore, antidepressants are useless, and serve to aid only Big Pharmacy, is far too sweeping, exaggerated, and generalized to be accurate. At best, it’s a thoughtless stance, which does not consider factors and variables that are still unknown. But above all, it does not consider the truth, lives, and stories of ALL people who suffer from depression, some whose lives actually can be and are made more livable by the use of antidepressants and other psychiatric drugs.

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    • thanks for your comments but they do appear to be a digression from the article above and seems to make assumptions about my beliefs which I am not sure where you get this from. I am sure you will agree, as is the focus of this article, that feeling good with narcotics does not mean one has a dysregulation in endogenous endorphins as has been claimed. The notion of “chemical imbalances” in depression or other states is an article of blind faith. I believe it is damaging to tell people they have a chemical imbalance or other neurochemical defect when this has not been shown to be the case. However as a psychiatrist, I do see people, who are suffering and desperate for relief. Sometimes I do use drugs, including MAOIs. I am not anti-drug, but I am opposed to pseudoscience and deceiving people by telling them that they have some flaw in their neurochemistry when this is no more based in science than the idea that depression and mania are caused by imbalances in black bile and yellow bile.

      I agree with you that it is important to consider the risks and balances and consider whether there might be circumstances where people are experience such acute suffering that using opiates may be appropriate as we do already use for pain. However, the study I have discussed, was adding buprenorphine to people after 1 or 2 antidepressant trials, not as a last resort, and not for people with the psychic pain that was driving them to become seriously suicidal. Interesting, a different study has looked at very low dose buprenorphine for people who are suicidal and suggested its possible use as an acute intervention for those who are risk of taking there lives due to mental anguish. I am not necessarily opposed to this idea, but the idea that this somehow means the problem is simply an abberation of the endogenous opioid system is disempowering, reductionistic, and false.

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    • Don’t rely on a pill to mask your suicidal thoughts, join others who are unhappy that society is driven by greed, self interest, and a lack of compassion so you won’t need pills to be happy.

      The very idea of getting rich from pills to keep you from committing suicide perpetuates a system driven by self interest, rather than truly caring for people who are sad and want to hurt themselves.

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  7. I had major depression. Took Paxil-crap, took lexapro-double crap, took effexor-suicidal. Accidently took Buprenorphine, thinking it was an anti-depressant and it worked with less than 1 mg. a day. Shrinks are afraid of anything that works that fast, because they would rather see you tortured for weeks and months with ssri’s or snri’s. For a lot of people, cognitive therapy is a great help. Psychiatrists generally don’t do cognitive therapy, because they would rather just dispense prescriptions and leave that to the psychologists. All psychoactive pills are addictive ambien to zoloft. I am now taking the best kept secret in either addiction therapy or depression therapy,—“Gabapentin”. Look it up for addiction and mood stabilization. Doctors don’t prescribe it generally, because it is off patent and cheap. another thing that works is cannabis, which is not considered, because then you won’t need big pharma or over priced specialists. Most psychiatrists are a scam.
    This author at least tries to be a little objective, but falls short when it comes to alternative therapies. Tell me doctor? Why is it that when you have a physical problem like heart, liver etc a thorough exam including mri’s and blood tests are done, but when it come to mental illness, almost never is there a brain scan or other tests to determine any underlying physical problem?

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    • thanks for your comment though I am not sure how I fall short on alternative therapies given this is not discussed or the focus of the above. Gabapentin btw is widely prescribed for anxiety, alcohol withdrawal and so on. It is no longer used for “mood stabilization” as it doesn’t work. Diagnosis in medicine is typically based on history and examination, laboratory and imaging are used to support diagnoses and there are many conditions where the diagnosis is made clinically – for example migraines, Parkinson’s disease, essential tremor, even epilepsy – no investigations are required to make the diagnosis though they may be used to support or exclude other diagnoses. It would, in my view be odd to use laboratory or imaging markers to confirm that someone is “depressed” given this is a subjective experience, in the same way we don’t use biomarkers to tell whether someone is in pain.

      As a neuropsychiatrist, I treat patients with problems like traumatic brain injury, Alzheimer’s, fronto-temporal degeneration, Lewy Body dementia, or emotional and behavioral changes due to neurological diseases (such as multiple sclerosis, Parkinson’s disease, limbic encephalitis) and frequently use laboratory investigations (for example paraneoplastic and autoimmune panels, Alzheimer’s markers, 14-3-3 protein, heavy metals, hormones etc), neurophysiological tests (e.g. EEGs) and imaging (MRI, MRA, FDG-PET) to support diagnoses or identify the cause of problems.



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  8. Nice smackdown, Vivek. It continues to amaze how strong the “confirmation bias” is in those who really, really want to believe it’s all in your brain chemicals, despite the almost total lack of evidence supporting that theory. They just haven’t identified the right chemicals yet, if only we keep researching… More like a faith community than a group of scientists.

    Very much appreciate your objective assessment of the literature and your willingness to call out the deceptive marketing practices of those who don’t always want to face the real truth about their practice of medicine.

    —- Steve

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  9. I realize there are real physical diseases as you mentioned, but to disregard depression as being subjective and not physiological is saying that you will sometimes prescribe a psychoactive drug, but basically only as a placebo. I know I am debating against a much better educated physician, but I can’t disregard the fact that you feel most depression is subjective with no physical abnormalities. Pain markers are usually rated as 1-10, and are related to the diseases that you mentioned and treat. As far as the last poster, Ii didn’t know this was suppose to be a smack down.
    BTW. Most physicians are loathed to prescribe Gabapentin for anything other than diabetic nerve pain or possibly restless leg syndrome. I do appreciate you having this forum and respect your credentials.

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    • I am not quite sure how you arrived at this conclusion. Of course there is a physiological basis to subjective experience, but it is neither necessary, nor most of the time relevant, to understand this level in order to intervene. Since we understand the physical basis of fear better than depression let me use this is an example. We respond to stimuli picked up in the prefrontal cortex, sensory cortex and hippocampus and that is interpreted by the amygdala, the emotional center of the brain. The amygdala has projections to the hypothalamus which stimulates release of hormones from the pituitary that send a flood of hormones releasing from the adrenal glands to activate us, as well as activating the locus caeruleus increasing heart rate and blood pressure, and the periaqueductal grey area which activates are flight, flight, freeze response etc. However we do not need to understand or think about any of this to help some overcome a phobia for example. And drugs like benzodiazepines which reduce the subjective experience of anxiety and fear do not target the fear circuits specifically, but have a general dampening effect diffusely on the brain by potentiating the major inhibitory neurotransmitter in the brain (GABA). In a similar way, whether one uses antidepressants or not is not contingent on the physical basis of “depression”. These drugs act in non-specific ways and had been used for many years before there was any claim about “chemical imbalances” or any real understanding of the emotional brain at all.

      In fact, the first antidepressant iproniazid was an antitubercular drug that had a number of psychiatric side-effects including being a mild euphoriant, that led to its use as a “psychic energizer” which is what “antidepressant drugs” were called before the 1960s when the idea that they might have some specific action on depression took hold. Even at that time, American psychiatrists could not be convinced to prescribe these drugs by marketing claiming they reversed some physical processes. Instead, these drugs were marketed as a way to gift a “lift” to patients and make them better able to engage in psychotherapy or life changes. In my view it is not necessary to think about the physiological basis of depression in order to help people and is often harmful.

      As an aside, most people prescribed pain killers or who experience pain (i.e. most of us) don’t have any disease to speak of. Headaches, lower back pain, and various other musculoskeletal pains are most often not related to any underlying disease process at all. Even 40% of abdominal pain or chest pain presenting to an emergency department has no pathological process found to explain it. So again, we approach pain as a subjective experience “pain is what the patient says it is” rather than from a physical perspective.



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      • Doctor, what is your opinion on using MDMA or Ketamine as an adj along with cognitive therapy. I know these are highly controversial, but anecdotal evidence supports some short term effectiveness. Will we start to see some alternative methods become more mainstream? Thanks again for sharing your knowledge.

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  10. “BTW. Most physicians are loathed to prescribe Gabapentin for anything other than diabetic nerve pain or possibly restless leg syndrome.”


    You should see the ‘other medications’ section on the BenzoBuddie’s site; neurontin is prescribed *all the time* off label.

    My shrink prescribed it to me for my ‘bipolar’…

    Handed out like candy from where I’m sitting. Not unlike benzos, ADs and opiates.

    humanbeing, RN

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      • No

        I did not see that it did anything at all. How would I have known, as I was taking 3 other meds???

        Just one of the many my shrink had me on, trying to ‘find the right combination’ while not recognizing that it was the drugs that were making me *crazy*.

        I didn’t have a lot of issues quitting the neurontin, but some do…funny, the shrinks never seem to be able to acknowledge the sometimes severe problems of coming off the ‘meds’…and don’t know crap about how to do it safely. It’s always your ‘mental illness’ reoccurring.

        But they sure *do* know how to whip out that prescription pad-and kick you out right at 15 mins cuz the drug rep is in the hall waiting:)

        At this stage in my career, I am convinced that the only ‘modern’ medicine that is truly helpful for the public is emergency medicine.

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      • Neurontin seems to have the least side effects. I take 200-300 mgs a day and it makes a difference for me . I was on buprenorphine and then Suboxone for several years and the only way I could get off was with Gabapentin-neurontin. Guess it works different for everyone, but 6000 mgs is pretty ridiculous. I think Buprenorphine can help someone going into depression, ward off the cycle of thinking that causes anxiety. Rumination was a bad problem for me as I had lost a son and couldn’t stop agonizing over the loss. I couldn’t even grieve. Tried everything and only Buprenorphine enabled me to come to terms and go through the cycle of grief, which btw never ends. This was with only a half of mg.

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  11. “But this idea is even more pernicious because of the lethality of buprenorphine and the fact we are already in the midst of a prescription opioid epidemic.”

    A concern that exists only because of the media. I challenge anybody to look at the statistics and compare opiates (taken alone, and especially non-synthetic) fatality rates to that of psychiatric drugs and to that of alcohol and tobacco. I did it once years ago and concluded that opiates have never deserved the negativity that surrounds them because of the government, the media, and consequently, society.

    The facts:
    1) Opium is a 100% natural chemical that we’ve evolved around so extensively over the millennia that we’re actually born with opiate receptors in our brains.
    2) Few people have ever died from ingesting natural opiates themselves, at any amount.
    3) Virtually all deaths are attributable to interactions with drugs that themselves kill astronomically more people completely on their own.
    4) Liver failure from the acetaminophen (Tylenol) in Vicodin/Norco is responsible for a majority of all deaths attributable to that drug even when drug interactions are included — and the DEA has even admitted on record that it forced drug companies to add the drug to hydrocodone tablets to identify and punish drug abusers.
    5) Unlike alcohol and benzodiazapine withdrawals, opiate withdrawals are virtually harmless, albeit unpleasant.

    Despite all of these facts, opiates have become the evil scourge of our generation, much as LSD and Cannabis were of the previous generation. Yet in all this time you can go to any corner store, grocery store or department store in the country and buy all the alcohol and tobacco you want and nobody can legally stop you from drinking and smoking yourself to death even though those two substances kill over a half a million people a year in the United States. And that’s not including all the people that are killed or otherwise adversely affected by the mind and behavior altering effects of alcohol such as car crashes, domestic assault, murderous rage (and murder), property damage, etc.

    A more reasonable society would ban alcohol and tobacco and if human nature demands mind and behavior altering substances, then legalize opiates and certain psychedelics. Of course, our species does not consists of reasonable societies.

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