Neurophilosophy is covering the history of psychedelic psychiatry, while Mind Hacks provides a personal look at one particular drug, DMT. The Neurocritic discusses ketamine, an anesthetic with hallucinogenic properties, which is attracting a lot of interest at the moment as a treatment for depression.
Ketamine, however, is not a "classical" psychedelic like the drugs that gave the 60s its unique flavor and left us with psychedelic rock, acid house and colorful artwork. Classical psychedelics are the focus of this post.The best known are LSD ("acid"), mescaline, found in the peyote and a few other species of cactus, and psilocybin, from "magic" mushrooms of the Psilocybe genus. Yet there are literally hundreds of related compounds. Most of them are described in loving detail in the two heroic epics of psychopharmacology, PIKHaL and TIKHaL, written by chemists and trip veterans Alexander and Ann Shulgin.
The chemistry of psychedelics is closely linked with that of depression and antidepressants. All classical psychedelics are 5HT2A receptor agonists. Most of them have other effects on the brain as well, which contribute to the unique effects of each drug, but 5HT2A agonism is what they all have in common.
5HT2A receptors are excitatory receptors expressed throughout the brain, and are especially dense in the key pyramidal cells of the cerebral cortex. They're normally activated by serotonin (5HT), which is the neurotransmitter that's most often thought of as being implicated in depression. The relationship between 5HT and mood is very complicated, and depression isn't simply a disorder of "low serotonin", but there's strong evidence that it is involved.
There's one messy detail, which is that not quite all 5HT2A agonists are hallucinogenic. Lisuride, a drug used in Parkinson's disease, is closely related to LSD, and is a strong 5HT2A agonist, but it has no psychedelic effects. It's recently been shown that LSD and lisuride have different molecular effects on cortical cells, even though they act on the same receptor - in other words, there's more to 5HT2A than simply turning it "on" and "off".
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How could psychedelics help to treat mental illness? On the face of it, the acute effects of these drugs - hallucinations, altered thought processes and emotions - sound rather like the symptoms of mental illness themselves, and indeed psychedelics have been referred to as "psychotomimetic" - mimicking psychosis.
There are two schools of thought here: psychological and neurobiological.
The psychological approach ruled the first wave of psychedelic psychiatry, in the 50s and 60s. Psychiatry, especially in America, was dominated by Freudian theories of the unconscious. On this view, mental illness was a product of conflicts between unconscious desires and the conscious mind. The symptoms experienced by a particular patient were distressing, of course, but they also provided clues to the nature of their unconscious troubles.It was tempting to see the action of psychedelics as a weakening of the filters which kept the unconscious, unconscious - allowing repressed material to come into awareness. The only other time this happened, according to Freud, was during dreams. That's why Freud famously called the interpretation of dreams the "royal road to the unconscious".
Psychedelics offered analysts the tantalizing prospect of confronting the unconscious face-to-face, while awake, instead of having to rely on the patient's memory of their previous dreams. To enthusiastic Freudians, this promised to revolutionize therapy, in the same way that the x-ray had done so much for surgery. The "dreamlike" nature of many aspects of the psychedelic experience seemed to confirm this.
Not all psychedelic therapists were orthodox Freudians, however. There were plenty of other theories in circulation, many of them inspired by the theorists' own drug experiences. Stanislav Grof, Timothy Leary and others saw the psychedelic state of consciousness as the key to attaining spiritual, philosophical and even mystical insights, whether one was "ill" or "healthy" - and indeed, they often said that mental "illness" was itself a potential source of spiritual growth.
Like many things, psychiatry has changed since the 60s. Psychotherapy is currently dominated by cognitive-behavioural (CBT) theory, and Freudian ideas have gone distinctly out of fashion. It remains to be seen what CBT would make of LSD, but the basic idea - that carefully controlled use of drugs could help patients to "break through" psychological barriers to treatment - seems likely to remain at the heart of their continued use.
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The other view is that these drugs could have direct biological effects which lead to improvements in mood. Repeated use of LSD, for example, has been shown to rapidly induce down-regulation of 5HT2A receptors. Presumably, this is the brain's way of "compensating" for prolonged 5HT2A activation. This is probably why tolerance to the effects of psychedelics rapidly develops, something that's long been known (and regretted) by heavy users.
Vollenweider and Kometeris note that this is interesting, because 5HT2A blockers are used as antidepressants - the drugs nefazadone and mirtazapine are the best known today, but most of the older tricyclic antidepressants are also 5HT2A antagonists. Atypical antipsychotics, which are also used in depression, are potent 5HT2A antagonists as well.
So indirectly suppressing 5HT2A might be one biological mechanism by which psychedelics improve mood. However, questions remain about how far this could explain any therapeutic effects of these drugs. Psychedelic-induced 5HT2A down-regulation is presumably temporary - and if all we need to do is to knock out 5HT2A, it would surely be easiest to just use an antagonist...
Vollenweider FX, & Kometer M (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11 (9), 642-51 PMID: 20717121
16 comments:
"Depression isn't simply a disorder of "low serotonin", but there's strong evidence that it is involved."
Only in a minority of patients. For most people exercise, healthy diet, and going out with friends is more likely to cure depression than taking pills to mess with serotonin levels. And for up to a third of people depression seems to be caused by low levels of inflammatory protein, i.e. the cytokine theory of depression. And for a bunch of other people depression seems to be caused by nutritional imbalances, like say a lack of magnesium.
It seems like while there may be some people with depression that is caused by some sort of chemical imbalance in the brain, that percentage is very small. And of those, it doesn't even seem like it's necessarily low serotonin that's the problem.
Rumor has it that Timothy Leary's ashes are orbiting the earth. I think he just decided to drop in on Neuro's blog. Yeah, let's give depressed and other MI patients psychedelics. That'll certainly solve the problem, just as it did for Leary and his ilk. With the exception of melancholia, "depression" is caused mostly by negative thinking (conscious and unconscious) and irrational guilt (good old super ego bashing a la Freud).
Ooooh Anonymous #2 sounds like a fun debate. "Depression is caused by negative thinking."
Wow that's a sweeping statement! Here we can have that whole really fun conversation of where do thoughts originate? If thoughts are a biological process than do the thoughts themselves cause brain changes, or do brain changes cause a difference of thought patterns?
We know from brain injuries that for sure, changes in the brains funtioning can change thought patterns. So the question of "human will" and does it exist in the way we think of it becomes rather pertinent when thinking of cause/cure for a disorder of thought patters as you term it.
There is no evidence that will exists or doesn't exist (correct me if I'm wrong, I'd LOVE to see such research!). Who was it, Stephen Hawking who believed that if we developed tools that could measure predicted outcomes precisely enough than we could predict all human behavior and all events in the future, with the possiblity of complete accuracy if our measuring devices ever achieved perfection (unlikely to ever happen).
The point being, does a person think "negatively" as a choice or as a result of life circumstances, or biological phenomenon in their brain? Are the percieved biological brain differences we observe in "depressed" vs. "non depressed" people the cause of, or the result of negative thinking?
And further could they both be part of a chain reaction in which they both cause and are caused by each other once some life event, situation of stress, biological tendency, choice of thoughts... etc... set them off course?
Sorry neuroskeptic.... not meaning to get off topic but I couldn't help but hit that "depression is caused by negative thought patterns"
I didn't here this post as implying that it would be good for people to take hallucinogens for mental health, it was more a presentation on the pros and cons (I read more cons than pros out of this, but such is my reading)
(oops, sorry about the double post)
Woah that was a mindblowing read, love the diagrams. Thanks Neo (Neuroskeptic) :)
Psychedelics to treat depression, bring it on I say. We need a culture drug in the West that isn't so monopolised.
Hmmm.. 5HT2A.. gosh what was it, I think the military is testing this stuff again.. 2008? still fuzzy but there was about a dozen? new ones they made. I think one of them was either the trigger or cure in a pandemic experiment which led to cruddy, alienish looking corpses.. I dunno.
I don't seem to notice any mention of John C. Lilly's work or self-experimentation with ketamine in the recent resurgence of interest. Maybe because he was a self-proclaimed addict? This would tend to cast a bit of a shadow.
Sorry I meant 1997? well somewhere in the 90s.. not 2008.
"For most people exercise, healthy diet, and going out with friends is more likely to cure depression..."
But those activities raise 5HT, so your point?
I think that depression is a combination of chemicals and insoluble dilemmas. Which comes first, deponent saith not. I can tell you that I have intractable pain from fibromyalgia and several other injuries sustained through my life, and have had a number of concussions, but I don't know if the depression came from that or from familial chemical tendencies or whathaveyou. I only know that it exists and gets worse and better at times.
I have tried everything from acupuncture to vitamins, chiropractic to physical therapy, to fight the pain and the depression. Some medications help, but perhaps it might even be defined as a cognitive habit. I can see where the transformative effect of a psychedelic experience could break through these 'habits' and maybe reset the expectations, the patterns. With the proper help and guidance, I'd certainly be willing to try it, since I'm not of childbearing age and am in considerable mental anguish at times. However, others' mileage may vary -- like, say, the DEA.
Hi there, I would be really interested in speaking to you in regards to this article. Is there any way that we can communicate via email? My email is skimordiegirl@yahoo.com I would like to talk more about 5Ht2a receptors and their role on vision. What happens if they malfunction... can they stop working completely?
Thank you,
Candi
Depression for me is caused by extreme loneliness or there is a sudden happenings in your life that is painful and is hard to forget in a snap as well. You can control depression but if you just keep you pain and you do not release it, chances are you are likely to get more depressed that will result makes you suicidal.
Great thing that the doctors are finding ways to make depression go away like these medications and alternative healing methods that will make us have new and improved holistic health and healing.
"Repeated use of LSD, for example, has been shown to rapidly induce down-regulation of 5HT2A receptors. Presumably, this is the brain's way of "compensating" for prolonged 5HT2A activation. This is probably why tolerance to the effects of psychedelics rapidly develops, something that's long been known (and regretted) by heavy users."
- I have found from personal experience that the common wisdom about LSD tolerance is false and full of holes of understanding. Personally I have tripped for several days in a row with only a little gain in tolerance. This is because addiction is a habituation and psychedelics allow you to see, and if you desire, dissolve the habits formed by the ego-personality.
Depression is withheld knowledge.It usually results from failing to plan for the future.For example you fall in love with someone, invest your entire well being in their existence, then they die. You failed to plan for the unexpected outcome.But by now you based your entire life on acivities that require that person as a catalyst. Remembering who you were before you became addicted to that person(or Thing!!!)constitutes retrieval of lost knowledge. If you do nothing else only remember. We trade knowledge for indentity. This is why the serotonin 2a receptor is so relevant to depression. The information behind that door can only be accessed through loss of identity (ie near death experiences, drug induced hallucinations situations that induce the belief that you have lost everything, drowning etc) Ilike to think of these situations as inducing a condition of perfect virtue. This why moral principles are so important in many religions. If you have nothing to loose God looks beautiful but if you have attachments he looks like the devil. The serotonin 2a receptor is the doorway to all that is angelic and demonic. Essentially it is a door that reveals a mirror in which you see yourself. If you're depressed it because you're struggling to hold out against the subconscious which is made up of all those things we have a deep persoal interest in not being aware of. The solution is a condition of complete sim-plicity costing not less than everything. Absolute surrender to the will of the absolue. The inhibition of the modifications of the mind.
I'll bet Neuroskeptic gets seriously depressed about the quality of these blogposts...
I found out that the new generation of psychedelics called benzydamine or dextrometorphane helps alot in depression and anxiety. I take every 1-2 months and it helps better then escitalopram or alprazolam.
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