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Thread: Low-dose Psilocybin Decreases Cerebral Blood Flow

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    Low-dose Psilocybin Decreases Cerebral Blood Flow 
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    Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin
    Robin L. Carhart-Harris, David J. Nutt et al
    PNAS

    Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
    http://www.pnas.org/content/109/6/2138.full

    Interesting to see a drug normally associated with an increase in thought frequency, creativity etc and "mind expansion" actually decreases CBF...
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    #2
    Bluelighter FlippingTop's Avatar
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    Thanks for posting this.
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    Really interesting.

    It makes me want to think of some possible explanation, since I enjoy mushrooms so much, and find them enlightening.
    Maybe by limiting cerebral blood flow, it "turns off (excess/rational) thinking" and lets one exist in the Now?
    Or it allows connections to be made that otherwise would be overlooked?
    That would be my way of understanding the idea that
    the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
    But I am not certain how close what I am saying is to the quote.
    For instance, what is "unconstrained cognition"?
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    #4
    Theres much debate that psychadelics truly aren't a higher state of consciousness, but indeed a lower, apt to allow random thoughts coming into play free of conditioned place preferenced/latent inhibited thought.

    "the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.
    But I am not certain how close what I am saying is to the quote.

    For instance, what is "unconstrained cognition"? "

    well the method of action partly causes decreased activity in these "connector hubs", the true terminology for that part would be a decreased in calcium dependent gap junction activity..
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    Bluelighter specialspack's Avatar
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    Quote Originally Posted by sekio View Post
    Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin
    Robin L. Carhart-Harris, David J. Nutt et al
    PNAS


    http://www.pnas.org/content/109/6/2138.full

    Interesting to see a drug normally associated with an increase in thought frequency, creativity etc and "mind expansion" actually decreases CBF...
    I'm surprised this hasn't already been discussed on here, maybe I just missed it... the big problem with this data is that it shows the opposite of what Vollenweider's group got - their PET scans showed increases in labelled glucose metabolism.

    The Imperial group have done a follow up study using MEG, which I believe supports the fMRI results although it's not yet been published.

    Vollenweider's explanation:
    “We have completed a number of similar studies and we always saw an activation of these same areas,” says Franz Vollenweider at the University of Zurich in Switzerland. “We gave the drug orally and waited an hour, but they administered it intravenously just before the scans, so one explanation is that the effects were not that strong.”
    http://www.nature.com/news/psychedel...tivity-1.9878#

    - seems pretty poor, but then so does the Imperial group's (from the paper sekio linked):

    The effect of psilocybin on resting-state brain activity has been measured before with PET and glucose metabolism (. This study found a global increase in glucose metabolism after oral psilocybin, which is inconsistent with our fMRI results. One possible expla- nation for this discrepancy relates to the fact that the radiotracer used to measure glucose metabolism (18F-fluorodeoxyglucose) has a long half-life (110 min). Thus, the effects of psilocybin, as measured by PET, are over much greater timescales than indexed by our fMRI measures. It is therefore possible that phasic or short- term effects of psilocybin show some rebound that is detected by longer-term changes in glucose metabolism.
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    I know the two states are not totally comparable, but it makes me think of a near death experience. When the brain is deprived of oxygen there can be psychedelic-like experiences. Although oxygen saturation remains high enough to maintain life, maybe the slight reduction from the mushrooms causes other neural mechanisms to activate that normally wouldn't be there?

    Quote Originally Posted by polarbearsarecool
    Theres much debate that psychadelics truly aren't a higher state of consciousness, but indeed a lower, apt to allow random thoughts coming into play free of conditioned place preferenced/latent inhibited thought.
    I'm not sure I agree with this. Think about substances like DMT. It can cause profound, life-altering psychedelic experiences, yet it is a neurochemical that is released when the brain is on death's door (i.e. the least metabolically active). It's possible that placing the brain into a lower metabolic state activates or enhances mechanisms that are not active in the absence of duress or stimulation. So it's not a matter of lower or higher, but certain things switching on in different metabolic states.
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    Quote Originally Posted by polarbearsarecool View Post
    well the method of action partly causes decreased activity in these "connector hubs", the true terminology for that part would be a decreased in calcium dependent gap junction activity..
    I don't follow this at all. How does reduction in the BOLD signal reflect gap junction activity? Why calcium modulated?
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    This seems to somewhat explain why some 5-ht2a agonists reset and sometimes elongate the length of the interval of recurrence of cluster headaches.
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    #9
    This makes total sense, if you think of the anterior cingulate cortex and medial prefrontal cortex as the brains "Filter" decreasing blood flow to them would allow the free thinking we get see with psychedelics
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    It also enhances visual accuity. Relation?
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    Quote Originally Posted by Apostacious View Post
    This seems to somewhat explain why some 5-ht2a agonists reset and sometimes elongate the length of the interval of recurrence of cluster headaches.
    Could you elaboate on this? I'm not seeing the connection.
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    #12
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    Quote Originally Posted by Foreigner View Post
    Could you elaboate on this? I'm not seeing the connection.
    The assumption being that reduction of cerebral blood flow would reduce the dilation of blood vessels pressing on the trigeminal nerve - the proximal cause of cluster headaches.
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    Quote Originally Posted by Thou View Post
    It also enhances visual accuity. Relation?
    Where is the evidence for this? This is a claim McKenna put forward that has since entered into drug myth, and as far as I am aware is unsubstantiated - see:

    http://www.bluelight.ru/vb/threads/1...y-psychedelics
    Last edited by specialspack; 28-09-2012 at 21:22.
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    #14
    why did they specify low dose ? is that just because they only did the experiment with a low dose ?
    Do the results suggest a high dose would be any different ?
    Also, would lower blood flow explain psilocybin helping reduce cluster headaches ?

    Great post by the way, I do a lot of mushrooms so it's good to have info like this.
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    Quote Originally Posted by webbykevin View Post
    why did they specify low dose ? is that just because they only did the experiment with a low dose ?
    Do the results suggest a high dose would be any different ?
    Also, would lower blood flow explain psilocybin helping reduce cluster headaches ?

    Great post by the way, I do a lot of mushrooms so it's good to have info like this.
    The title of this thread is a little misleading I think. Subjects in this study (all experienced with psychedelics) received 2mg of psilocybin IV. This is generally thought to equate to a moderate dose of oral psilocybin. Certainly the subjects reported quite strong effects.
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    #16
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    Is oral psilocin's BA really that low? I was under the impression that anything less than 5mg is low dose, 5-20 medium dose, 20+ high, when admin orally. (at least this is for the esters.. 4aco in particular)

    Either way 2mg of a tryptamine is not very much!
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    #17
    Quote Originally Posted by sekio View Post
    Either way 2mg of a tryptamine is not very much!
    unless you're a rat
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    #18
    Psychedelics and Brain Imaging - Dr Robin Carhart-Harris

    http://vimeo.com/41094552


    cheers
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    Quote Originally Posted by sekio View Post
    Is oral psilocin's BA really that low? I was under the impression that anything less than 5mg is low dose, 5-20 medium dose, 20+ high, when admin orally. (at least this is for the esters.. 4aco in particular)

    Either way 2mg of a tryptamine is not very much!
    According to Hasler et al (1997), BA of psilocin after oral psilocybin dosing was estimated at 52.7 +/- 20%.

    2mg was chosen as the dose after a tolerability study (Cahart-Harris et al, 2011), where they claim, using the ASC scale to rate intensity of experience:

    Global and subscale ratings were generally lower for subjects administered 1.5 mg, but not to a statistically significant degree. At 1.5 mg, the mean global rating was roughly consistent with ratings previously recorded after a ‘low’ oral dose of psilocybin (i.e. ~8 mg), and at 2mg, mean global ratings were roughly consistent with ratings recorded after a ‘medium’ oral dose of psilocybin (i.e. ~15 mg) (Hasler et al., 2004)
    There were actually a few bits of video interview floating around with the subjects describing the experiences - I'll see if I can find them, but they talk about 5-10 minutes of fairly strong open eye visuals, typical psychedelic mindstates etc.

    It would be great if someone could repeat the fMRI experiments with oral dosing - ideally with simultaneous fMRI/PET...

    Refs:

    Hasler et al 1997 - Determination of psilocin and 4-hydroxyindole-3-acetic acid in plasma by HPLC-ECD and pharmacokinetic profiles of oral and intravenous psilocybin in man - http://www.ncbi.nlm.nih.gov/pubmed/9204776

    Hasler et al 2004 - Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study - http://www.ncbi.nlm.nih.gov/pubmed/14615876

    Carhart-Harris et al 2011- The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability - http://www.ncbi.nlm.nih.gov/pubmed/20395317
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    #20
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    Quote Originally Posted by Foreigner View Post
    Think about substances like DMT. It can cause profound, life-altering psychedelic experiences, yet it is a neurochemical that is released when the brain is on death's door (i.e. the least metabolically active). It's possible that placing the brain into a lower metabolic state activates or enhances mechanisms that are not active in the absence of duress or stimulation. So it's not a matter of lower or higher, but certain things switching on in different metabolic states.
    I've read Rick Strassman's book. I also listened to a few interviews re. his book in which he expressed his frustration at those who read 'The Spirit Molecule' and walked away with the idea that dimethyltryptamine is an endogenous neurotransmitter secreted by the pineal gland during key moments of personal significance, e.g., death. As far as I'm aware, there is absolutely no evidence that this is the case.
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    ^ thank you for that PA, as I was just reading through this thread that is what jumped out at me as complete hogwash. . .

    Funny how much people have glommed onto that idea.
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