Commenting on the Kastrup-Imperial College Debate: Part 2

While the majority of the general public has never had experiences with psychedelic compounds, by contrast, coffee is one of the most ubiquitously ingested beverages throughout the world. One of the main reasons for this is due to the stimulatory effects of the chemical caffeine which is found in coffee beans. Many people claim that their brain doesn’t feel “primed” or “ready to go” until they’ve ingested their morning brew. A 2018 fMRI study in Scientific Reports observed that 200 mg of caffeine effected 60 caffeine-naïve human subjects by creating a widespread increase in resting brain entropy.

The definition of entropy is the measurement of the variety of configurations possible within a system. Brain entropy is defined as the number of neural states a given brain can access. A 2018 fMRI study in PLOS One observed the level of resting brain entropy of 892 human subjects and found that greater entropy positively correlated with intelligence. From the study: “This relationship between high brain entropy and high intelligence indicates an essential role for entropy in brain functioning. It demonstrates that access to variable neural states predicts complex behavioral performance, and specifically shows that entropy derived from neuroimaging signals at rest carries information about intellectual capacity.”

Based on the conclusions of both studies, it’s intriguing that caffeine would have such an effect on the processing potential of the brain coinciding with the internalized perception of “alertness”. It’s also quite interesting to observe that much like all serotonergic psychedelics (DMT, Ayahuasca, Psilocybin, LSD) significantly decrease alpha oscillatory strength, a 2002 study in Neuropsychobiology and a 2012 study in Neuropharmacology also observed decreases in alpha strength from caffeine. Even more interesting (based on part 1 of this series), is the results of a 2012 study in the Journal of Caffeine Research in which it was found that caffeine increased gamma-band power compared with placebo control in both low-gamma (30–50 Hz) and high-gamma (50–80 Hz) bands.

What about the effects of caffeine on cerebral blood flow?

A 2009 fMRI study in the journal Human Brain Mapping tested the effects of caffeine on cerebral blood flow (CBF). It was found that caffeine decreased cerebral blood flow by an average of 27%. Similar reductions of CBF were observed in other fMRI-caffeine studies as well (Life Sciences - 1990, Physiological Measurement - 2004, Journal of Cerebral Blood Flow & Metabolism - 2013).

Oxygen extraction fraction (OEF) represents the fractional amount of oxygen extracted from the arterial blood by the surrounding tissue during its passage through the capillary network. A 2017 study in the Journal of Cerebral Blood Flow & Metabolism measured the changes in OEF and CBF following caffeine ingestion. Much like the earlier studies cited above, caffeine induced a decrease of CBF by roughly 30%. However, an increase in OEF of roughly 30% “suggests that the cerebral metabolic rate of oxygen (CMRO2) remains stable between normal and challenged brain states for healthy subjects”. Similarly, a 2009 study published in Neuroimage found that while 200 mg of caffeine induced a 35% decrease in CBF, CMRO2 rate (oxygen metabolism) did not change. This led the researchers to state: “A calibrated-BOLD methodology using R2* is a promising approach for evaluating CBF and CMRO2 changes in response to pharmacological interventions.”

A 2013 rat study in The Journal of Neuroscience Methods observed that increased brain entropy positively associated with functional connectivity between brain regions and could be estimated by analysis of gamma oscillatory power. A 2018 study in the journal Chaos observed that increased entropy-complexity coincided with imagery tasks associated with gamma band activity. From the study: “The elevated complexity during the visuomotor or imagery task arises mostly from the activity of high frequency bands (beta 1, gamma 1, and gamma 2) than from the intermediate frequency bands (theta and alpha), showing that complexity is not just a property of the low frequency components of the spectrum.”

What does any of this have to do with psychedelics and the debate between Kastrup and the Imperial Team?

Nothing… yet everything.

Dr. Kastrup’s presentation of data attempts to frame that psychedelics induce decreased cerebral blood flow indicating decreased metabolism alluding to a disconnect from materialists’ explanatory mechanisms. This seems like an interesting perspective at first glance but when taking into consideration wider data points and looking at the effects of other commonly ingested substances such as “caffeine”, one might begin to question the “mainstream” interpretation of fMRI brain imaging as a whole. We’re not questioning the data but rather the interpretation of the data. The studies regarding OREF and CBF indicate that it is possible to have significantly altered CBF that doesn’t intrinsically mirror changes in metabolism. Since the fMRI studies involving psychedelics didn’t measure OREF, it’s not clear whether metabolic activity is altered regardless of changes to CBF. Another example of stable metabolism in the face of decreased CBF is during cerebral hypoxia induced via hyperventilation. A number of studies indicate that there is no change in metabolism based on simultaneously measuring increases in OREF (Journal of Neurosurgery - 2000, Journal of Neurosurgery - 2002, Journal of Cerebral Blood Flow & Metabolism - 2002).

This is an example of why we believe that arguments based on the results of scientific studies must be cognizant of the limitations of the correlates utilized… in this case cerebral blood flow. CBF is a known proxy for neuronal activity but it is clear that it does not always reflect metabolic changes. In fact, later on this piece we will link to a study that observed an evoked fMRI BOLD response without neuronal activation modulation. Decreased CBF doesn’t always equate to “loss of ability” based on examples of increased entropy occurring synchronously with reductions in CBF. We believe that biomarkers of measurable endpoints such as increased entropy coinciding with increased intelligence are key points to focus on when analyzing brain data. If entropy can lead to greater potential abilities or perceptual changes, the measurable correlates of entropy should be identified. What good is CBF as a measurement of brain activity when information such as processing potential, entropy alterations, oscillatory changes, metabolic shifts, and neural activity induced by pharmacological interventions cannot be accurately deciphered without extensive interpretation/filtration? CBF can be taken into account when analyzing brain data but to attempt to frame it as the primary data point for accurate assessment of neurological activity is misguided at best.

If the “mainstream” scientists of today have not yet mapped out the mechanistic correlates (it’s possible they have) between caffeine ingestion, decreased CBF, receptor affinity, biochemical cascade effects, increased entropy, decreased alpha waves, increased gamma waves, and the overall experiential effects of coffee… it is obviously a stretch to request them to explain the cerebral effects of psychedelic experiences. Under the guise of what Kastrup is presenting, it seems plausible that one doesn’t even need to point to the confounding effects of hallucinogens in order to perplex a certain group of materialists in terms of brain imaging. While it’s likely that Kastrup will protest caffeine claiming it to be incomparable to psychedelics… let us remind him that the conversation revolves around administering substances to humans and monitoring changes in brain activity/imaging. One surely cannot be expected to explain the effects of psychedelics without first explaining the effects of coffee…

(Another commonly ingested substance… alcohol has been observed to induce significant changes in cerebral blood flow. Multiple studies indicate that alcohol ingestion leads to increases in cerebral blood flow (Journal of Studies on Alcohol & Drugs - 1993, Alcoholism: Clinical and Experimental Research - 2012, Alcohol & Alcoholism - 2013, Psychopharmacology - 2015). This is yet another example of potentially “mainstream” counterintuition when comparing the sedative effects of alcohol occurring synchronously alongside increased CBF versus the stimulatory effects of caffeine coinciding with decreased CBF.)

While our focus in Part 1 was in regards to providing multiple points of evidence indicating decreases in slow oscillatory activity and increases in fast oscillatory activity is par for the course in terms of psychedelic administration, the added concept of entropy is intriguing. A 2017 fMRI study in the journal Scientific Reports observed that Ayahuasca ingestion induced a significant increase in brain entropy. We don’t find it surprising that Ayahuasca has also been observed to increase gamma oscillatory power in multiple studies.

A 2016 fMRI study in the journal Human Brain Mapping observed that “LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales”. We don’t find it surprising that LSD has also been observed to increase gamma oscillatory activity.

A 2014 write-up by Dr. Robin Carhart-Harris in Frontiers in Human Neuroscience noted that psilocybin induced an increase in brain entropy. In this case we also don’t find it surprising that psilocybin has been observed to increase gamma oscillatory power in multiple studies.

Are we starting to see “broad patterns” here people?

“Comparing visionary to placebo state is best based on a comparison of time-averaged mean CBF (metabolism) for each condition, I think.” - Kastrup

We’re not exactly sure how Dr. Kastrup has come to this conclusion. It is our opinion that there is no “best” being that all the equipment utilized to study the brain (EEG/MEG/fMRI/PET/CT/NIRS) has it’s strong points and limitations in one form or another. Whether a handful of mainstream neuroscientists are excited about a specific gadget is irrelevant to our initiative to identify “broad patterns” by looking at “data as a whole”. It is our perspective that all quality data from all brain research equipment should be valued and patterns should be noted if possible. We cannot pick and choose which data we feel is more important than others. We can only do our homework in terms of looking at the widest body of quality data and see if any patterns emerge. Ultimately how the data is weighed is based on A) the number of studies, B) the number of subjects within these studies and C) the consistency of results.

Thus far, Kastrup has presented the decrease in CBF during altered states as deviating from the mainstream scientific perspective of how the brain “should” operate. In the past he has cited neuroscientist Dr. Christof Koch’s reaction to the 2012 psilocybin fMRI study results as an example of surprise at the finding. We must admit that citing mass/mainstream consensus or expertise/authority has never been our forte since we’ve observed consistent perspective based flaws from many “leaders” in various fields. It appears that scientific research in modern times has become overly specialized in the sense that many researchers are relatively unaware of data in periphery fields. Without being exposed to the information of periphery fields, it seems increasingly difficult to make sense of what one is looking for within their own specialized branch of research. However, we do believe that Dr. Kastrup does deserve a materialist based explanation in terms of the mechanisms for the deviation of projected neural activity imaging from psychedelics. It doesn’t appear that many of the mainstream researchers with which he engages with have done this so far.

In 2017, Kastrup would publish a write-up titled, “Self-Transcendence Correlates with Brain Function Impairment” in the Journal of Cognition and Neuroethics. In this piece, he presented various forms of activity that he associates with brain function impairment (cerebral hypoxia, generalized physiological stress, electromagnetic impairment, trance induced impairment, chemical impairment, & physical damage).

The formal definition of the term “impairment” regarding physiology is as follows: any loss or abnormality of physiological, psychological, or anatomical structure or function, whether permanent or temporary. It seems that Kastrup’s perspective is focused on presenting the perspective of loss of physiological function while our perspective is based on presenting an abnormality of function. Loss of function is implicitly negative as it pertains to neurology while abnormality of function is not implicitly negative or positive… it is simply just that… abnormal.

It is our opinion that it is best to refrain from labeling brain function as “impaired” or “enhanced” until we analyze the effects and after effects of the experience. We do not consider all altered states to coincide with a loss of brain function. In fact, we believe some “altered” states are actually indicative of “enhanced” brain function in which measurable, quantitative abilities and benefits are amplified (example: effects of increased entropy/intelligence). In other cases, we agree that loss of function does take place when unequivocal injury or danger to the brain occurs. However, we must remain cognizant of the fact that following acute injury, autonomic regenerative processes occur that can potentially play a key role in altered experiences. For example, a 2016 study in Frontiers in Neuroscience observed that the endogenous hallucinogen, DMT, diplayed potent protective mechanisms against hypoxia in human cortical neurons and microglia-like immune cells. This leads us to hypothesize that the endogenous protective mechanisms to alleviate physical damage and induce regeneration might also coincide with “visionary” states during acute injury. While DMT undoubtedly acts as a hallucinogen when ingested at doses above 0.2 mg/kg, there lies the possibility that it also plays a much more subtle and versatile endogenous role as other researchers have alluded to. This is why we prefer to refer to all of these states as “altered” coinciding with “altered brain activity” deviating from the norm.

In Part 1, we presented 7 EEG studies published in peer-reviewed journals and 1 yet to be published study that observed increases in gamma oscillations following the ingestion of psychedelics. However in Kastrup’s pieces, he utilizes primarily fMRI data from psychedelic studies which for the most part observe decreases in cerebral blood flow which constitutes his stance of “less brain activity”.

The question that follows… who is correct?

Q4LT’s perspective is quite straight forward… according to the current data (2018), serotonergic psychedelics coincide with overall decreased cerebral blood flow and increased gamma oscillatory activity. Both factors are clear correlates to the visionary experience being that these are two clear consistencies observed from 4 fMRI studies and 8 EEG studies.

The next question is… how can this be?

Based on the literature it appears as though there are some clear pathways that have been discovered. The serotonergic based psychedelics have been observed to create their effects by stimulating the 5-HT2A receptors in the brain. This has been confirmed by in vitro studies as well as in vivo studies in which the 5-HT2A antagonist (ketanserin) blocks the psychedelic effects as well as reversing the oscillatory changes from them. The stimulation of the 5-HT2A receptor on GABAergic interneurons induces stimulation of GABA release which induces inhibition of neural activity. GABA levels in the anterior cingulate cortex effectively predict changes in whole-brain cerebral blood flow. The increase in GABA levels are inversely correlated with BOLD signaling inducing a global decrease in CBF. In synchronous fashion, the inhibition of interneuronal activity has been observed to directly coincide with gamma oscillatory activity. We’ve already outlined in Part 1 that gamma oscillatory activity appears to be key in terms of visual processing, especially in the visual cortex. We don’t feel that this alteration in visual processing is detached from increased brain entropy associated with increased functional connectivity as a measure of gamma waves.

An interesting write-up in the journal Neuroscience and Biobehavioral Reviews outlined key issues regarding the interpretation of BOLD signaling. One of the main issues presented is that increased BOLD signal may reflect reduced deactivation, increased activation, or both. In the same vein decreased BOLD signal can reflect increased deactivation, decreased activation, or both. The balance between neuronal excitation and neuronal inhibition can effect BOLD response in non-linear manners. This is important in the sense of observing the relationship between glutamate (an excitatory neurotransmitter) and GABA (an inhibitory neurotransmitter) levels. While GABA levels are increased from serotonergic psychedelics, glutamate levels are also increased. Both GABA and glutamate have been observed to distinctly modulate gamma oscillations. There lies the possibility that psychedelics induce predominantly neuronal inhibition while simultaneously inducing excitatory activity to a lesser extent reflecting the BOLD signal changes.

The only question one might have is what does decreased strength in slower oscillatory power and increased strength in fast oscillatory power mean in the face of decreased cerebral blood flow?

In our view, it means that there is currently an aspect of brain imaging and mechanics that is not well integrated. This is no surprise being that scientific exploration is never stagnant and certain “layers” of the brain such as astrocytes are currently lacking in mainstream discussion. It’s been estimated that adult human brains contain tens of billions of astrocytes with each of these star-shaped cells contacting up to 2 million synapses. Over the past 20 years, it’s been established that astrocytes play key roles in signaling throughout the brain, regulate cerebral blood flow, modulate gamma oscillations/recognition memory, maintain energy demand of neurons as well as the supply of nutrients/oxygen, and influence bi-directional blood flow at blood vessels. A 2018 study in the journal Glia observed unexpected BOLD signal generation without neuronal excitation. This led the researchers to hypothesize regarding the presence of another cellular source for BOLD signal generation. From the study: “Unexpectedly, astrocyte-evoked BOLD signal accompanied oxygen consumption without modulation of neuronal activity. Our data provide causal evidence that astrocytic activation alone is able to evoke BOLD signal response, which may lead to reconsideration of current interpretation of BOLD signal as a marker of neuronal activation.”

Seems important… no?

A 2016 write-up in PLOS One presented a new computational model for neuro-glio-vascular coupling. The researchers cite that while CBF measurement is useful, it is limited in terms of deciphering mechanisms from the variables underlying neurovascular coupling. From the study: “We showed a predominant neuronal contribution for low level discharges and a significant astrocytic contribution for higher level discharges. Besides, neuronal contribution to CBF was linear while astrocytic contribution was nonlinear. Results thus indicate that the relationship between neuronal activity and CBF magnitudes can be nonlinear for isolated events and that this nonlinearity is due to astrocytic activity, highlighting the importance of astrocytes in the interpretation of regional recordings.”

This paper is interesting regarding the citation of predominant neuronal contribution for low level discharges and a significant astrocytic contribution for higher level discharges. We believe that the reference to “low level discharges” correlates with slow wave oscillations (theta/alpha) while the reference to “high level discharges” correlates with gamma waves. This essentially insinuates that physiological, mechanical adjustments are made once threshold’s are reached since neuronal low level discharge is linear while higher level discharges are not. From our research, this is rather consistent when studying the adaptive mechanisms of the body. For example, following neuronal stimulation or astrocyte calcium ion uncaging, moderate increases in astrocyte intracellular calcium levels correlate with dilation but large increases correlate with vasoconstriction. The other alternative is that cerebral blood flow continues to increase indefinitely in conjunction with intensity of experience eventually leading to a syndrome called… “brainexplosionitis”.

One of the interesting conversations regarding reduced CBF and astrocyte signaling has to do with hypoxia. Unlike neurons which rely on oxidative metabolism, astrocytes rely mainly on glycolysis allowing them to function normally in low oxygen environments. This is why it seems imperative that astrocyte function pertaining to the psychedelic experience (or even all mystical states) is fully explored being that these experiences correlate with sustained decreased CBF. The fact that astrocytes appear to be intimately involved with non-linear influences on CBF, contribute to high level discharges, and the modulation of gamma oscillations leads us to believe that research in this specific field might offer answers into “visionary” states.

For some additional perspective, ketamine is a hallucinogen but isn’t serotonergic but rather an antagonist of the N-methyl-D-aspartate (NMDA) receptor. There are multiple studies showing that Ketamine induces increases in cerebral blood flow (Anaesthesia - 1995, Anaesthesiology - 2003, Anaesthesiology - 2005, Psychopharmacology - 2015). There are also studies observing very similar oscillatory activity from ketamine as the oscillatory activity from serotonergic hallucinogens in terms of decreases in slow bands (alpha/theta) and increases in gamma (Clinical Neurophysiology - 2016, Frontiers in Pharmacology - 2016, Translational Psychiatry - 2017). In terms of the perspective Kastrup has presented, it would appear that ketamine “lines up with materialism” based projections of how the brain should work based on the increases in CBF coinciding with hallucinations. From our perspective, (we hope that it’s quite clear by now) this is much too simplistic of a working model of the brain and the mechanisms of abnormal experiences… the key word is abnormal. It is quite clear that different substances affect the brain through different pathways of receptor affinity leading to differential cascade effects coinciding with the experience. Attempting to extract precise information when using raw CBF as a foundation for analysis is futile when used singularly. Based on inconsistent and inconclusive information regarding CBF, we are more interested in actualized endpoints like functional connectivity, entropy, and oscillatory changes that coincide with perceptual changes. This is why when Dr. Kastrup states, “comparing visionary to placebo state is best based on a comparison of time-averaged mean CBF (metabolism) for each condition, I think”… we reply with… “we think you are incorrect and have provided evidence to support this claim”.

We believe neuroscience is still truly in it’s infancy and that the interpretation of data from all imaging devices should be carefully examined against each other in normal and abnormal states.

(A 2016 study in Brain Research observed the effects of methamphetamine and cocaine on the brains of rats. It was found that each drug induced opposite BOLD signals when measured via fMRI. This is yet another example of similar compounds inducing differential cascade effects effecting CBF while maintaining comparable experiences. Once again, CBF is not a useless correlate of neurological activity… just limited.)

In terms of the suppression of slow oscillatory and increased fast oscillatory activity from serotonergic psychedelics… we would like to utilize a metaphor as to how it could account for the experience.

Let’s say that 100 people run a 1 mile race. The average speed of the finish time for the group is 12 minutes. The top 10 racers finish the race with an average speed of 5 minutes while the 10 slowest racers finish the race in 25 minutes. If we were to discard the 90 slowest people in the group of the race, the average speed of the finish time drops from 12 minutes to 5 minutes.

We believe this could be akin to what is taking place in the brain during psychedelic experiences… processing speed increases due to the suppression of slow waves and increase in fast waves. If the majority of oscillations within the brain are of a speed faster than normal waking consciousness, it would indeed be labeled as abnormal (a derivative of “impairment”). It doesn’t necessarily mean that a “loss of function” is taking place but simply abnormal processing speed is being observed coinciding with an abnormal experience.

This overall discussion of mechanisms do not deviate from the perceived mechanisms of the brain because they are just that… documented mechanisms observed via scientific methodology. Whether a few mainstream scientists are aware of these mechanisms or not is irrelevant to the general field of scientific research that is publicly available. With all due respect to Kastrup and Dr. Koch… what Dr. Koch believed 6 years ago in terms of neuroimaging is entirely irrelevant to the field of neuroscience in 2019 and beyond.

The amusing thing regarding all of this is… we don’t have a problem with idealism. It’s perfectly fine if idealism is the true underlying philosophy of reality. We just don’t really understand Kastrup’s foray into citing brain imaging studies and antagonizing psychedelic researchers in support of idealism. We believe that whether mechanisms can be deciphered to properly explain an occurrence or not is completely irrelevant to the notion of idealism. In addition, other undeniable occurrences such as the placebo effect offer enough challenges for materialism based discussions regarding the anomalistic effects of “intent” in order to avoid debates regarding neuroimaging equipment output. A recently published piece titled, “26 Controversies & Challenges in fMRI” by Dr. Peter Bandettini offers additional discourse for questioning the interpretation of fMRI BOLD signaling. While Kastrup might object to these types of debates regarding fMRI imaging as a way for materialists to “claim a different mapping to make sense of different experimental observations”… this is simply the nature of mechanistic discussions. A true materialist scientist (which we are definitely not) will always believe that a rational, materialistic based mechanism can explain occurrences from a materialistic perspective. This is a scientist essentially fulfilling their duties as a… scientist. While Kastrup might claim that this is akin to “internally-contradictory bullshit ” akin to changing the rules of the game while you are playing it… we see no issues with researchers continuing to develop theories that build upon more updated knowledge. Our interjection within this conversation is simply based on what we believe to be incomplete projections and interpretations of how the brain is operating during transcendental states.

(An example of researchers continuing to develop theories based on more updated knowledge is the genetic correlation with disease. Initially it was believed that genetic expression was fixed and disease was inevitable for those with the incorrect expression(s). This mental framework dominated research and the mentality of medical practitioners. However, in the 1990’s the emerging field of epigenetics began to realize that internal and external environmental factors played key roles in the manner in which genes were expressed. In essence, the initial belief was incorrect and has continued to evolve over time as more information is generated in the field of genomics and epigenetics. However, that doesn’t automatically equate to all researchers and medical practitioners to operating with this relatively newfound knowledge. This is why it’s important to be cognizant of who you are discussing certain issues with… they could possibly not be as up to date as they could be.)

From everything we have researched, accessing mystical states are very replicable and there are certain underlying mechanics that remain quite consistent amongst them all. However, if we simply relied on CBF and fMRI imaging to decipher the mechanics of replicability… we’d be completely at a loss. We… like Kastrup might just observe a consistent decrease in CBF and shrug our shoulders in perplexment. This is why we believe that all equipment should be utilized to study the brain and properly integrated in order to better understand strange occurrences. Dr. Joe Dispenza claims to have completed over 8,500 EEG brain maps of participants at his workshops. He states that at this point he and his team are extremely capable of identifying the pre-cursor activity to mystical states… regardless of lacking any “peer-reviewed” material… we believe him.

E-mail me at q4lt00@gmail.com for any questions or comments regarding this piece.