10 Biocrisis and Resplendence: Planetary Reflowering

The rape of Gaia – “Mother Earth” – by the patriarchal imperatives of dominion over nature and business-as-usual exploitation is a suicidal insanity running through our cultural mind set, which humanity currently lacks the collective will to alleviate. Intervention for the common good is urgently necessary. For the mind at large to awaken even for a moment and become acutely aware of the carnage wrought upon the planet through the relentless exploitative impact of a single species Homo sapiens, it is obvious that, by its very compassion for the mortal coil it will impart to the beholder urgent tenacity to protect the living planet. This is precisely what I experienced in being galvanised to write these articles after a quantum change experience on sacred mushrooms after a seven year karmic drought, because of closed angle glaucoma. It is critical for our own survival and that of the living diversity of life as a whole.

The Full Scope: Climate Crisis, Mass Extinction. Population and Nuclear Holocaust

Fig 19: (1) World population is predicted to continue to rise through to 2100 (Gerland et al. 2014), with the majority of the increase in sub-Saharan Africa (inset). This will increase the world population to 10 billion, with immense pressure on the African continent's carrying capacity and pressure of migration on all continents. (2) Predicted long term effects of climate change (Burke et al. 2018) could lead to a catastrophic cumulative heating over millennia, taking the planet back to the previous Eocene peak hot period 50 million years ago, placing many of the plant and animal species on which we depend well out of their evolved climate zone, potentially leading to human extinction because of our continuing dependence on highly evolved plant and animal species (Burke et al. 2018). (3) Threatened species by group (Guardian). (4) This situation is unsustainable and leads directly to mass extinctions of biodiversity, which would take up to 50 million years to be addressed by subsequent evolution, as exemplified by previous mass extinctions. (5) Species losses of a variety of animal and plant phyla. The incipient sixth mass extinction that started in the Late Pleistocene has already put over a quarter of mammal species under acute risk of extinction (Leakey & Lewin 1995, Kolbert 2014, 2021, Davis et al. 2018, Dawson 2016). Detailed calculations of mammalian species indicate a time frame of millions of years to recover from the current mass extinctions, by evolving new life forms, but those lost will never be recovered. Insects are also suffering catastrophic population decline due to habitat destruction. (7) Protected areas are manifestly insufficient to protect biological and genetic diversity. International agreement is urgently needed to extend these areas. (8) Scorched-earth clear felling for palm oil plantations has felled a third of Borneo's forest almost overnight. Such wholesale habitat destruction is even worse than burning the rainforest because all living diversity is eradicated in favour of one monoclonal species. (8) Coral bleaching shows how climate change can lead to wholesale mass extinction of species in some of the most intense oceanic biodiversity hotspots, leading to a barren ocean.

The global biomass of biodiversity

Human intrusion into all available habitats causing wholesale natural habitat destruction means that the biomass of livestock is over 14 times that of all wild mammals and the biomass of humans is over 8.5 times that of all wild mammals. Bar-On et al. (2018) assemble the overall biomass composition of the biosphere, establishing a census of the ≈550 gigatons of carbon (Gt C) of biomass distributed among all of the kingdoms of life. We show that terrestrial biomass is about two orders of magnitude higher than marine biomass and estimate a total of ≈6 Gt C of marine biota, doubling the previous estimated quantity. The global marine biomass pyramid contains more consumers than producers. Finally, we highlight that the mass of humans is an order of magnitude higher than that of all wild mammals combined and report the historical impact of humanity on the global biomass of prominent taxa, including mammals, fish, and plants.

Fig 19b: The biomass of humans plus livestock as of 2018 is 22.5 times that of all wild mammals. Graphical representation of the global biomass distribution by taxa. (A) Absolute biomasses of different taxa are represented with the area of each cell being proportional to that taxa global biomass.  (B) Absolute biomass of different animal taxa. Related groups such as vertebrates are located next to each other.

The global biomass of wild mammals

A study by scientists at Israel’s Weizmann Institute of Science (Greenspoon et al. (2023) concludes that wild land mammals alive today have a total mass of 22m tonnes. Humanity now weighs in at a total of around 390m tonnes. Domesticated species, such as sheep and cattle, in addition to other hangers-on such as urban rodents, add a further 630m tonnes. Thus as of 2023 wild land mammals represent only 22/(390+630)=0.02 or 2%. So the figure has risen to 46 times from 2018. The team led by Ron Milo has updated the biomass of world mammals. Biomass as a metric allows us to compare species with very different body sizes, and can serve as an indicator of wild mammal presence, trends, and impacts, on a global scale. Here, we compiled estimates of the total abundance (i.e., the number of individuals) of several hundred mammal species from the available data, and used these to build a model that infers the total biomass of terrestrial mammal species for which the global abundance is unknown. We present a total wet biomass of ≈20 million tonnes (Mt) for all terrestrial wild mammals (95% CI 13-38 Mt), i.e., ≈3 kg per person on earth.

Fig 19c: Left Top: The global mammalian biomass distribution is dominated by humans and domesticated mammals, including livestock and pets. Bottom: enlarged view of the biomass of wild terrestrial (Left, grouped by order) and marine mammals (Right, grouped by family, or few families). Top right: The relative number of species, individuals, and total biomass of each taxonomic order of wild land mammals. The relative biomass contribution of each order is also indicated by the animal silhouette sizes and corresponding percentages.  Lower right: The estimated total biomass is noted for each continent, together with the name of the top mass contributor and its relative biomass contribution to the said continent.

The universe as we know it has been in existence for some 13 billion years, but for over around a quarter of this cosmic lifetime, around 3.6 billion years, life and its diversity and complexity has continued to evolve to the point of human emergence amid climax diversity, which has taken around 66 million years to recover from the mass extinction caused by the Chicxulub asteroid that extinguished the dinosaurs. Our impact is rapidly becoming worse and setting us for a warming taking us back 50 million and yet we remain unable to give the priority to correct it due to our own folly. More troubling, it runs the risk of a Permian type extinction, the most catastrophic mass extinction of multicellular life ever, which like our own climate crisis, was caused by extreme global warming.

Fig 20: (a) The five mass extinctions dominated by the Permian, in which up to 95% of marine fauna expired. ( b) The Permian was not caused by an incoming asteroid but a huge peak in atmospheric CO₂, precipitated by massive eruptions which resulted in the Siberian Traps. The eruptions continued for roughly two million years and spanned the Permian–Triassic boundary, around 251.9 million years ago. (b, c) Historic temperatures and atmospheric CO₂ since the Cambrian, 500 million years ago both show a massive peak at the boundary (marked * in (c) and (d)) (Mulhern 2021). This resulted in the oceans becoming depleted in oxygen, making them oceans uninhabitable particularly to more temperate species, likely exacerbated by lethal H₂S contamination. (e) A 1.5-foot slab of rock from southern China shows the Permian-Triassic boundary. The bottom section is pre-extinction limestone. The upper section is microbial limestone deposited after the extinction. Three species that became extinct. (f) A fossilised spiralling shark tooth from Helicoprion, an extinct Permian shark species. (g) Diademaproetus, one of the trilobites that were plentiful in the world’s oceans but went extinct at the end of the Permian. (h) Paramblypterus, a species of fish that became extinct during the Permian.

During the end-Permian (P-T) extinction, 95 percent of all species on Earth became extinct, compared to only 75 percent during the Cretaceous-Tertiary (K-T) extinction, when a large asteroid impact, possibly exacerbated by ensuing volcanic activity, caused the dinosaurs to disappear. The impact of Homo sapiens on our planet is a striking example of how life can evolve to evoke existential crisis on a planetary scale, threatening both a mass extinction of living diversity by habitat destruction, runaway global heating from fossil fuel consumption and a possible nuclear holocaust, but there are others. Severe global heating can lead to the oceans becoming anoxic, resulting in oceanic bacteria using sulphate to poison the oceans and atmosphere with hydrogen sulphide.

We are used to the idea of the Gaia Hypothesis – that life is an integral part of a self-correcting global biochemical and geochemical process that keeps Earth conducive and habitable for life provided critical tipping points are not transgressed, to push this system beyond a point of no return. But what happens if things go too far? There is a known counterpoint to Gaia, and that is the Medea Hypothesis (Ward 2008) that under certain circumstances, living systems can also precipitate biochemical and geochemical feedback process that can bring about the mass extinction of life, like a mother killing her children.

The central cause of the Permian extinction is temperature-dependent hypoxia (Penn et al. 2018):

The conventional wisdom in the paleontological community has been that the Permian extinction was especially severe in tropical waters.” Yet the model shows the hardest hit were organisms most sensitive to oxygen found far from the tropics. Many species that lived in the tropics also went extinct in the model, but it predicts that high-latitude species, especially those with high oxygen demands, were nearly completely wiped out ( study co-author Jonathan Payne).

Since tropical organisms’ metabolisms were already adapted to fairly warm, lower-oxygen conditions, they could move away from the tropics and find the same conditions somewhere else,” Deutsch said. “But if an organism was adapted for a cold, oxygen-rich environment, then those conditions ceased to exist in the shallow oceans (study co-author Curtis Deutsch).

The huge igneous layers of the Siberian Traps (about 7 million km² (3 million sq mi) of basaltic rock, with a volume of around 4 million km³ (1 million cu mi)) were formed by flood basalt volcanism from a mantle plume, as in Iceland and Hawaii which rose until it impacted against the bottom of the Earth's crust pouring from great cracks in the land itself. As the magma rushed out into the air from its deep Earth origin, it carried enormous volumes of volcanic gas into the atmosphere, including hydrogen sulphide, methane and particularly carbon dioxide. If flood basalts are combined on a global scale with the more explosive volcanism that in addition, throws great quantities of ash and volcanic dust into the atmosphere, one might expect major effects on animals and plants.

Although the global heating caused by the erupted CO2 would not necessarily be enough on its own to cause a mass extinction of this scale, it could have set off a diabolical series of events that led to mass extinction. The Warner the tropical oceans the more the animal oxygen consumption. Normally, the deep ocean gets its oxygen from the atmosphere at the poles. Cold water there soaks up oxygen from the air and because cold water is dense, it sinks and slowly moves equator-ward, taking oxygen with it. The warmer the water, the less oxygen can dissolve and the slower the water sinks and moves toward the equator. The resulting atmospheric warming would in turn, warm surface ocean water enough to cause oceanic oxygen starvation by disrupting this conveyor belt flow, thus bringing less oxygen into the deep oceans. Once the oxygen is gone, the oceans become the realm of oceanic bacteria that obtain their oxygen stripping oxygen from sulphur oxide compounds such as sulphate, producing hydrogen sulphide, which kills aerobic organisms, as well as destroying the ozone layer protecting terrestrial plants. Methane produced in the ample swamps of this time period then has little to destroy it, so the atmosphere becomes laden with hydrogen sulphide, methane and ultra-violet radiation (Ward 2007, 2008). This scenario has been applied both to the Permian and succeeding Triassic-Jurassic (T-J) extinction (Kump, Pavlov & Arthur 2005, Richoz et al. (2012).

CO₂ levels are determined by the imbalance between carbon sequestration (burial in sediments, capture by plants), and carbon emissions (decomposition and volcanic activity). Imbalances in this system created a downward trend in CO₂ levels, leading to a glaciation period around 300 million years ago. This was followed by a period of intense volcanic activity, doubling CO₂ concentration to about 1000 ppm. Levels then dropped until they reached today’s concentrations during the [peak Eocene to] Oligocene era, 33 to 23 million years ago, when temperatures were still 4 to 6 degrees C higher than today. It can be said that history was shaped by CO₂ levels, and the types of climates they would allow. Looking back at the 2 extra degrees of warmth last time CO2 levels were this high (Pliocene era, 3 million years ago), should be enough of a call to action, considering the damage two more degrees would cause today. (Mulhern 2021). 

Under a business-as-usual emissions scenarios, by 2100 warming in the upper ocean will have approached 20 percent of warming in the late Permian, and by the year 2300 it will reach between 35 and 50 percent. This study (Penn et al. 2018) highlights the potential for a mass extinction arising from a similar mechanism under anthropogenic climate change (Justin Penn).

The minimum land area requiring conservation attention to safeguard biodiversity

Fig 21: Minimum land area for conserving terrestrial biodiversity. Components include PAs (light blue), KBAs (purple), and ecologically intact areas (dark blue). Where they overlap, PAs are shown above KBAs, which are shown above ecologically intact areas. New conservation priorities are in green. The Venn diagram shows the proportional overlap between features.

Ambitious conservation efforts are needed to stop the global biodiversity crisis (Allan et al. 2022). We estimate the minimum land area to secure important biodiversity areas, ecologically intact areas, and optimal locations for representation of species ranges and ecoregions. At least 64 million square kilometers (44% of terrestrial area) would require conservation attention (ranging from protected areas to land-use policies) to meet this goal.

Fig 22: Gap analyses of species and ecoregion coverage within areas above. (A) Percentage of the distribution of each species (in different taxonomic groups; freshwater includes crabs, shrimp, and crayfish) and ecoregion area that overlaps. Boxplots show the median and 25th and 75th percentiles. (B) Percentage of species and ecoregions with an adequate proportion of their distribution overlapping existing conservation areas to meet specific coverage targets for species or ecoregions (orange).

More than 1.8 billion people live on these lands, so responses that promote autonomy, self-determination, equity, and sustainable management for safeguarding biodiversity are essential. Spatially explicit land-use scenarios suggest that 1.3 million square kilometers of this land is at risk of being converted for intensive human land uses by 2030, which requires immediate attention. However, a sevenfold difference exists between the amount of habitat converted in optimistic and pessimistic land-use scenarios, highlighting an opportunity to avert this crisis. Appropriate targets in the Post-2020 Global Biodiversity Framework to encourage conservation of the identified land would contribute substantially to safeguarding biodiversity.

Fig 23: National-level land area for conservation and projected habitat loss. Estimated proportion of each country requiring effective conservation attention to safeguard biodiversity that is projected to suffer habitat conversion by 2030 (orange) and 2050 (red) or that is projected not to be converted (blue), according to SSP3 (a worst-case scenario). Gray areas are outside the land identified for conservation. We excluded 85 countries with a land area <10,000 km²  from the figure.

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Fig 24: Evolutionary tree of life (King 2021c), with entheogenic molecules. Preserving the diversity of life and of conscious life in evolutionary time scales
is the prime responsibility of our sentient incarnation. Background: Amazon burning.

Fig 25:  Scenario maps Half Earth Project show (1) protected areas, (2) protected+community, (3) human pressures (4) biodiversity priority, (5) biodiversity richness and (6) biodiversity rarity. These show the difficulty of planning for a half-Earth scenario because some countries have high value habitats which urgently need conserving while others lack any significant protected areas. Furthermore protected areas are not identical with the biodiversity priorities. Habitats involving priority species and rare species are quite distinct from areas with the greatest richness (Rinnan & Jetz 2020). This means that protecting half Earth is going to require massive funding of some developing countries and wide scale consent and economic motivation on the part of developed countries  to resolve these questions. The science is critical to make the process as effective as possible but this is also going to take a huge change in the human world view to upgrade its urgency sufficiently.

If you look at the Amazon Basin it looks as though there is little overlap between biodiversity richness and human pressure, but we know that's not true because the Amazon is being ravaged by fire, mining and agriculture. Moreover The priorities for biodiversity also lie, prominently lie along the Andes, with high overlap with human impact.

Turn now to Africa and you will see a big conflict between human pressure and biodiversity priorities in the North East Congo and south to the Cape of Good Hope.  This means that stopping a serious mass extinction is going to have to involve a new kind of global planning and financing to compensate affected parties and to ensure consistent standards of protection and mitigation. Predictions of biodiversity at 2100 remain contradictory depending on how the driving factors interact (Sala et al. 2000). Wilderness areas halve the extinction risk of terrestrial biodiversity (Di Marco 2019).

Fig 26: Top left: Predicted loss of mitochondrial cytochrome c oxidase subunit I haplotypes for nine montane aquatic insect species in Europe under business as usual IPCC 2080 CO2 emission scenario (Bálint et al. 2011).  Top right: Comparison of recent and distant past extinction rates with rates at which species are “committed to extinction” during the 21st century (Pereira et al. 2010). Bottom left: Map of expected change in biodiversity for the year 2100 under antagonistic interaction between drivers such as climate and habitat loss when the total biodiversity change equals the change resulting from the driver that is expected to have the largest effect and is calculated as the maximum of the effects of all the drivers (Sala et al. 2000).  All of the key tropical rainforest would be seriously affected. Bottom right: Estimated recent and future global biodiversity trends resulting from land-use change, with and without coordinated efforts to reverse trends (Leclère et al. 2020).  Habitat effects on their own contribute up to 20% loss in diversity (grey) unless adequate measures are taken (ochre). Mean extinction probability across studies making predictions of the future effects of climate change suggest a mean extinction probability of 10% across taxa and regions, whereas empirical evidence gave a mean probability of 14% (MacLean et al. 2011).

Davis et al. (2018) note that the incipient sixth mass extinction that started in the Late Pleistocene has already erased over 300 mammal species and, with them, more than 2.5 billion y of unique evolutionary history. At the global scale, this lost phylogenetic diversity (PD) can only be restored with time as lineages evolve and create new evolutionary history. Given the increasing rate of extinctions however, can mammals evolve fast enough to recover their lost PD on a human time scale? We use a birth–death tree framework to show that even if extinction rates slow to pre-anthropogenic background levels, recovery of lost PD will likely take millions of years.

This is going to take a paradigm shift in world views to get anywhere in time. It needs to convey an urgency and a sense of cosmological meaning to support the undertaking both scientifically and religiously to actually get there. There has to be some sheer inspiration and conviction to do this.

Human impact is causing a mass extinction of biodiversity on a time scale that is almost as acute in terms of the adaption of life as the Dinosaur extinction and is rapidly approaching a series of tipping points that could throw the entire planet into a far less hospitable state, not just for the diversity of life but for our own survival. As the Earth heats due to CO₂ and methane emissions, the albedo ^[73] of the white, light-reflecting poles shrinks, so that it absorbs more light increasing the heating. Destabilising the methane hydrates on the ocean floor can lead to a world-wide eruption of CH₄ which is 20 times more active in solar heating than CO₂. At the same time the entire forested areas of the planet that fix carbon are being replaced by pasture and agriculture, compounded by massive fires both lit intentionally to clear forest and arising naturally from lightning strikes due to increased heat and the drying out of forest areas.

Fig 27: Left: Summary of major environmental-change categories expressed as a percentage change relative to the baseline given in the text. Red indicates the percentage of the category that is damaged, lost, or otherwise affected, whereas blue indicates the percentage that is intact, remaining, or otherwise unaffected (Bradshaw et al. 2021). Right: Loss of evolutionary history is variable across mammalian orders. The heights of the bars show the amount of unique evolutionary history attributable to each mammal order at a preanthropogenic baseline (130,000 y ago). The right-hand y axis shows this same value as a percentage of global mammal PD at this baseline. The heights of the colored bars show the contribution to global PD projected to remain after 50 y of status quo conservation. Warm colors represent proportional contributions that are high for an order’s SR; cool colors show the reverse. The orders Didelphimorpha to Microbiotheria are shown at standard (A) and enlarged (B) scales (Davis et al. 2018).

As I was completing this work on on Boxing Day 2021, E O Wilson regarded as Darwin’s heir passed away. Here are three statements he made about Biodiversity in interview about his book “The Meaning of Human Existence”:

We are by instinct related closely to the survival of our distant ancestors by a driving need to strike nature as hard as we could, and to draw as much as we could from it. And we haven’t lost that at all. And now we come to a higher-level recognition that we struck too hard, and too far, and we are threatening the world that we first entered so aggressively and successfully in Africa. And we somehow have got to pull back our instincts to exploit and subordinate and convert to our immediate welfare—because if we take too much more of the Earth’s biodiversity we render the biosphere unstable. And we could, in the worst of circumstances, reach a tipping point in which the whole thing collapses—and we with it.

The living world the biosphere is a razor thin layer of organisms that have evolved over billions of years to create close to exactly the right combination of species and their interactions to maintain the conditions that they live in. Our minds and our bodies are particularly well designed by natural selection to live in those exact conditions and if we change it in any significant way, we die quickly, and so we should keep in mind that, when we destroy the living world by allowing species to go extinct, you're weakening the biosphere and eventually, you may reach a tipping point in which the whole thing starts to unravel, and when that happens pfuttt the end of everything.

Part of our problem is that we're a species that is narcissistic. We're intensely social and intensely interested in other people and that's how we keep our groups united and well coordinated. The result is that we're geniuses at social intelligence and really stupid when it comes to understanding how to manage the environment. We are a  badly adapted species right now. We have created civilisations in which we lead and live on parts of the planet on our own. And we haven't gotten over our emphasis on forming groups and having groups compete with each other. IT's easy for us to think that the world was made for us and we don't really need to know about the 8 million or so species on this planet, even when we're told that keeping them intact and making sure they continue to live is probably necessary for our long-term existence.

Fig 28: Phylogenetic distribution of hidden diversity estimated from consensus of delimitation results. Each silhouette represents a mammalian order with its shadow reflecting the ratio of predicted species to recognised species. Striped silhouettes represent orders with conflicting delimitation results that were not included in the predictive analysis (Parsons et al. 2022). The uncertainties may be much larger in other groups e.g. arthropods.

The Covid-19 pandemic has shown us a world which cannot realistically modify business as usual exploitation to address the human impact on the biosphere that precipitated the pandemic through trafficking and exploitation of wild animals. This inability risks a  potentially irreversible planetary tipping point. The fact that we can even temporarily be stopped in our tracks by a mere virus underscores the vulnerability of the human population to misadventure and the fragility of technological civilisation. By comparison with dealing with a pandemic, the cumulative problems of human impact are far more deleterious to both future quality of life and to the world’s economic viability, and could result in the mortality of billions of people. The problems are made all the more intractable because action requires international cooperation to transform our energy and consumption economies, but this is mired by national and political interests and resolute will can be unravelled all too easily by a single populist defector in a position of power, disrupting the capacity of the world to act cogently and scientifically.

Underlying the climate crisis is a much more serious and potentially devastating one for humanity’s future quality of life, economic future and survival as a species, and that is the mass extinction (Leakey & Lewin 1996) of biodiversity, driven both by whiplash climate change and wholesale habitat destruction further exacerbated by deforestation and the burning of both the tropical rainforests and temperate forests of Earth, as well as the conversion of vast wilderness areas to monoculture. Whole geographical regions of the planet, both at cooler poles where temperatures changes are magnified and in the hotter drier tropics are likely to devastate their plant and animal diversity. The issues of biocrisis (King 2006-2020) and mass extinction are more serious than climate change or human induced pandemics and require a combined strategy of mitigation of habitat destruction, replanting of wilderness areas, conversion of food production and consumption to less polluting and carbon-intensive practices and collecting as much genetic diversity as possible in gene banks to conserve plant, bacterial, and fungal diversity. The fate of insects and other small multi-celled animals is also highly important for overall planetary fertility, as exemplified from honey bees to humming birds.

(a) Half Earth The biosphere needs immediate protection from human impact over a full half its surface and restoration by a clear dedicated program (Wilson 2016, Le Page 2018, Baillie & Zhang 2018, Dinerstein et al. 2019, Lambert 2020, Convention on Biological Diversity), and assisting diversity to replenish in the wilderness is essential for the long-term robustness of the biosphere’s diversity and of human species over evolutionary time scales. Although we are stripping the biosphere, we are very small on the face of the planet and dependent on stable food supplies. Planetary changes crossing tipping points, would have a much more serious long term impact on the viability of human species, let alone the economy, than by adopting the precautionary principle. Climate change remains a serious long term risk to biodiversity and the human population. Changes in the ocean level, once initiated will continue for up to 1000 years due to changes in the planetary albedo as the white polar caps melt. They could render vast land areas uninhabitable to humans and for food production reducing the economic carrying capacity of the planet for human life for millennia to come, with increasing destertification in some areas and flooding in others all impacting on biodiversity. Pollution, from estrogenic chemicals to ocean plastics, also needs urgent containment.

Fig 29: Left: Current state of world nuclear weapon stockpiles. Right: Tsar bomba 50 megatons video. Black rose video.

(b) Nuclear Holocaust  We remain in a situation of mutually-assured destruction due to a massive overkill of nuclear destructive power, which could also lead to a human and biodiversity genocide. This remains a key challenge and a dark comment on the patriarchal male-combat winner-take-all death-risking reproductive strategy, extrapolated to utopian proportions, which urgently needs to be addressed for the safety of the human species and the biosphere. This is human maleficence being appropriated to create a hair-trigger potential for mass destruction, rather than using this technology to avoid astronomical threats to biospheric survival.

The Federation of American Scientists notes: “Despite progress in reducing Cold War nuclear arsenals, the world’s combined inventory of nuclear warheads remains at a very high level: roughly 13,100 warheads as of early-2021. Of these, nearly 9,600 are in the military stockpiles (the rest are awaiting dismantlement), of which some 3,800 warheads are deployed with operational forces, of which up to 2,000 US, Russian, British and French warheads are on high alert, ready for use on short notice. … All the nuclear weapon states continue to modernise their remaining nuclear forces, adding new types, increasing the role they serve, and appear committed to retaining nuclear weapons for the indefinite future”.

(c) Population and Patriarchy Population also remains a critical issue. This article presents a perspective in which consciousness is not just a human faculty but is shared widely by the biota, conveying at its heart, a reverence for the continuity and sacredness of conscious life. Patriarchal religions and cultures claim to represent the sanctity of life, but have abused it, both by suppressing female reproductive choice to ensure male paternity certainty and by encouraging unrestrained reproduction of their adherents as a means to social and world dominance, accompanied by dire penalties, from stoning for adultery, through enforced female veiling, chaperoning by male relatives, female genital mutilation, limitations on female education, careers and freedom of the female race to associate, and choose their/our own futures and sexual partners.

Fig 30: Recent and future population growth of world religions (Pew Research 2017, Wikipedia).

As noted in Sexual Paradox: Complementarity, Reproductive Conflict and Human Emergence (Fielder & King 2017) this frustrates the evolutionary process towards higher intelligence we have experienced in our XY-chromosomal evolutionary emergence.

Christianity and Islam together comprise a majority of the world population with religious believers constituting 84.5% of people. Heaven and Hell cosmology, discarding the living planet and natural diversity, in favour of a reliance on the after life, is in frank contradiction to, and conflict with, ensuring a sustainable and  immortal Paradise on Earth. This is not just a crime against nature, it is a crime against humanity and reality itself. Therefore the main thrust of Symbiotic Existential Cosmology is to change the religious weltanshauung, to that of the living immortality of life as a whole because transforming the religious paradigm is precisely the point of highest remedial capacity.

As can be seen from fig 19b the combined biomass of humanity and livestock is already 22.5 times that of all wild mammals an unsustainable ratio in evolutionary terms.  From fig 19(1) although population growth rates have begun to ease, the world population will still rise to 2100 putting severe pressure on sub-Saharan Africa and unsustainable pressure on biodiversity worldwide.

Both contraception and abortion have been opposed as violating God’s invocation to go forth and multiply, playing a central role in driving the population explosion and hence planetary destabilisation. Muslim and secondly Christian birth rates are the highest on the planet. Abortion is opposed as a heinous sin, but the sanctity of life is not just for a single offspring but the viability of our species in a finite enclosed biosphere. Therefore upholding the sanctity of life depends on respecting the ability of the females of the species, who bear responsibility for the ongoing immortal continuity of human life, to make reproductive choices and choices whether to sustain a pregnancy in terms of their bodies, and their future responsibilities, as mothers of children they need to support. At the same time, beginnings of a severe downturn in reproduction rates insufficient to maintain the population are in some developed countries turning into a flood that is also going to cause a population bust and seriously ageing populations, so both rampant opposition to abortion and the employment and career pressures on women in developed countries need to be removed, so that  human population dynamics can become culturally and biologically sustainable.

A revolutionary female-inspired economic antidote to the paradigm of the GDP and exponentiating growth imperatives, comes from Kate Raworth (2012), in her discussion paper  “A safe and just space for humanity” , forming an interactive template for regenerating a fair, sustainable social dynamics in the closing circle of the natural planetary ecosystem and environment, originally prepared under the auspices of Oxfam in the run-up to Rio+20. This is built on “A safe operating space for humanity” in which Johan Rockström et al. (2009)  propose numerical boundaries for seven parameters: climate change, ozone depletion, ocean acidification, biodiversity, freshwater use, the global nitrogen and phosphorus cycles, and change in land use. The authors argue that we must stay within all of these boundaries in order to avoid catastrophic environmental change.

Fig 31: (Left) Beyond the boundary: The inner green shading represents the proposed safe operating space for nine planetary systems. The red wedges represent an estimate of the current position for each variable. The boundaries in three systems (rate of biodiversity loss, climate change and human interference with the nitrogen cycle), have already been exceeded. (Right) The Doughnut Economics model forming a closing circle balancing the outer limits of the sustainable biosphere with the inner shortfalls of human society spanning health, education, energy, food gender equality and social equity.

In Kate Raworth’s words ^[74]:

The goal of the doughnut is to meet the needs of all people within the means of the planet. Sometimes when I present the idea of Doughnut Economics, people say. "Is this capitalism? Or is this communism? Or is it socialism?" And you think 'Really Are these the only choices we have?' The -isms of the last century? Can we not come up with some ideas of our own and create new names for them and see new patterns?

Governments in every country are almost addicted to citing GDP figures as if this was proof of success and yet it's so clearly not. Because we have climate breakdown and Covid lockdown and financial meltdown, we have to pursue something far richer to move from this pursuit of endless growth, which we can now see is hitting us with crisis after crisis, moving too a goal of thriving. And the doughnut is possible to turn not into a single number, but into a dashboard. We can hold policy makers to account and say every year you need to talk about how you are making progress on these different dimensions of the Doughnut.

The outside of the doughnut is created by leading Earth system scientists just a decade ago. These are the nine life-supporting systems of planet Earth. To have a stable climate, healthy oceans, recharging fresh water. And they drew these and called them the planetary boundaries.  But I thought if we go to the centre of the circle where we use hardly any of the Earth's resources, that's not thriving, that is actually death and destitution for billions of people. We need to convert Earth's lands for food, for water, for housing for energy. So I drew this inner circle and so just as there is an outer limit of humanity's pressure on the planet so too there must be an inner limit. o the hold in the middle is a place where people are left falling short on the essentials of life. It's where people don't have the food, water, energy, healthcare, housing, education, political voice that every person has a claim to meeting. We want to leave nobody in this hole. Get everybody into the green ring of the Doughnut itself.

And I think smart policy makers realised that they don't need a solution to financial crisis and a different one to climate crisis and a different one to health emergencies. They need a paradigm that no longer pushes for endless growth, but instead focuses on thriving, on resilience and on well-being within communities.

We began with downscaling in rich cities, in high-income nations because they are the ones that have the greatest obligation to transform, to come back within the planetary boundaries. But I believe the framework that we've created can absolutely be adapted and used in low income countries and cities.

Since 2012, there have been initiatives to downscale the Doughnut Economy, so it can apply to individual countries and cities, starting with developed economies where there is an impending need to face these realities, with projects in Amsterdam and “Regenerate Costa Rica” and the spinoff DASH project where researchers have applied the Doughnut to the needs of 150 countries.

In short: (1) Give half the Earth back to re-wilding the wilderness, so there is enough species diversity for the biosphere to evolve. (2) Transition immediately to renewable energy. (3) Decentralise the food supply chains to protect humanity.      (4) Ensure the genetic diversity of our food and medicinal species. (5) Eliminate nukes and consider how best to avoid a massive asteroid Earth strike and protection from a nearby supernova. (6) Teach people how to live in symbiotic urban culture. (7) Use technology for the benefit of life as a whole, not for humanity alone, or an artificial intelligence takeover (Werthner 2022). (8) Celebrate the perennial wonder of existence throughout our generations forever Amen.

“A human being is a part of the whole, called by us the 'Universe,’ a part limited in time and space. He experiences himself,

his thoughts and feelings as something separated from the rest — a kind of optical delusion of his consciousness.

This delusion is a kind of prison for us, restricting us to our personal desires and to affection for a few persons nearest to us.

Our task must be to free ourselves from this prison by widening our circle of compassion

to embrace all living creatures and the whole of nature in its beauty” (Einstein)

Symbiotic Existential Cosmology is written to fully sacralise nature and the diversity of life as the supreme spiritual meaning of existence, in a universe whose climax is conscious life immortal unfolding in ever deepening illumination.

Karen Armstrong (2022) in “Sacred Nature” notes the urgency of this reflecting Kate Raworth's statement above:

Today that link between nature and humanity has become even more poignant, as we consider the damage we have inflicted on our environment. We cannot delight in nature any more without knowing that we face the urgent task of saving it from human destruction. 

In the dynamic of concentric circles, of “The Great Learning” (Bloom 1999), the extension of each circle signifies a moment when we are compelled to transcend ourselves and our obsession with “me” and “mine.” The Chinese rituals of family life were painstakingly contrived to make this expansion of sympathy habitual. But to that we should add a new circle, which transcends our focus on humanity. When finally we realise that our very existence depends upon nature, it will be time to surrender our anthropocentrism and include the entire cosmos in our ultimate concern. The Confucian scholar Tu Weiming (1998) argues that we must go beyond the secular humanism that formed the anthropocentric ethos of the Enlightenment. We should develop an anthropocosmic mentality that unites the individual with the community and preserves the harmony between the human species and the non-human world.

Crisis and Resplendence

Communique on Preserving the Diversity of Life on Earth for our Survival as a Species

Affirmations: How to Reflower the Diversity of Life for our own Survival

5 Psychedelics in the Brain and Mind

While the brain is an electro-chemical organ, whose excitations are pulses and waves of electrical excitation, communication between neurons is predominantly chemical, via synaptic bulbs which release neurotransmitter molecules that bind to receptor proteins in the membrane of the target neuron that are either ionotropic and open ion channels, causing an electrical voltage, or metabotropic, activating proteins which alter the way the target neuron behaves.

There is widespread agreement that all neurotransmitters, like dopamine, can act as neuromodulators under certain conditions. Which role a molecule is playing in given circumstances tends to be defined by its function and activity. In general, neurotransmitters are released from one neuron into the synaptic space that connects it to another neuron; within milliseconds, they cause the gates of ionotropic receptor proteins to open and allow ions and other charged molecules to flood into a neuron, changing its internal voltage. Once the voltage passes a threshold value, the neuron fires an electrical signal to other neurons.

In contrast, neuromodulators are often released en masse at sites all over the cortex to seep through brain fluid and reach many more neurons. Binding to metabotropic receptors, whose protein cascades can affect both the nucleus and modulate neighbouring receptors, they act over seconds and minutes to make it more or less likely that the neuron will fire an electrical signal. They can alter the strength of connections between neurons, turn up the “volume” of certain neurons compared to others, and even affect which genes get turned on or off. These changes happen to individual neurons, but when a whole network is blanketed with neuromodulator molecules landing on the receptors of thousands or millions of neurons, due to major ascending pathways such as those of serotonin, nor-epinephrine, dopamine and acetyl-choline the molecules can “wash” into the intercellular fluid creating neurosystem-wide effects which influence every neural function, from sleep-wake cycles to attention and learning.

Fig 32: Left: Serotonin 5HT2a receptors are widely distributed across the cortex (Stein 2007). Centre: Ascending serotonin and nor-epinephrine pathways from basal brain centres fan out across layers of the cortex, modulating modes of sleep, wakefulness, mood, vigilance and drive. Right: 5HT2a receptors line pyramidal cells traversing the cortical layers.

Eve Marder, recognised for her pioneering studies on neuromodulators notes: By washing through the brain, neuromodulators allow you to govern the excitability of a large region of the brain more or less in the same way or at the same time. You’re basically creating either a local brain wash or more extended brain wash that is changing the state of a lot of networks simultaneously.

The primary excitatory neurotransmitter is the amino acid glutamate and the primary inhibitory one is gamma-amino-butyric acid or GABA, modulated by alcohol and sedatives. Their mutual interaction generates waves of excitation and inhibition identified with brain activity in the electroencephalogram.

Fig 33: Metabotropic and ionotropic actions of

neurotransmission and neuromodulation.

Other neurotransmitter molecules including serotonin (5-hydroxy-tryptamine derived from the amino acid tryptophan), nor-epinephrine and dopamine (derived from tyrosine) have a modal modulating effect on brain activity mostly through slower-acting metabotropic receptors. Serotonin and nor-epinephrine pathways regulate modes of organismic behaviour, including sleep and mood in serotonin, vigilance in nor-epinephrine, and reward seeking in dopamine. The level of neurotransmitters in the synaptic junction is also regulated by transporter proteins which mop up unused neurotransmitters after the event, to avoid the brain being flooded with effects that are now over.

Each of the classical neurotransmitters have both ionotropic and metabotropic receptors as targets with the exception of mono-amines, where only the serotonin 5HT3 receptor is ionotropic and differs structurally and functionally from all other metabotropic receptors which are hepta-helical G-protein-linked and all have a common evolutionary tree universal to life, fig 115.  Postsynaptic 5-HT3 receptors mediate fast excitatory synaptic transmission in neocortical interneurons, amygdala, and hippocampus. Nicotinic acetylcholine receptors are ionotropic. At the neuromuscular junction they are the primary receptor in muscle controlling muscular contraction.  Muscarinic acetylcholine receptors are metabotroic and modulate alertness. Glutamate has both ionotropic NMDA and AMPA receptors and metabotropic mGLu receptors. GABA A recptors are ionotropic while B are metabotropic. The 5-HT3, nicotinic and GABA A receptors all consist of five subunits arranged around a central ion conducting pore.

The term “psychedelic” has been eloquently (and compellingly) defined by Grinspoon and Bakalar (1979) to indicate “A drug which, without causing physical addiction, craving, major physiological disturbances, delirium, disorientation, or amnesia, more or less reliably produces thought, mood, and perceptual changes otherwise rarely experienced except in dreams, contemplative and religious exaltation, flashes of vivid involuntary memory, and acute psychosis.” The classic psychedelics, including psilocin, mescalin, dimethyl-tryptamine and LSD all have a common action on serotonin receptors in the brain. By interrupting psychedelic action with an inhibitor, Franz Vollenweider et al. (1998) established that the principal action of psychedelics was at the serotonin 2HT2a receptor, widely distributed in the cortex, fig 34(a), and densely expressed in layer 5 pyramidal neurons. Their detailed interaction with the spectrum of brain receptors can be seen in fig 34(h) and the close relationship between psilocin (4-hydroxy-dimethyl-tryptamine) and serotonin (5-hydroxy tryptamine) in fig 34(l).

Serotonin has multiple modal behavioural roles in the brain as a regulator of sleep and mood. The class of anti-depressants called  SSRIs, or selective serotonin reuptake inhibitors, increase the levels of serotonin by inhibiting its reuptake by transporter proteins. Entactogens such as MDMA, or ecstasy, go further and reverse the transporter, so as to dump an acute dose of serotonin, leading to the entactogenic high, accompanied by pleasurable and affectionate interpersonal contact. Both these agents can subsequently lead to serotonin depletion, the “Tuesday blues” or longer term withdrawal effects in antidepressants, but neither induce the psychedelic state. By contrast psychedelics have little physical dependence potential, because the acute effects rapidly wane if they are repeatedly dosed, until after a refractory period of days.

Fig 33b: Full psychedeic agonist psychedelic 25CN-NBOH — 5HT2a coupling
involving differential G q and -arrestin engagement (Kim et al. 2020).

Outlines of an understanding of how psychedelics act have required protracted investigation and are still under exploration. Psychedelics are agonists that turn on serotonin receptors, rather than blocking their action, just as is serotonin itself, but the way psychedelics do this seems to involve a distinct protein cascade. As shown in fig 34(b), while all serotonin agonists active the protein c-fos, psychedelics also active the developmental protein early growth response 2 or  egr-2. Fig 34(c) shows this is confirmed in vivo in mice. There has also been found from multiple researchers to be interactions between 5HT2a and metabotropic glutamate MgluR2 receptors, fig 34(d) involving psychedelics, which may explain how psychedelics, in addition to causing a standard serotonergic effect, also have the bizarre sensory and existential effects they are renowned for, by modulating excitatory glutamate activity. Kim et al. (2020) have further explored the relation between psychedelics and the G q subunit of the heterotrimeric G-protein responsible for psychedelic activation and its deactivation by -arrestin.

When we come to studying the effects on the brain in electrical and metabolic brain studies, the results are complex. There are two principal ways of studying brain activity, one is to place electrodes, or superconducting magnets on the scalp and record the electrical activity in electro- and magneto-encephalograms (EEG and MEG) and the other is to use metabolic measures using functional magnetic resonance imaging (fMRI), or positron emission tomography (PET) requiring a radio-active tracer. fMRI BOLD uses blood oxygen level dependent imaging and PET can sample for glucose.

Fig 34: (a) Left healthy person's excitatory 5HT2a receptors are widespread across the cortex. Mentally "at-risk" patient right shows lower activation (Hurlemann et al 2008). (b) In vitro and (c) in vivo investigation of protein activations caused by 5HT2a has shown a consistent differential activation of egr-2 (early growth response 2) transcription factor in psychedelics, as opposed to universal activation of c-fos (Nichols & Sanders-Bush 2002, González-Maeso & Sealfon 2003, González-Maeso et al 2007). (d) Serotonin agonism also appears to be linked to a pairing of 5HT2a with an adjacent glutamate mGluR2 metabotropic (G-protein-linked) receptor where egr-2 is blocked by an mGluR2 agonist (Bockaert et al, Fribourg et al, Kondo & Sawa, Uslaner et al, Gewirtz & Marek, Delille et al). (e) Persistence homological scaffolds for placebo (left) and psilocybin (right) showing greater inter-connective persistence (Petri et al). (f) PET study of 15-20 mg psilocybin taken orally over a 48 minute period 90 minutes after consumption, which shows frontal activation by comparison with a resting state (Vollenweider et al 1997).  (g) Reduction in amygdala activity in patients with treatment-resistant depression. Stabilisation of the DMN also occurred. Half of patients ceased to be depressed and experienced changes in their brain activity that lasted about five weeks (Carhart-Harris R et al. 2017). (h) Heat map of normalised receptor interactions (Ray 2010). Activity dark blue=0 to red=4 (orange for 2a and 2c, black no data). (i) LSD increases global functional connectivity of higher-level integrative cortical and sub-cortical regions (Tagliazucchi et al. 2016). (j) A recording during the 12 minutes after intravenous administration of psilocybin 2mg (~15 mg orally), which shows reduced activity in medial frontal cortex  (mPFC), posterior cingulate cortex (PCC) and other areas (Carhart-Harris et al 2012a, Lee & Roth). (k) PET study of 5HT2a sites where psilocybin acts, with red and yellow having highest density (Hasler & Quednow).  (l) Comparative electric fields of serotonin and psilocin. (m) Increases in activity associated with autobiographical memories on psilocybin. (n) Greater late phase activations during autobiographical recollection under psilocybin than placebo (Carhart-Harris et al. 2012b). (o) Changes in fMRI whole cerebral blood flow (CBF) on LSD, resting state functional connectivity (RSFC) increased between V1 and a large number of cortical and subcortical brain regions, but decreased between the parahippocampal  (PH) and the retrosplenial cortex (RSC) and PCC, although increased between the PH and dorsal mPFC and right dorsolateral prefrontal cortex (Carhart-Harris et al  2016a). (p) Reductions in alpha (8-15 Hz) and delta (1-4 Hz) MEG power with ego-dissolution on LSD attributed to cortical desynchronisation (Ibid). (q) Corresponding decreases in MEG for psilocybin (Muthukumaraswamy et al. 2013). (r) Source localisation of one of several networks with reduced power, again associated with desynchronisation (Ibid). (s) fMRI BOLD Variance time courses into the four regions of peak statistical significance for psilocybin and placebo. (t) Statistical significance for decreased low frequency power (LFP) and power spectrum scaling exponent α after psilocybin infusion. Statistical significance of increased power point rate (PPR) and decreased point process interval (PPI) after psilocybin infusion (Tagliazucchi et al. 2014). (u) Distinct receptor phosphorylation barcodes in psychedelics. (Vandermoere & Marin 2014). (v) Increased functional connectivity after psilocybin between the DMN and (i) r-fronto-parietal, (ii) DAN dorsal attention network, (iii) SAL salience network, (iv) TPN task positive network, (v) thalamus to TPN (Carhart-Harris et al. 2013), consistent with the “unconstrained mind” (Lifshitz et al. 2018).

While one might expect that something causing visions, or even hallucinations, might result in enhanced brain excitation, some aspects of the psychedelic state, such as ego loss might also arise from a reduction in activity. Early scans of subjects on psilocybin, fig 34(f) indeed showed increases, as has a later study on LSD when the visual areas are examined, fig 34(o), but the scientific community was surprised when a team led by Robin Carhart-Harris and David Nutt, fig 34(j), found that there was a significant and unexpected reduction in activity. At the time, Franz Vollenweider commented: “We have completed a number of similar studies and we always saw an activation of these same areas. 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.”  Carhart-Harris et al. injected psilocybin and waited only a short period before the scans began. Psilocybin is a pro-drug, which is converted to psilocin, the active ingredient. The former is converted to the latter both by stomach acids and in the liver by alkaline phosphatase (Dinis-Oliveira 2017).

 Fig 35: LEFT (Above) MEG complexity measures are greater for waking consciousness than sedative-induced anaesthesia, but greater still for psychedelics. Increased complexity and correlations of measures. For all three there is reliably higher spontaneous signal diversity, than placebo even when controlling for spectral changes (Schartner et al. 2017).  Below left: Structural-functional similarity calculated as the Spearman correlation between vectorised structural and functional connectivity matrices. Below right: Brain networks of significant functional connectivity differences (r values) between placebo and LSD. LSD makes globally segregated brain sub-states more complex and more decoupled from structural constraints, as well as reducing functional connectivity of the anterior medial PFC, which is thought to subserve processes of reality monitoring (Luppi et al. 2021). RIGHT: Upper Left: Simulation of Lempel-Ziv complexity against Lyapunov exponent measured for a deterministic system. Lower left: The same measure in terms of the experimental K-statistic . Right: LSD, propofol anaesthesia and seizures normalised to the conscious state show that LSD enhances complexity, and brings the conscious brain state closer to criticality (Toker et al. 2022).

However Robin Carhart-Harris subsequently associated these results with a reduction in the activity of the default mode network (DFM). This was discovered a few years earlier from a pattern of apparent reductions in activity in certain areas during specific tasks that showed up as increased activity when resting (Raichle et al. 2001, Raichle & Snyder 2007). The DFM is thought to have a  critical survival role in formulating responses to actual or incipient crises, making active use of the brain during down times from activity to be better prepared. In fact there are many resting state networks and the fundamental idea is that the brain has two complementary modes of activity which can occur together, a passive role responding to incoming environmental or sensory priorities and an active role generating activity beneficial to the organism’s survival, with both of these processes superimposing during activities, so one or the other appears more prominent. Areas noted in these studies as having reductions were the medial frontal cortex  (mPFC), posterior cingulate cortex (PCC), parahippocampal  (PH) and the retrosplenial cortex (RSC). The PCC in particular is characterised in measuring how much you are “caught up” in your feelings and responses, as opposed to just having them. Carhart-Harris et al. (2013) also investigated (v) the connection between the DMN and other networks such as the saliency (SAL) and dorsal attention (DAN) networks and found psilocybin increased functional connectivity between several areas which normally have orthogonal non-interactive relationships confirming the increased functional connectivity of diverse regions under psychedelics.

Carhart-Harris cites the results as evidence of a reduction in default mode network activity consistent with silencing the internal dialogue and ego loss (Pollen 2018). A second researcher Justin Brewer has also found a similar reduction in people meditating (Brewer et al. 2011). This has led to the idea that stopping the internal dialogue of the default mode can result in ego dissolution, because the distinctions between self and other become blurred and the role of the ego as the strategic basis of the default mode network means that silencing it could induce a state of union, in which self and universe become one. Functional imaging has linked the precuneus, an integral component of the default mode network to the processes involved in self-consciousness, such as reflective self-awareness, that involve rating one's own personality traits compared to those judged of other people (Cavanna & Trimble 2006). This thesis supports the notion that both psychedelics and meditation can induce states of ego loss, but the effects of psychedelics are very profound and striking and experientially different from a meditative state of controlled repose, so quietening the resting state networks is a necessary gateway to both, but is not sufficient to explain the vast experiential territory of the psychedelic conscious state.

Millière R et al. (2018) express it this way: “even forms of putative “total” self-loss involving the radical disruption of both narrative and multisensory aspects of self-consciousness are best thought of as a family of states which can differ from a phenomenological perspective with respect to variables that are not directly related to self-consciousness. Indeed, strong forms of drug-induced ego dissolution may involve a very vivid and rich sensory phenomenology, perhaps as a result of decreased sensory gating, while available evidence on some “selfless” states induced by meditation suggests that their phenomenal content is very sparse (e.g., in states of so-called “pure consciousness” achieved in Samadhi practice).”

Carhart-Harris also compared the degree of reduction with subjects’ personal reports of the experience during the session and found that the reduction was greater in subjects who reported evidence of ego or subject-world dissolution such as “I existed only as an idea, or concept”, or “I didn't know where I ended and my surroundings began”, suggesting the effect is genuine. The result is also consistent with heightened activity in other brain areas, particularly those involved in the subjective effects of visions and synesthesia ^[30], which would tend to affect sensory areas rather than associative or frontal areas.

Subsequent studies, both on psilocybin and LSD using MEG fig 34(p, q), give further insights into this situation. The psilocybin study was again by injection but the listed subjective responses showed marked effect differences between subject and placebo, indicative of the psychedelic state. In both studies there was found to be a reduction in oscillatory power, which in the LSD study was strongly associated with ego loss.

Fig 36: Subjective responses within 15 mins of exiting the scanner (Muthukumaraswamy et al.2013).
Right: Increased global integration in the brain after psilocybin therapy for depression, but not for escitalopram (Daws 2022).

This reduction in overall power is consistent with increased desynchronisation in the signals, as in wave superposition of decoherent signals, which rise and fall at different instants are more likely to cancel one another, resulting in lower net oscillatory power.  This is consistent with diverse interacting signals arising from the stimulatory effects of the psychedelic on usually less associated areas, resulting in more information arising to the conscious level which would normally be filtered out, disrupting the usual flow of attention identifying and streamlining the ordered thought process. The psilocybin study also attempted to identify the source localisation of the resting state networks using independent component analysis (ICA) which determined up to seven, rather than just one, as illustrated in fig 34(r).

Evidence corroborating this interpretation came from a further ingenious experiment from another team led by Carhart-Harris, to analyse “homological scaffolds” of brain activity under psychedelics.  Fig 34(e) shows the result, in which there is a far richer network of homological scaffolds in play under psilocybin (right) with the “doors of perception” thrown open than in the normal mental state (left). This technique takes filtered correlations between the time series of the fMRI voxels, forms linkage graphs between each correlated series and then applies algebraic topology using the cliques of three or more to determine and weight the connections. Their evolution over time is also used to show that, while most of the population of psychedelic scaffolds have shorter duration than the fewer number in the placebo state, some psychedelic ones last significantly longer. This is also supported fig 34(s, t), by increased fMRI variance in the hippocampus and anterior cingulate and changes in power spectrum and other measures (Tagliazucchi et al. 2014). A further study (Lord et al. 2019) has explored recurrent BOLD phase-locking patterns (PL states). A similar result 5(i) shows LSD increases global functional connectivity of higher-level integrative cortical and sub-cortical regions (Tagliazucchi et al. 2016).

Fig 36b: (1) The principal cortical gradient of the transmodal association cortex pole (or “TOP”) of the human brain, expressed in a variety of measures, forming a hierarchical gradient down to primary sensory areas (Huntenburg et al. 2018). (2) Vatansever et al. (2017) used task-based fMRI to illustrate how the default mode network (DMN) and the fronto-parietal network (FPN), work collectively in cognition to guide complex behaviour. These demonstrate that the FPN is active after a rule change — the “acquisition phase”—suggesting its involvement in encoding the contingencies upon which the decision is based. Later, the “application phase” — when the individual understands the rule, activity within the FPN is reduced, and activity within the DMN increases (Margulies & Smallwood 2017). (3) Vidaurre et al. (2017) show that ongoing states are hierarchically organised, forming temporal groupings referred to as “metastates.” These reflect a dissociation between states anchored by regions of the cortex concerned with constrained neural processing (such as the sensorimotor systems), from those anchored by transmodal regions of the cortex. Spending time in states anchored in transmodal cortex, including those dominated by the DMN, predict better executive control and higher intelligence. (4) Subregions of the posterior cingulate cortex (PCC) within the white ellipse) and how each is functionally connected with (“echoes”) different whole brain intrinsic connectivity networks (shown by colour) (Braga & Leech 2015). The motor cortex has similar subdivisions sampling sensory and cognitive data (Gordon et al. 2023). (5) Timmermann et al. (2023) show increased global functional connectivity (GFC) under DMT, with corresponding decreased resting state between-network segregation in FPN, DMN, salience (SAL) and limbic (LIM). (6) Timmermann et al. (2023) show a compressed principal gradient under DMT consistent with dysregulation of the separation between abstract associate areas and sensory processing.

In a 2023 study to explore the changes induced by the psychedelic DMT on fundamental neurodynamic networks, including the default mode (DMN) and fronto-parietal (FPN), a them led by Robin Carhart-Harris has performed the first experiment combining combining concurrent fMRI and EEG investigations.

At dosages consistent with the study, they note:

DMT, induces a deeply immersive and radically altered state of consciousness. DMT is thus a useful research tool for probing the neural correlates of conscious experience. Here, fMRI results revealed robust increases in global functional connectivity (GFC), network disintegration and desegregation, and a compression of the principal cortical gradient under DMT. The present findings advance on previous work by confirming a predominant action of DMT – and likely other 5-HT2AR agonist psychedelics – on the brain’s transmodal association pole, i.e., the neurodevelopmentally and evolutionarily recent cortex that is associated with species-specific psychological advancements, and high expression of 5-HT2A receptors.

The transmodal association cortex pole (or “TOP”) of the human brain sits at the upper end of a hierarchical gradient of cortical organisation, while unimodal sensory areas sit at the lower end. The TOP is linked to abstract semantic representations, longer temporal windows of information processing, and is relatively more detached from sensory input, while also appearing later in primate cortical expansion and development. These findings suggest that the subjective effects of psychedelics depend on the dysregulation of the association cortices. Evidence from neuroimaging studies also suggests that this cortical dysregulation may result in the disinhibition of “lower”, evolutionarily and developmentally “earlier” systems such as the limbic system. This also throws light on aspects of the role of the DMN, not just in the resting state, or phenomena of ego loss, but in active situations, in which the FPN plays a role in cogitative planning of solutions, while the DMN takes over once these strategies are established and have become familiar. It is also consistent with the phenomena of a sensory flood, as lower level sensory and perceptual networks become more globally interactive with higher abstract networks involving our entire conception of reality.

Barrett et al. (2020) found that psilocybin significantly decreased both the amplitude of low frequency fluctuations as well as the variance of BOLD signal in the left and right claustrum. Psilocybin also significantly decreased functional connectivity of the right claustrum with auditory and default mode networks (DMN), increased right claustrum connectivity with the fronto-parietal task control network (FPTC), and decreased left claustrum connectivity with the FPTC. DMN integrity was associated with right-claustrum connectivity with the DMN, while FPTC integrity and modularity were associated with right claustrum and left claustrum connectivity with the FPTC, respectively. This suggests a major role for altered claustrum signalling in psilocybin's effects.

A theoretical idea advanced to explain salient features of the brain dynamics in psychedelic experiences is the notion of increased entropy. Carhart-Harris et al. (2014) note that “There is an emerging view in cognitive neuroscience that the brain self-organizes under normal conditions into transiently stable spatiotemporal configurations that this instability is maximal at a point where the global system is critically poised in a transition zone between order and chaos”. The paper then goes on to identify “metastability” of a brain network in terms of the variance in the network’s intrinsic synchrony over time and to claim the psychedelic state has higher entropy than the normal waking mental state. While the dynamical details of this have been criticised (Papo 2016), they do serve to have conceptual explanatory power. Edge-of-chaos dynamics and transitions from chaos to order in critically poised sensitive states are essential to a dynamical model of the brain to avoid the dynamics becoming locked into sub-optimal ordered states, by using the butterfly effect and its “ergodic” ability to fully permeate the space of possibilities.

A distinction is then made between two modes of cognition, primary consciousness “a mode of thinking the mind regresses to under certain conditions, e.g., in response to severe stress, psychedelic drugs and in REM sleep”, including magical thinking, “a style of cognition in which supernatural interpretations of phenomena are made”  and secondary consciousness “the consciousness of mature adult humans”. The article then takes the view that “the mind has evolved (via secondary consciousness upheld by the ego) to process the environment as precisely as possible by finessing its representations of the world, so that surprise and uncertainty (i.e., entropy) are minimized.” It then argues “that secondary consciousness actually depends on the human brain having developed/evolved a degree of sub-criticality in its functionality, i.e., an extended ability to suppress entropy and thus organize and constrain cognition. It is argued that this entropy-suppressing function of the human brain serves to promote realism, foresight, careful reflection and an ability to recognize and overcome wishful and paranoid fantasies. Equally however, it could be seen as exerting a limiting or narrowing influence on consciousness”. This leads to the conclusion that “that the underlying neurodynamics of primary states are more “entropic” than secondary states i.e., primary states exhibit more pronounced characteristics of criticality and perhaps supercriticality than normal waking consciousness — implying that the latter is slightly sub-critical, if not perfectly critical.”

Fig 37: Left: REBUS model of lowered potential energy landscapes causing increased upwelling on psychedelics. Right: CTSC model of thalamic filtering. The filter function of the thalamus, under the control of the CSTC feedback loops, is postulated to protect the cortex from exteroceptive sensory information overload, as well as from internal over-arousal. The model predicts that sensory overload of the cortex may result from thalamic gating deficits, which may be caused by ketamine e.g. by blockade of NMDA-mediated glutamatergic (Glu) cortico-striatal  neurotransmission, or excessive stimulation of 5-HT2 receptors—e.g., by psilocybin. James et al. (2022) have also applied Keppler's (2018) zero point field model of consciousness to ayahuasca and DMT.

This leads to a discussion of the role the default mode network is claimed to have maintaining the ego through the internal dialogue, leading to forms of mental illness involving the oppression of over-weaning order, such as depression, where repetitious rounds of internal dialogue occur, reinforcing a pessimistic existential outlook. It is also an ongoing feature of the fear of inevitable death that plagues human society.

As noted, there are some major issues with simply using entropy as a measure of criticality (Papo 2016). Highly entropic systems can be products either of chaotic criticality, or noisy randomness and entropy is itself not a measure of either complexity or criticality. That said, the general theme of balancing novelty with uncertainty is characteristic of brain dynamics, much of which has characteristics of pink, or 1/f noise displayed by edge-of-chaos dynamics, and human creations such as musical compositions, which ideally balance history and novelty.

A second notion is the cortico–striato–thalamo–cortical (CSTC) model which involves circuits between the cortex and the thalamus that mediate control of sensory information flow to the cortex and awareness and attention (Vollenweider and Geyer, 2001). This model highlights 5-HT2a receptor activation on circuits between the thalamus and cortex to explain the subjective effects of psychedelics (Geyer and Vollenweider, 2008). In this view, psychedelics impede sensory gating functions of the thalamus, allowing increased sensory and interoceptive information flow from thalamus to cortical regions. This reduction in sensory gating is proposed to lead to sensory overload of the cortex that results in both the observed perceptual effects and cognitive changes.

A third related notion, extending the entropy idea is that psychedelics may act to “flatten the potential energy landscape” between attracting brain states (Carhart-Harris & Friston 2019), which has received some tentative support in an LSD study (Singleton et al. 2021).  The 2019 paper notes “We call this formulation ‘relaxed beliefs under psychedelics’ (REBUS) and the anarchic brain, founded on the principle that — via their entropic effect on spontaneous cortical activity— psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system.” 

A key characteristic of some neural nets using an energy landscape to reach and optimum is to run the simulation at a higher temperature of random fluctuations at first to avoid the system getting stuck in an “alpine lake”, gradually lowering the temperature to reach a quasi-optimal minimum, in a process called annealing. This is a similar process to using a transition from chaos to order to enter a quasi-optimal strange attractor. The idea is that the higher energy landscape is a way the brain filters the doors of perception, by impeding upwelling stimuli using top-down control and that when the landscape is flattened using psychedelics, new information can flood into conscious awareness.

A core basis of this argument is valid – that the brain has evolved to streamline conscious existence for survival, by filtering out uncertainty to enable rapid and decisive decision-making, ensuring organismic survival, consonant with Aldous Huxley’s (1954) notion in “The Doors of Perception “that everyday reality imposes a filter and that psychedelics, by reducing the filter can enable individual consciousness to perceive the “mind at large”.

There are also scientific hints that psychedelics, such as DMT, which it is also believed occurs naturally in the brain has neurogenerative effects. Ly et al. (2018) report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo.

Fig 38: (1) Changes in neuronal structure, spinogenesis and the involvement of the 5-HT2a receptor in neural plasticity. (2) The involvement of DMT in neurogenesis. Neurospheres were cultured for 7 days in the presence of DMT. (3) Live-cell images of rat embryonic cortical neurons (DIV6) expressing Myc–5-HT2AR–CFP, b2AR-ECFP, or ECFP. Signals from the fluorescent protein and fluorescent plasma membrane marker in cyan and white. Widefield images of rat embryonic cortical neurons (DIV6) that were administered compounds DMT, psilocin and psilocybin with (+) and without (−) electroporation, which creates temporary openings in the plasma membrane, which enables highly charged molecules to pass through and access the intracellular space. The membrane-permeable 5HT2a agonists DMT and psilocin were able to promote dendritogenesis regardless.

These changes are accompanied by increased synapse number and function. DMT treatment has also been found to activate the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks (Morales-Garcia et al. 2020). Increased hippocampal neurogenesis also occured in mice treated with 0.1 mg/Kg, who also extinguished cued fear conditioning significantly more rapidly (Catlow et al. 2013). Similar plas1city changes have been aaributed to all classic psychedelics (Ly e al. 2018, 2021, Sotille et al. 2022). Vargas et al. (2023) further show fig 38(3) that this is common to classic psychedelics and involves intra-neuronal 5HT2a receptors also consistent with the metabotropic findings of fig 34 (b, c, d and u).

6 Therapy and Quantum Change: The Results from Scientific Studies

The theme of ego-dissolution and the DMN is also discussed with Robin Carhart-Harris at length in Michael Pollen’s (2018) work. It provides a general perspective in which to understand the basis of some of the outstanding claims about the mental states psychedelics induce. As noted, psychedelics have been found to share characteristics both with meditative states and religious contemplation, in which experimenters have found a reduction in the activity of the DFM. Silencing of the internal dialogue in ego dissolution also involves extensive sensory-existential changes in which the boundary between self and other/world becomes blurred. It is important to understand that dissolving of the DMN in the acute psilocybin phase is naturally followed by a reintegration to an active and more functional DMN than in depressive illness. Carhart-Harris extends this blurring to explaining the magical thinking that frequently leads people experiencing deep insights under psychedelics to describe them as veridically true – revealed truths rather than just a personal opinion. He suggests that one explanation of this is that relative judgment that something is just a personal opinion requires separation of subjectivity to carry weight, but in the state of union no such distinction exists.

This raises a fundamental question. Are the insights real or illusory? This is the same question that plagues the status volitional will. Reductionistic materialists attempt to finesse this position by claiming we are simply the product of our circumstances and the causality of brain processes and that the notion of ‘free-will” is just an illusion resulting from evolution requiring us to invest in the notion as a rationale to proceed on the basis of an organismic personal autonomy that doesn’t actually exist. Subjective consciousness then becomes an epiphenomenon, having no causal effect on the material world.

However, most people and the law act on the conviction that we are intentional beings who have consequences on the world around us and that we are accountable for our actions. Premeditation is in criminal law the defining foundation of conscious intent that determines the severity of a crime. We thus need to assess deep psychedelic experiences by the same token. Reports from very astute and trustworthy individuals consistently declare that a genuine veridical experience has taken place, having the nature of truth of the same status as both swearing legal evidence and a replicable observation of the physical world.

Aldous Huxley ^[31] wrote in The Doors of Perception: “Each person is at each moment capable of remembering all that has ever happened to him and of perceiving everything that is happening everywhere in the universe. The function of the brain and nervous system is to protect us from being overwhelmed and confused by this mass of largely useless and irrelevant knowledge, by shutting out most of what we should otherwise perceive or remember at any moment, and leaving only that very small and special selection which is likely to be practically useful. According to such a theory, each one of us is potentially Mind at Large” …  “In the final stage of egolessness there is an 'obscure knowledge' that All is in all — that All is actually each. This is as near, I take it, as a finite mind can ever come to 'perceiving everything that is happening everywhere in the universe.”

Huxley is highly critical of the limiting nature of the doors of perception’s usual filter: “To make biological survival possible, Mind at Large has to be funnelled through the reducing valve of the brain and nervous system. What comes out at the other end is a measly trickle of the kind of consciousness which will help us to stay alive on the surface of this particular planet. To formulate and express the contents of this reduced awareness, man has invented and endlessly elaborated those symbol-systems and implicit philosophies which we call languages. Every individual is at once the beneficiary and the victim of the linguistic tradition into which he or she has been born — the beneficiary inasmuch as language gives access to he accumulated records of other people's experience, the victim in so far as it confirms him in the belief that reduced awareness is the only awareness and as it be-devils his sense of reality, so that he is all too apt to take his concepts for data, his words for actual things.”

This criticism has become even more urgent and critical in a time of planetary climate and ecocrisis, when this reduced tribal awareness driven by ego-consciousness is causing dire risk of a mass extinction of the diversity of life and potentially the extinction of the human species.  To a reader not familiar with these states, it is hard to give credibility to the notion that a person under the influence of an agent originally labelled as an “hallucinogen” that is known to have both transcendent and potentially diabolically dysphoric dimensions as Huxley emphasised in “Heaven and Hell” (1956) can also have experiences with the long-lasting therapeutic relief or mystical insight, let alone be literally and veridically true.

However this is precisely what a number of studies, where precisely these insights under psychedelics have been repeatedly shown to have long lasting insights and benefits, both in severe depression and in people suffering a terminal condition and in normal people experiencing mystical states  (Carhart-Harris t al. 2016b, Griffiths et al. 2006, 2008, 2011, 2016, 2021). 

Fig 39: (a) Assessments of improvement in depression, anxiety and quality of life up to 6 months after psilocybin study in subjects facing life-threatening cancer (Griffiths  et al. 2016) (b) Improvements in subjects with treatment-resistant depression after psilocybin study (Carhart-Harris et al. 2016b), compared with Ketamine (Zarate et al. 2012).  (c) Assessments 2 & 14 months after the psilocybin study Griffiths et al. (2006, 2008). The largest study of its kind (Goodwin et al. 2022) has confirmed these findings.

The titles of these research papers “Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance”, “Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later”, and “Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer” indelibly attest to the genuine long-term effects that these experiences induced. Ketamine has similarly shown promise in treatment-resistant depression, though effects do not last as long as those observed with psilocybin. A possible mechanism has been found in the disassembly of perineuronal nets restraining new synapse formation in established learned memories (Venturino  et al. 2021). Other evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner (Kadriu et al. 2021). The notion Craddock that ketamine and psychedelics share an interaction with microtubules affecting consciousness does not at this point have evidential support.

Fig 40: Selected results from Griffiths et al. (2018). All at 6-months after, except for the top-left rating of psilocybin effect.

A later study (Griffiths et al. 2018) combined the use of psilocybin with meditation and other spiritual practices, echoing the way in which movements such as the Native American Church and the Union Vegetale provide a spiritually conducive context to engender positive outcomes, designed to tap into quantum change experiences – sudden, distinctive, benevolent, and often profoundly meaningful experiences that are said to result in personal transformations that affect a broad range of personal emotions, cognitions and behaviours (Miller, 2004; Miller and C’de Baca, 2001). The discussion notes that: “The study showed robust interactive positive effects of psilocybin dose and added support for spiritual practices on a wide range of longitudinal measures at 6 months including interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death transcendence, daily spiritual experiences, religious faith and coping, and rating of participants by community observers. Analyses suggest that the determinants of these effects were the intensity of the psilocybin occasioned mystical experience and the rates of engagement with meditation and other spiritual practices. Most broadly, as a model system for studying so-called quantum change experiences, which have been described for centuries but which have eluded rigorous prospective experimental analysis, further investigation of psilocybin-occasioned experiences may have broad implications for the development of drug and non-drug interventions in both therapeutic and nontherapeutic applications in order to engender enduring positive trait-level changes in attitudes and behavior and in healthy psychological functioning”.

Miller (2004) notes: “The person typically experiences mystical quantum change passively, not a product of personal will or control, and has a difficult time expressing the experience in words. They usually are intensely positive, joyful experiences, and often the person senses the presence of an awe-inspiring transcendent Other. Often there is a noetic element of revelation, a sudden knowing of a new truth. An experience of unity is common; for example, an ineffable oneness with all of humankind, with nature, or the universe. In these respects, the mystical type of quantum change is similar to common reports of near-death experiences (Lorimer 1990). At the most mystical level, quantum changers seemed to become more alike, as if they had in some way glimpsed the same truth. They often voiced the experience of being interconnected with and part of all of humanity and creation. Those who had experienced themselves in the presence of a transcendent Other gave strikingly similar descriptions. They felt awe but rarely fear, for in its presence they had experienced unspeakable love and acceptance. The insightful type of quantum change lacks most of the mystical components save one: the noetic element of sudden realization or knowing with great and sudden force, and in the moment of seeing, the person recognizes them for authentic truth (or Truth). Their effect tends to be a reorganization of one’s perceptions of self and reality and a cathartic, ecstatic, sense of relief and release. They knew instantly they had passed through a one-way door through which there was no return. They were changed, freed right then, and knew it immediately. Often, characteristics that had been valued least became most important [spirituality and generosity] , and those that had ranked as highest priorities [such as status and possessions]  fell to the bottom”.

A further study (Griffiths et al. 2019) compared “God-encounter experiences” under classic psychedelics and naturally.  While “the Non-Drug Group was most likely to choose "God" as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose "Ultimate Reality." Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. … These experiences were rated as among the most personally meaningful and spiritually significant lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences.  A long-term increase in mindfulness is also noted (Madsen et al. 2020).

Having these mystical experiences, the patient is able to overcome their depression or reframe that depression and return to a more baseline mental being. It really seems to restore … the wellness and balance in the life of the patient. It's quite magical. We don't know yet, but I strongly suspect that you cannot separate the two [effects therapeutic and psychedelic]. Hallucinating is an essential part of the way these drugs work. Chris Koch chief scientist of the Allen Institute's MindScope Program.”

Bill Richards ^[32] notes that mystical experience isn’t something vague, but a specific form of human consciousness. ‘When it’s expressed through questionnaires you can find evidence of  six categories, which [are]: unity; transcendence of time and space; intuitive knowledge (what William James called the noetic quality); a sense of sacredness or awesomeness; deeply felt positive mood, such as joy, peace, love, purity; and claims of ineffability and what we call paradoxicality — that it’s very hard to put these experiences into words and when people try to express it they keep contradicting themselves, that’s the paradoxicality: 'I died but I’ve never been so alive, the ultimate reality was one but it was many, it was beyond time but it included time’ — ultimately the Buddhist claim of the nothingness that contains all reality. And it seems contradictory, but mystics would say the problem isn’t in the experience; it’s in our ability to express the experience within language, at this point in the development of language. And that the answer, the truth is always "both and" rather than "either or”.’

As a warning to unsupported experiences in a bad setting, a survey by Griffiths’ group of extreme, challenging experiences (Barrett et al. 2016, Carbonaro et al. 2016), 1993 individuals (mean age 30 yrs; 78% male) completed an online survey about their single most psychologically difficult, or challenging experience (worst “bad trip”) after consuming psilocybin mushrooms. 39% rated it among the top five most challenging experiences of his/her lifetime. 11% put self or others at risk of physical harm; factors increasing the likelihood of risk included estimated dose, duration and difficulty of the experience, and absence of physical comfort and social support. 2.6% behaved in a physically aggressive or violent manner and 2.7% received medical help. Of those whose experience occurred >1 year before, 7.6% sought treatment for enduring psychological symptoms. Three cases appeared associated with onset of enduring psychotic symptoms and three cases with attempted suicide. Intriguingly, the degree of difficulty was positively associated with enduring increases in well-being. Despite difficulties, 84% endorsed benefiting from the experience and the researchers noted that the incidence of risky behaviour or enduring psychological distress is extremely low when psilocybin is given in laboratory studies to screened, prepared, and supported participants.

It is extremely significant that facing the fear of immanent death, possibly in pain and debilitation, which is the most real and terrifying crisis any conscious mortal being can face, can be redeemed on an ongoing, not just a transient basis, by a psychedelic experience. This attests to these experiences not being illusory but evidential to the conscious mind as the antidote to the mortal dilemma. This is precisely what “moksha”, the primary goal of all Eastern spirituality, seeks to attain through a lifetime of renunciation and devoted meditation. It also stands as highly evidential that in their signature work “The Psychedelic Experience”, Leary, Alpert and Metzner  (1964) presented a guide for readers to navigate the psychedelic state, framed as a modern representation of the Bardo Thodol or Tibetan Book of the Dead – “The Great Liberation upon Hearing in the Intermediate State” – (Lāma Kazi Dawa-Samdup Eng trans 1927), the Tibetan Buddhist manual for successfully negotiating death and rebirth.

Michael Pollen notes a conversation with Roland Griffiths, in which, despite being a world renowned academic researcher leading the field, he has to pick his words very carefully: "The first time I raised [Bob] Jesse’s idea of the betterment of well people with Roland Griffiths, he seemed to squirm a bit in his chair and then chose his words with care 'Culturally right now that is a dangerous idea to promote’ ". However Roland later commented "We're all dealing with death – this is far too valuable to limit to sick people", afterwards carefully amending it to "This will be far too valuable to limit to sick people".

A Psychedelics Pioneer Takes the Ultimate Trip

Marchese (2023) NYT

As the founding director of the Johns Hopkins Center for Psychedelic and Consciousness Research, Dr. Roland Griffiths has been a pioneer in investigating the ways in which psychedelics can help treat depression, addiction and, in patients with a life-threatening cancer diagnosis, psychological distress. He has also looked at how the use of psychedelics can produce transformative and long-lasting feelings of human interconnectedness and unity.  Griffiths, who is 76, has been diagnosed with Stage 4 metastatic colon cancer, in all likelihood terminal, that has brought forth transcendently positive feelings about existence that he calls the great mystery of consciousness. “We all know that we’re terminal,” says Griffiths, “So I believe that in principle we shouldn’t need this cancer diagnosis to awaken. I’m excited to communicate, to shake the bars and tell people, ‘Come on, let’s wake up!’ ”

In spite of the diagnosis, life has been more beautiful, more wonderful than ever. When I first got that diagnosis, because I work out regularly, I watch my diet, I sleep well, this came out of left field. There was this period in which it felt like I was going to wake up and say, “Boy, that was a bummer, a bad dream.” But soon I started to contemplate the different psychological states that would be naturally forthcoming: depression, anxiety, denial, anger, or adopting some belief system of religious outcomes, which as a scientist I was not cut out to do. I went through those, exploring what life would be like if I inhabited those reactions, and I quickly concluded that that was not a wise way to live. I have a long-term Vipassana meditation practice and the focus there is on the nature of mind, of consciousness, and one comes to see that thoughts, emotions, are transient. That practice — and some experience with psychedelics — was incredibly useful because what I recognized is that the best way to be with this diagnosis was to practice gratitude for the preciousness of our lives. Grasping for the cure wasn’t useful.

After getting the diagnosis, I had no immediate interest in psychedelics. I felt in many respects that I was having a very psychedelic-like experience. There was this awakening, this aliveness, and I hesitated to take a psychedelic because I wondered whether it was going to disrupt that. Then a question arose: Is there something I’m avoiding by not taking a psychedelic? Am I defending against some dark, fearful thing I’m in denial about? Am I papering it over with this story of how great I’m doing and actually I’m scared to death? I thought, Well, this would be an interesting stress test. So I did a session with LSD. First, asking myself, “Is there something I am not dealing with?” The answer came back: “No, the joy you’re experiencing is great. This is how it should be.” Then I asked a question directly of the cancer: “What are you doing here? I got nothing back. Then I wanted to humanize it, and I said: “I really respect you. I talk about you as a blessing. I have had this astonishing sense of well-being and gratitude, despite everything that’s happening, and so I want to thank you. This process, is it going to kill me?” The answer was, “Yes, you will die, but everything is absolutely perfect; there’s meaning and purpose to this that goes beyond your understanding, but how you’re managing that is exactly how you should manage it.” So then I said: “OK, there’s purpose and meaning. I’m not ungrateful for the opportunity, but how about giving me more time?” [Laughs.] I got no response to that. But that’s OK.

Our first study was in cancer patients. Ironically enough, these were cancer patients who were depressed and anxious because of a life-threatening diagnosis. The findings of that study were profound: A single treatment of psilocybin produced large and enduring decreases in depression and anxiety. I’ve had some limited experience with psychedelics since then. We’ve now treated hundreds of participants with psychedelics and before sessions, one of the key things that we teach them is that upon taking a psychedelic, there’s going to be an explosion of interior experiences. What we ask them to do is be with those experiences — be interested and curious. You don’t have to figure anything out. You’re going to have guides, and we’re going to create this safety container around you. But here’s the trick: These are not necessarily feel-good experiences. People can have experiences in which they feel like they come to this beautiful understanding of who they are and what the world is, but people can also have frightening experiences. The preparation we give for these experiences is to stay with them, be curious and recognize the ephemeral nature of them. If you do that, you’re going to find that they change. The metaphor we use is, imagine that you’re confronted with the most frightening demon you can imagine. It’s made by you, for you, to scare you. I’ll say: “There’s nothing in consciousness that can hurt you. So what you want to do is be deeply curious and, if anything, approach it.” If your natural tendency is to run, it can chase you for the entire session. But if you can see it as an appearance of mind, then you go, “Oh, that’s scary, but yeah, I’m going to investigate that.”

Griffiths in one of the psilocybin treatment rooms. 

The approach that you’re describing is pretty far from the typical mind-set of many doctors, who are working within a framework of curing, fixing, prevention. So if the ultimate goal is to help more otherwise healthy people get safe access to the potential benefits of using psychedelics, which of course would need to be used in a safe setting and supervised by trained experts, wouldn’t that require a radical rethinking by medical practitioners about what helping people even means? 

Yes, it will. One of the inspirations for the endowment is that it’s not aimed at patient populations. Right now, there’s money pouring into this area, but that’s all going to be patient-related — there’s a pathway to medical approval. I do have concerns that we don’t replicate the mistakes that occurred in the 1960s, which over-promoted psychedelics’ use culturewide. They’re so powerful that if misaligned with cultural institutions, they can result in cultural kickback. In the 1960s they became aligned with the antiwar movement and radicalized-youth movement that was terrifying to existing political structures and institutions, and as a consequence, legislation was put up against them, funding dried up. We need to proceed cautiously. It’s going to be critically important not to threaten existing cultural institutions. So I’ve been a proponent of medicalization, because with medicalization, we already have regulatory structures in place. It goes through F.D.A. approval; they’re going to set standards to maximize safety by specifying who should be eligible to receive, who is authorized to prescribe, and under what conditions treatment should occur. So I’m cautious, but that’s why I’ll have the endowment in perpetuity. If we look at the long range, this could be critical to the survival of our species.

It is Griffiths’s belief that humanity has developed — and is developing — technologies that could threaten its ongoing survival. He also believes that psychedelic experiences can provide the basis for moral and ethical principles that would lessen the likelihood that humanity will drive itself off a cliff. Because there’s something about the nature of these experiences under these certain conditions that produce remarkable experiences of interconnectedness of all things. At the deepest level, if we recognize we’re all in this together, then we have the kernel of what I suspect is most religious traditions and impulses and that is realizing that the Golden Rule makes a lot of sense. After we spoke, Griffiths mailed me a medallion embossed with an image of mushrooms and inscribed with the phrase “May you remain aware of awareness.”

I’ve noticed that often when you discuss human consciousness and our awareness of the preciousness of life, you talk about those things as an awe-inspiring “mystery.” What do you get out of putting it in those terms? Because consciousness may be a mystery now, but I’ve read theories that are convincing, to a layperson like me, that thoughts come from emotions and our emotions are one of the body’s mechanisms of maintaining homeostasis. Or as far as the awareness that life is precious, I could easily imagine that biophilia has evolutionary advantages. So I don’t see why these states of being have to be understood as mysteries. Does it diminish them to see them as explainable? 

I can easily inhabit an evolutionary account that explains how we have come to be who we are — with the exception of the question of interiority! Why would evolution waste its precious energy on our having interior experiences at all? I don’t get that. To me, it’s a very precious mystery, and that mystery, if you want to put it in religious terms, is God. It’s the unknowable. It’s unfathomable. I don’t believe in God as conceptualized within different religious traditions, but the mystery thing is something that strikes me as undeniable. I want everyone to appreciate the joy and wonder of every single moment of their lives. We should be astonished that we are here when we look around at the exquisite wonder and beauty of everything. I think everyone has a sense of that already. It’s leaning into that more fully. There is a reason every day to celebrate that we’re alive, that we have another day to explore whatever this gift is of being conscious, of being aware, of being aware that we are aware. That’s the deep mystery that I keep talking about. That’s to be celebrated!

On the question of authenticity of the psychedelic experience, opinions vary.  David Nichols (2011), the Perdue pharmacologist who founded the Hefter Institute to support psychedelic research and synthesised the psilocybin for Griffith's experiments said "If it gives them peace, if it helps people to die peacefully with their friends and their family at their side, I don't care if it's real or illusion". But Roland Griffiths acknowledges "authenticity is a scientific question not yet answered – all we have to go by is the phenomenology” – i.e. the quality of personal reports. In response to Michael's "staunchly materialist" world view Roland replied "Okay then, but what about the miracle that we are conscious? Just think about that for a second, that we are aware and that we are aware that we are aware! How unlikely is that?”

Primary consciousness associated with reduction of the internal dialogue and ego-dissolution is not just a question of flawed magical thinking that the mind regresses to, but is shared by psychedelics, meditation and deep religious contemplation, all of which in varying ways seek to calm the internal dialogue, attributed to inhibition of the DMN.

Michael  Pollen cites a number of themes relating to this, including the undifferentiated inclusive mentality of the child mind advanced by Alison Gopnik  who co-hosted a talk with Robin Carhart-Harris (2016), echoing sayings of Yeshua and Don Jose Matsuwa. Gopnik refers to a wider nuanced “lantern awareness” which becomes a starker “spotlight awareness” of the Cartesian theatre in adulthood, which as we age, becomes more and more locked into habitual routines that have been found successful in the past. It also applies to releasing the inability of the ordered mind to think outside the box and to be creative, as opposed to conservative and analytic consciousness, which is strongly history-based, rather than novelty-based.

But there are also outstanding differences between psychedelic experiences and meditative and contemplative ones, which are essential to understand and are pivotal to the central enigma of existential cosmology. Mediation seeks to achieve enlightenment by careful top down control, mediated by equanimity, rejection of grasping desires, one-pointed concentration and compassionate emotion. Religious contemplation seeks repose in prayer and devotion. Thus the person involved finds a degree subjective fulfilment, amid acceptance of a spiritual or religious doctrine they are already committed to.  Although these experiences of ego dissolution may induce positive outcomes for the individual, they also tend to confirm established beliefs, rather than open the floodgates to new ideas challenging one’s preconceived assumptions. By contrast, psychedelics are liable to induce insights of a novel and existentially challenging nature, such as the somewhat baffling notion of “the mind at large” as a spontaneous discovery.

Psychedelics provide a complex cyclonic perturbation of existential and sentient consciousness, not a simple “enlightenment pill”.  Bill Richards notes: ’The relation of the drug to the experience is not like taking an aspirin to get rid of your headache. What the psychedelic substance … they all seem to be skeleton keys that open up the mind, that give you an opportunity to explore, but where you go and what happens depends on who you are, kind of who you are, your maturity, your life history, your capacity to be able to choose to trust unconditionally, your feeling of safety, your courage. So much more is involved than just taking the drug.’

What we are dealing with in psychedelics is a whole constellation of mental states, depending on the circumstances and mind set of the person involved. They can take on visionary aspects of traditional notions such as soul theft and sorcery and invoke complex detailed visions from which the word ‘trip’ arises, including specific socio-cultural motifs such as snakes and animistic visionary deities. Some of these can be hilarious, others frightening. Some can be profound, others frivolous or meaningless. Some can lead to messianic delusions and others to creative art, musical composition and scientific discoveries. Albert Hoffman has stated that Karry Mullis, who invented the polymerase chain reaction that is now identified to be the core of molecular biology techniques and essential for Covid-19 testing, told him he credited its discovery to his use of LSD in his student days where he synthesised LSD. It was reported that he was actually coming down from a trip when the idea struck him. We are dealing with an agent invoking as many diverse features as existence can provide. The critical issue underlying this retinal carnival of experiences is how it can reveal underlying experiential knowledge difficult or impossible to gain through any other route.

Their political liberalism and nature-relatedness dimensions have been confirmed (Nour et al. 2017, Lyons & Carhart-Harris 2018).  Nearly nine hundred participants provided information about their naturalistic psychedelic, cocaine, and alcohol use, and answered questions relating to personality traits of openness and conscientiousness, nature relatedness, – “I am not separate from nature but part of nature” – and political attitudes. Participants also rated the degree of ego dissolution experienced during their “most intense” recalled psychedelic experience. Analysis revealed that lifetime psychedelic use (but not lifetime cocaine use or weekly alcohol consumption) positively predicted liberal political views, openness and nature relatedness, and negatively predicted authoritarian political views, after accounting for potential confounding variables. Ego dissolution correlated significantly with these effects.

Psychedelics clearly have political and revolutionary implications that can lay siege to traditional cultural values. It is admitted that the initial wave of repression of psychedelics was political in nature in response to a social movement rejecting the core tenets of a consumer society polarised between materialistic exploitation and religious and sexual conservatism. Fifty three years later, we find ourselves only moderately emerging from a period of repression lasting half a century, still tightly regulated, so as to be applicable only to scientific studies, largely on pathological conditions of depression and terminal illness, or direct scientific inquiry but not for the betterment of sane and healthy people.

There is a deep parallel between the Catholic repression of gnostic elements in the Inquisition that arose ultimately from cross fertilisation of ideas during the Crusades, and of the witch hunts against older spiritual beliefs centred around the ancient European Goddess whose practices Christianity replaced and the reaction to the social values emerging from psychedelics in the 1960s.

The same repressive end result as the middle ages Christian repressions of dissent occurred when LSD become popularised and suddenly, because it had not yet become illegal, huge quantities of very pure acid flooded into rock culture, by devoted underground chemists not seeking financial rewards but for the “common good”, celebrated by the Beatles’ “Tomorrow Never Knows” citing Leary’s Bardo Thodol, and “Lucy in the Sky with Diamonds”, while on the East Coast of the US, Timothy Leary was pronouncing “turn on, tune in and drop out” and on the West Coast, the Grateful Dead, playing “Dark Star” on acid, the Electric Kool-aid Acid tests and the Merry Pranksters, were blowing young peoples minds, while the infectious ethic of free love was shredding conventional sexual morality.  This blew the cover on just how seriously the political and revolutionary implications of psychedelics were laying siege to traditional cultural and particularly commercialistic political and religious values.

Despite the fact that many of these events passed safely without incident, that LSD didn’t split peoples chromosomes, that groups of people hadn’t stared at the sun until they went blind, by the mid-1960s the backlash against the use of LSD and its perceived corrosive effects on the values of the Western middle class resulted in governmental action to restrict the availability of psychedelics by making any use of them illegal. Both LSD and psilocybin were declared "Schedule One" substances. The governors of Nevada and California signed bills into law on May 30, 1966 and the rest of the world followed shortly after, fulfilling the dark ending of Huxley’s (1962) allegory in “Island”, in which the people of Pala consume yellow mushrooms which they call “moksha” to induce visionary states, but are in the end subjected to a military takeover by a neighbouring conservative religious culture. The picture hardened with the case of Charles Manson. The prosecution contended that, while Manson never directly ordered the murders, his ideology constituted an overt act of conspiracy.

However that didn’t stop consumption of psychedelics, which have remained an underground transformative staple at music festivals, forming the entheogenic ^[33] counterpoint to MDMA’s entactogenic love-in experience in the rave party scene. Entheogen (see Ott 1993) is a term that, by its own meaning infers that deity emerges from the sacrament rather than vice versa, confirming the overwhelming impression from this class of agents that they have transcendent dimensions. Stanislav Groff coined the term “holotropic” ^[34], to cover wholeness seeking in all its forms from experiencing the totality as in the mind at large to peri-natal experiences of a physical rebirth struggle.

But repressive legislation of the war on drugs has still had a mind-numbingly counter-productive effect. People are incarcerated for long periods for simple possession of psychedelics. For four decades they were effectively eliminated from scientific knowledge, or assessment. Society as a whole has had almost no opportunity to figure out what role these profoundly transformative agents have in world culture, despite the fact that the natural entheogens have been used for millennia for spiritual and therapeutic purposes in every culture that has consumed them. This means that the role of entheogens has until subtly in the 21st century, been suppressed entirely by the very world societies that have claimed to be the pillar of scientific enlightenment. At the same time, while psychedelics continue to be used devotedly by an underground network of devoted psychonauts, they tend to be trivialised as mere entertainment. Their potential impact on society’s, and the planet’s future, remains occluded as an illegal recreational playground of no confirmed value, or significance.

Currently natural psychedelics are used scientifically in research, and particularly into therapy for pathological conditions of depression and terminal illness. They also continue to be used in some settings for religious and spiritual purposes such as Santo Daime, the Union Vegetale and the Native American Church, much as they have for centuries. Finally they are used  recreationally as an illegal but sometimes tolerated fringe activity, partly because they are easy to cultivate and almost impossible to eradicate. All of these uses create a gloss on the phenomenon which clouds its full potential. Recreational use tends to trivialise it and reduce it to the pursuit of pleasure. Spiritual and religious use tends to reinforce existing attitudes, from Christian doctrine to tribal sorcery and witchcraft.

Demonstrating just how complex the discourse on sacred mushrooms are, Andy Letcher in “Mad Thoughts on Mushrooms” (2007) cites three dominant discourses in a Foucauldian sense: (1) Psychotic where hallucinogens are perceived to induce psychosis, (2) Therapeutic, where they are seen to have therapeutic value when confined to the clinic, and (3) Prohibitionary when they escape the clinic and should be suppressed by the full force of the law. In this view the pendulum swung firstly from (1) –> (2) –> (3) and is now swinging back towards (2) while still remaining a discourse of containment and marginalisation on the part of academics, out of realistic fear of a regulatory backlash.

Running counter to these three dominant discourses are four resistive discourses: (4) Recreational ,in which breaking the bounds is advocated both for the pleasure these experiences brain and for the pleasure of transgression against the imposed restrictive order;  (5) Psychedelic, for their ability to reveal or make manifest the hidden dimensions of the self; (6) Entheogenic, stemming ultimately from Gordon Wasson's religious experiences on mushrooms in a group conference in which Carl Ruck coined the term, meaning  “generating God within,” or “becoming God within”, and finally; (7) Panpsychic / Animistic, that is, they evoke, not theophany but animaphany. Here, mushrooms are not regarded as altering, consciousness but as adjusting what it is possible to perceive, and therefore the spirits and beings occasioned by mushrooms are neither hallucinations nor some aspect of the self, but beneficent discarnate entities with whom the practitioner attempts to forge relationships. They thus tend to evoke states of consciousness in which the consciousness of animals and plants, to other, e.g. spirit entities, or the mind at large, are experienced.

David Luke (2020) also lists a diverse collection of anomalous experiences spanning the transpersonal and psychedelic including (a) synesthesia, (b) extra-dimensional percepts, (c) out-of-body experiences, (d) near death experiences, (e) entity encounters including (mythological beings, chimeras, extraterrestrials, angels and celestial beings, semi-divine beings such as Jesus or Buddha, demons, monsters and beings of death), (f) interspecies communication, (g) possession, and (h) telepathy, precognition, clairvoyance and psychokinesis. DMT is particularly prone to spirit images, as illustrated in “Ayahuasca Visions” (Luna & Amaringo 1991). Shaun Smith (2015) notes the contrasting neurotheological view of theistic phenomena being explained through neurobiology with the theoneurological view of Robert Strassman (2001,2014) in which God or deity is able to alter neurobiology through "the spirit molecule" DMT. Not all of the examples cited by Luke are psychedelic induced and several of the psychedelic examples  echo in greater intensity and embellishment those in dreaming and hypnagogic imagery, in which the subject finds themselves immersed in perceived situations and encounters with entities that evaporate with arousal. These can be considered as visions at the periphery of the nierika portal.

At an extreme, we have Terrence McKenna's far-fetched statement identifying mushroom spores, rather than the cosmological consciousness and visions they evoke, as galactic entities of enlightenment spread across the universe:

“I am old, older than thought in your species, which is itself fifty times older than your history. Though I have been on earth for ages, I am from the stars. My home is no one planet, for many worlds scattered through the shining disc of the galaxy have conditions which allow my spores an opportunity for life.” (McKenna 1993 210).

There is a fine line between this kind of statement, which most people will find unbelievable fantasy, and a much more widely held, meaningful and validating discourse that the mushroom experience can evoke a universal consciousness that may inform in meaningful, or even urgent ways, the ensuing direction a person’s life needs to take.

(Yaden et al. 2021) call for epistemic humility ^[35] regarding psychedelics and the hard problem: “We conclude by calling for epistemic humility regarding the potential for psychedelic research to aid in explaining the hard problem of consciousness while pointing to ways in which psychedelics may advance the study of many specific aspects of consciousness.” Epistemic humility is applying a rule that we can’t assess reality in itself – the very core of the psychedelic experience of “ultimate reality” unless we do so with the filters of the doors of perception slammed shut!

How they can say this, while holding the purse strings of the dominant therapeutic discourse, is extremely  troubling.

Their reasoning is not really about psychedelics but about the confounding nature of the hard problem: “The hard problem of consciousness is currently not scientifically answered, and it is not clear that a scientific answer is even possible, which is why it is called “a hard problem.” They then note that the hard problem is often described in terms of the “explanatory gap” (Levine, 1983), noting: “This phrase may be an understatement – there is far more than a gap, but rather a yawning chasm between our current scientific understanding and the prospect of explaining the hard problem of consciousness.” This is the chasm of the psychedelic experience in which materialistic science fails the test because it can’t explain conscious volitional will either. To use the term scientific in this way is a contradiction to the meaning of science ^[36] as a word which embraces knowledge more generally than physical investigation.

Although psychedelics may not of themselves automatically solve the hard problem, the psychedelic experience cited in this article has led to the cosmological description in this article, which does provide a concise solution to the hard problem. The problem is not with psychedelics, but the assumptions of materialism and physicalism of the current dominant fashion in scientific exploration of brain states. This is confirmed by their statement that: “it is not clear that a scientific answer is even possible”. This highlights what the author sees as a dangerous development in psychedelic research, where the agent most startlingly evoking subjective changes to experience is being filtered through a materialistic filter by the very academics acting as the mediators of therapeutic use and research into these agents. This looks to be an example of the dominant discourse in therapeutic use being applied by the mediators of the research to undermine both the psychedelic and entheogenic resistive discourses and the validity of psychedelics outside the laboratory as agents of cosmological investigation.

Note that the symbiotic cosmology does not conform to the philosophical classification in Yaden et al. (2021) into 3 broad categories: materialist, dualistic, and monistic. Symbiotic Existential Cosmology is a form of interactive complementary aspect monism with is implicitly panpsychic so it is not materialist, but neither is it simple dualism or monism. It is a description based on complementarity extending the  wave-particle complementarity of quantum physics to a cosmological subject-object complementarity in which the two complements cannot be separated in a dualism, just as wave and particle aspects are alternate manifestations of a single quantum identity which cannot be separated, yet it is not monistic because it is a complementarity, not simply a monistic theory of a cosmic mind alone.

Yaden et al. (2021) attempt to justify their conclusion by citing four authors, (Blackmore, 2013; Letheby, 2015; Bayne and Carter, 2018; Johnson, 2020). A viewing of Susan Blackmore’s 2020 Tucson talk however makes clear that she considers the debate whether psychedelics reveal new discoveries or merely cause distortions of the psyche will only be revealed by the new wave of psychedelic research which I support. Bayne and Carter do not treat the hard problem as such, but critique the idea of layers of consciousness and the simplistic notion that psychedelics per se invoke a "higher" form of consciousness, or even that what psychedelics do reveal can be classified in terms of one-dimensional layers, with which this article again agrees. In fact the notion of the nierika advanced in this article is more like a cyclonic vortex having a multitude of divergent experiential features, some illusory and some informative, with the centre of the cyclone providing a portal to deeper forms of experience which may have abstract or cosmological value. This is not a linear indexed description and the subjective process of entering such states requires going “deeper into the abyss” of unconstrained consciousness rather than any simplistic view of “higher" conscious states.

Letheby invokes three descriptions of psychedelic experience: (1) Yes – by inducing mystical states of consciousness, psychedelics afford direct knowledge of supernatural, transcendent dimensions of reality (the entheogenic resistive discourse). (2) No – since materialism or physicalism is true, there are no transcendent realities, and psychedelics just cause compelling hallucinations or delusions (the dominant hallucinogenic and psychotomimetic discourse). (3) Neither – a third view that psychedelics can afford genuine epistemic benefits, even if materialism is true and there is no transcendent reality. Rather than helping us learn new factual information, psychedelics then allow us to understand or appreciate already-known (or otherwise knowable) facts in deep, vivid, affectively and motivationally significant ways. This is again taking a position with implicit dependence on a materialistic viewpoint, while conceding psychedelics may reveal epistemic benefits, so it is confining its own conclusion by its founding assumption of materialism. The symbiotic cosmology is again neither simply an old view, nor is it materialistic. It has resemblances to Upanishadic thought dating back to 700 BC, but it is not a monist theory and is based extensively on detailed investigation of quantum reality, chaotic systems, evolutionary origins of membrane excitability and neuroscience in a novel cosmological description induced by a mushroom experience.

Matt Johnson (2020) , who is both a cited reference and also a co-author of Yaden et al., takes issue with the very concept of consciousness itself as “sloppy”, noting that “one might question whether the different concepts associated with consciousness should even be identified under a singular construct.” This has some validity, for example the subjectivity of consciousness is distinct from its features of coherent attentiveness and from the distinct nature of specific qualia and with notions of self-consciousness and the cognitive mind of thoughts and verbal processes. But consciousness is all these things in a coherent concept, integral to our existential condition, so sloppy is derogatory and unscientific. Consciousness is our most enduring and all-encompassing arena of experience. It is not sloppy! It is fundamental and essential!

In dealing with the hard problem, Matt says "Explaining the existence of experience itself, which is the “hard problem” of consciousness, is at present something that appears outside of the realm of empirical science. Some philosophers and scientists have disputed the existence of this hard problem, but I do not think the problem should be dismissed”.

But empiric ^[37] means “experience”, as does experiment, and there is abundant evidence coming also out of the Johns Hopkins team attesting to experiments confirming experiential observations of quantum change involving “ultimate reality” (Griffiths et al. 2018, 2019). These represent statistical evidence, just as the moksha epiphany does. The claims about consciousness and the experiments on mystical states are thus presenting mutually-contradictory academic reasoning. A critique is made of psychedelic states as having no evidential value based on a preamble assessment that the hard problem is empirically unscientific. This contradicts the definition of empirical, whose root lies in subjective accounts, by invalidating veridical reporting. The legal system depends centrally on veridical evidence.  It is integral to interrogating the subjective condition sine qua non. So the materialist assumption is empirically counterproductive.

In summing up Johnson states: “I suggest that psychedelic science has, to date, not provided substantial advancement in our understanding of any of these concepts [easy or hard] purported to relate to consciousness”.  This is a very pessimistic and confounding view for research in psychedelic science that is showing real promise of cultural benefit. Given a priori assumption of the hard problem’s quasi-unscientific status, it is hard to see how substantial advancement could ever occur on either the role of psychedelics as an informant of the nature of reality, or the status of the hard problem itself. This again underlines the fallacy of academic reasoning that is subservient to the materialistic hypothesis to the extent that no other type of cosmology can be entertained and no empirical result can be gained except by objective means. But biogenic/panpsychic cosmology is biologically precise and seamlessly consistent with multiple steps of the evolutionary pathway so it is a meticulous natural description, consistent with quantum and dynamical physics and with neuroscience. Therefore such reasoning is integral to the scientific discourse.

This error of empiricism applies critically to analysis of the symbiotic cosmology because the principal evidence for it has to come veridically from first person reports. We can’t directly see the consciousness of others, so it is impossible to see the consciousness in simpler life forms or physical processes directly. One can rightly conclude that panpsychic cosmology is the only class of cosmology in which conscious volitional intent is real, so by the veridical test of validity Occam's razor cuts for panpsychism as a necessity.  This is because volitional will implies the conscious mind affect the physical brain and hence the physics of the universe. Therefore mind is a complementary aspect of the physical universe. To a materialist this appears to be adding something that is unnecessary but from the veridical perspective it is essential, because materialist cosmology does not admit conscious volitional will. The inescapable solution is quantum panpsychism.

The problem for mechanists is that intervening states of consciousness are largely inaccessible. But organismic consciousness is evident in humans and mammals generally and is accessible also in other forms in deeply unbounded mental states of meditation or psychedelic transcendence, in which organismic consciousness is asymptotically convergent to an unbounded abstract state identifiable to the subject with the mind at large. Thus the two accessible avenues for scientific discovery are the organismic state and the mind at large. This is why the role of psychedelics becomes sine qua non optimal. If you take them out of the equation, you really have only sparse states of meditative vigil and the dreaming state. Thus to discount the importance of psychedelics is futile and counterproductive.

Yaden et al. nevertheless do concede the potentiality of psychedelics to address the hard problem: “The scientific study of psychedelics and consciousness, in all of its meanings, is still nascent. While we cannot, at present, see any clear scientific traction resulting from the intersection of psychedelics and the hard problem of consciousness, we are open to the possibility of being proven wrong.” This article now of full book length monograph articulates a strategic response.

Moreover several researchers state that the subjective experience of psychedelics, not just their physiological or neurochemical attributes are potentially pivotal in their beneficial effects. Yaden and Griffiths (2020) conclude that:

Based on the results from experimental studies of moderate to high dose psychedelics we believe that the case for subjective effects playing a major role in enduring beneficial effects is compelling. Across a number of studies, when the intensity of the subjective psychedelic effect is controlled, certain subjective effects predict desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects.

Johnson (2022) in reviewing Chris Letheby’s “Philosophy of Psychedelics” (2021) concurs with both this viewpoint and the central role of a “natrualism” that leads to a more supernatural worldview that is not just a comforting delusion:

Letheby argues based on the evidence that subjective experience does play a causal role in long-term benefit. This is supported by studies showing that the mystical-type nature of the experience can predict how therapeutic or otherwise positive the sessions will be in the long term, providing information in some cases that is above and beyond the predictive value of the dose itself or the participants’ ratings of drug intensity. Letheby posits that the subjective experience causes lasting therapeutic benefit independent of whether the session involved or left patients with supernatural ideation.

Letheby argues, successfully in my opinion, that the core mechanism of psychedelic therapy benefit is not the provision of a comforting delusion, for example, one in which people shift to a more supernatural worldview. He argues instead that “naturalism” is the lens through which the key mechanisms of psychedelic therapy can be understood by combining empirical evidence across multiple disciplines through scientific reasoning. … Letheby believes that changes in self-representation are the missing link connecting mystical experiences to therapeutic outcomes

Safron & Johnson (2022) examining both present trends and future possibilities, note the relationship between psychedelics and natural dreaming states:

While we agree that some psychedelic experiences may be understood as a transient form of psychosis, we would add that the same thing can be said about dreaming.  … Intriguingly, while the mechanisms of action for both classic and non-classic psychedelics vary, there appear to be multiple pathways for inducing states in involving greater tendencies for imagining novel scenarios under states of more vivid and intense conscious experience, potentially contributing to the phenomenology of a “waking dream.” While a detailed exploration is beyond the scope of the present discussion, partially overlapping effects from classic psychedelics, anticholinergic drugs (e.g. tropanes), kappa- receptor agonists (e.g. Salvia divinorum), and NMDA-receptor antagonists (e.g. dextromethorphan, or ketamine) suggest that anything that disrupts global integration processes while maintaining (potentially elevated) consciousness has the potential to induce profoundly altered states, and potentially altered traits.

They conclude the following about the future of psychedelics as a discovery process in the context of formative quantum change experiences:

While we must continue to seek the most powerful and encompassing models we can find, we must also avoid the temptation of assuming that a single account will be adequate for explaining the diverse range of effects associated with different psychedelics under different sets and settings. Some may suggest that the mystic nature of psychedelic experiences reveal the truth of a perennial religion, and perhaps even the veracity of metaphysical principles that some would consider to be supernatural (Timmermann et al., 2021). Others might conclude that egoless experiences reveal that selves were illusions all along (Millière et al., 2018; Milliere and Metzinger, 2020), so pointing to the veracity of some schools of Buddhist thought.

In particular Timmermann et al. (2021) cite a move away from physical materialism:

Results revealed signifcant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism, post use. With the exception of fatalism, these changes endured for at least 6 months, and were positively correlated with the extent of past psychedelic-use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience.

On the other hand, Millière et al. (2018) cite a diversity of selfless states in both psychedelic and meditative experiences:

We suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that “self-loss,” far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices.

Milliere and Metzinger, (2020) go further and address the foundational question of the link between subjective consciousness and self-awareness in states of ego-dissolution:

Let us call the general claim that some basic form of self-consciousness or sense of self is ubiquitous to all conscious experiences, the Ubiquity Thesis.

For example, the subjective effects of certain psychoactive drugs, and particularly those of classic psychedelic drugs such as LSD, psilocybin, or 5-MeO-DMT, present a special interest for the assessment of the Ubiquity Claim. Indeed, these drugs are known to have dramatic effects on self-consciousness, and some reports even suggest that they might temporarily suppress any form of self-consciousness – a phenomenon known as ‘drug-induced ego dissolution’ in the scientific literature (Nour & Carhart-Harris, 2017).

In his article “Being for no-one: psychedelic experience and minimal subjectivity”, Chris Letheby (2020) asks whether reports of drug-induced ego dissolution provide us with solid evidence against so-called “subjectivity theories of consciousness”, according to which phenomenal consciousness constitutively involves a minimal form of self-awareness or “subjectivity”. Letheby argues that the alternative notion that putatively selfless states of consciousness associated with depersonalization might not in fact be phenomenally conscious at all, does not work well for reports of selfless states of consciousness induced by classic psychedelic drugs, particularly potent and fast-acting psychedelics such as DMT and 5-MeO-DMT, because there is little doubt that the relevant states are phenomenally conscious.

Miguel Sebastián (2020) argues that given a proper understanding of a minimal form of self-awareness that he labels “Perspectival First-Person Awareness” (or PFP-awareness), it becomes apparent that even putatively selfless states of consciousness do not entirely lack self-awareness. PFP-awareness is anchored in a non-conceptual, identification-free self-attribution that defines the ultimate origin of the first-person perspective of conscious experience. … He concentrates on the phenomenology of states induced by psychedelic drugs, meditation and dreams, as they have been claimed to present the biggest threat to the Ubiquity Thesis. First, he argues that although there are good reasons to think that some forms of self-awareness that typically accompany our ordinary experience can be compromised in altered states of consciousness, this does not mean PFP-awareness is absent in these states.

Thus we see that paradoxically, the psychedelic experience, although being regarded as a highly exotic mental state, also has foundational insights about the universality of both subjective consciousness and self-consciousness.

The thesis in this monograph takes a form of a scientific investigation that sets up a verifiable framework to present a cosmology, consisting of interlocking biogenic, panpsychic and symbiotic aspects, scientifically accounting for the flowering of conscious life in the universe, that has components of discourse (2) that they are therapeutic, (5) that they reveal the self, (6) that they induce moksha and (7) in that this is not a theistic description of reality, but one in which consciousness as we know it is widespread in all eucaryote organisms, and in the mind at large through them, so that the animistic actually has a valid cosmological basis.

The Indigenous Psychedelic Dimension

Kerowen Cornelius (2023) reviewing the ethical implications of the scientific explosion of interest in psychedelics as therapeutic tools, for indigenous communities, who have a long history of sacred and medicinal use, cites Yulia Celidwen’s efforts to form a consortium to address these concerns:

Over thousands of years, Indigenous communities have cultivated relationships with and accumulated knowledge on psychedelics such as psilocybin mushrooms, the Amazonian botanical brew ayahuasca, and the West African shrub iboga. More recently, psychedelics have exploded onto the stage of Western science. Clinical trials of these substances in the past 15 years have produced remarkable results in the treatment of depression, addiction, post-traumatic stress disorder, and end-of-life anxiety. Media buzz has generated a rush to legalize their therapeutic use, catapulting the global psychedelic drugs market from $3.8 billion in 2020 to an estimated $11.82 billion by 2029. But both Native and non-Native critics say the industry is ignoring the emotional, cultural, and ecological harms it is causing the Indigenous peoples who originated psychedelic medicine.

Many Indigenous Nations are concerned they are being excluded from psychedelic spaces that extract their knowledge, threaten what they see as their intellectual property, and detach their medicines from their spiritual contexts, the paper finds. In addition, international demand is driving people to unsustainably harvest iboga, the plants used to make ayahuasca, and the hallucinogenic cactus peyote. Meanwhile, burgeoning retreat centers that offer psychedelic therapy often charge thousands of dollars for experiences that culturally appropriate Indigenous traditions yet share few benefits with these often impoverished communities.

Celidwen et al. (2023) in Lancet notes:

The resurgence of Western psychedelic research and practice has led to increasing concerns from many Indigenous Nations regarding cultural appropriation, lack of recognition of the sacred cultural positioning of these medicines, exclusionary practices in research and praxis, and patenting of traditional medicines. Indigenous voices and lead- ership have been notably absent from the Western psychedelic field currently widely represented by Westerners. An Indigenous-led globally represented group of practitioners, activists, scholars, lawyers, and human rights defenders came together with the purpose of formulating a set of ethical guidelines concerning traditional Indigenous medicines current use in Western psychedelic research and practice.

A global Indigenous consensus process of knowledge-gathering was engaged which identified eight interconnected ethical principles, including: Reverence, Respect, Responsibility, Relevance, Regulation, Reparation, Restoration, and Reconciliation. A summary of the work is presented here with suggested ethical actions for moving forward within Western psychedelic research and practice spaces.

The first and foremost of these is reverence for nature and the diversity of life.

Reverence for Mother Nature

Traditional Indigenous medicine is an ethical, ecosystem-protective, and holistic system of medicine that interconnects humans and the environment. A sense of reverence for the planet guides all relationships, as well as a commitment to preserve all life. Traditional Indigenous medicine from a systems and relational perspective prompts insight for compassionate living and awareness of collective care to sustain the well-being of the medicines themselves as well as all future generations.

Concrete problem

Western psychedelic research and practice has its roots within traditional Indigenous medicines systems yet have turned ‘kincentric’ approaches (treating all relationships, including medicines, as kin) to anthropocentric approaches (human-centric). This anthropocentric approach fails to adequately reference or acknowledge Indigenous paradigms in Western procedures, thus expropriating Indigenous knowledges while separating the medicines from the context of their original environments.

Reverence-governed actions

The explicit acknowledgement of Indigenous Peoples and their traditional medicines and practice as the root of Western psychedelic research and practice; Western psychedelic research and practice references Indigenous concepts of reverence as guided by local Indigenous scholars and communities; the Western psychedelic research and practice community takes action to support Indigenous Nations protection of the at-risk land and natural environments where these traditional Indigenous medicines originate; support Indigenous Peoples in their fulfillment of the right to life and of the right to live in peace on ancestral lands.

Four later sections in this work – Psychedelic Agents in Indigenous American Cultures , Shipibo: Split Creations and World Trees, Meso-American Animism and the Huichol and Redemption of Soma and Sangre in the Sap and the Dew, deal in detail with indigenous use as a pivotal heritage of psychedelic knowledge.

The Devil’s Keyboard: Sanity, Hallucinations and Visions in the Sappy, Conscious Human Brain

The mammalian brain is not just a seething storm of electrical excitations reverberating through neural networks, but is driven at all stages through the intervening sappy connections that neurotransmitters, neuromodulators and receptors provide between one neuron and the next in the passage of such excitations as they develop strange attractors and other dynamic phenomena of cerebral processing. Neuromodulators do not just affect our moods but are key players in major life decisions. We can better understand these by examining the way psychoactive agents act on many receptors at once, like chords, sequential melodies, or extreme dissonances, enhancing some receptors and depressing the activity of many of others, leading to unpredictable and sometimes uncontrolled consequences and the ways human society, for better or worse, chooses to use these substances to ensure “sanity” or achieve insight.

Fig 41: The Devil’s Keyboard Plot of receptor binding in pKi of major classes of psychoactive drugs, from antipsychotics through antidepressants and antihistamines to entactogens and entheogens, generated using the PDSP database (http://pdsp.med.unc.edu/dataMining/pdspConfigGraph.php and PLoS ONE 5/2 e9019 1-17). Five key classes of modulatory neurotransmitters, serotonin, acetyl-choline, dopamine, histamine and nor-epinephrine, cross indexed against key classes of psychoactive agents – typical and atypical antipsychotics, antihistamines, tricyclic and SSRI , SNRI antidepressants, entactogens, and psychedelics for receptor activity as inverse agonist, antagonist, agonist and super-agonist.  An inverse agonist binds to the same receptor-binding site as an agonist and not only antagonises the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signalling (when present). If we look across receptors and the various molecules used to alter the flow of these pathways, we begin to gain an understanding of how psychoactive molecules in the sappy biochemical brain activate positively and negatively  the “Devil’s keyboard”  of receptors bound to by these molecules, many of which act on several receptors at once.

Two key primary agents are the amino acid glutamate and the closely related gamma-amino-butryic acid (GABA) which form the excitatory and inhibitory components driving the oscillations of the central pathways for information processing. Both these two are primal amino acids found in the Murchison chondrite and scattered in cosmic gas clouds, so they are not just a quirk of biology. These have both ionopore receptors, which can excite or inhibit electrical oscillations and slower longer-acting metabotropic receptors which modulate overall activity on a contextual basis by signalling to protein pathways interacting with the nucleus and adjacent receptors.

Along with these two, there are several additional simple molecules, many amines, such as dopamine, nor-epinephrine, serotonin (5OH-tryptamine) and complementing them, acetyl choline that, like glutamate and GABA, have an ancient origin as social signalling molecules in single-celled eucaryotes and which also have both ionotropic and metabotropic receptor versions. The amine and choline pathways also form the complementary components of the bodily adrenergic and cholinergic autonomic nervous system. Other receptors have more complex substrates such as the polypeptide endorphins of the opioid receptor.

Antipsychotics – Agents of Darkness

At the negative extreme a dark, diabolical side of psychotherapeutic agents, is presented in the form of antipsychotics. Although an affront to human autonomy, these are admittedly less damaging than a long line of previous diabolical and devastating treatments for key psychotic conditions, from schizophrenia to mania and depression.

The treatment of mental illness has a long tortured history. Lobotomy was one of a series of radical invasive physical therapies that signalled a break with a psychiatric culture of therapeutic nihilism that had prevailed since the late nineteenth-century. The new "heroic" physical therapies devised during this experimental era, including malarial therapy for general paresis of the insane, deep sleep therapy, in which the patients were put into long deep coma, insulin shock therapy, in which patients were repeatedly injected with large doses of insulin in order to produce daily comas over several weeks, cardiazol shock therapy and electroconvulsive therapy, both of which induced seizures, and finally prefrontal lobotomy helped to imbue the then therapeutically moribund and demoralised psychiatric profession with a renewed sense of optimism in the curability of insanity and the potency of their craft at the cost of a complete loss of autonomy and identity by the vulnerable afflicted.

Patients of lobotomy were, immediately following surgery, often stuporous, confused, and incontinent. Some developed an enormous appetite and gained considerable weight. Seizures were another common complication. Emphasis was put on the training of patients. Following the operation, spontaneity, responsiveness, self-awareness, and self-control were reduced. The activity was replaced by inertia, and people were mostly left emotionally blunted and restricted in their intellectual range. Walter Freeman ( the father of the Walter Freeman who proposed strange attractors in brain states) described one 29-year-old woman as being, following lobotomy, a "smiling, lazy and satisfactory patient with the personality of an oyster" who could not remember his name and endlessly poured coffee from an empty pot. The originator of the procedure, Portuguese neurologist António Moniz, shared the Nobel Prize for Physiology or Medicine of 1949 for the "discovery of the therapeutic value of leucotomy in certain psychoses", which has been the subject of continuing controversy. Lobotomy has become a disparaged procedure, a byword for medical barbarism and an exemplary instance of the medical trampling of patients' rights.

Fig 42: (Left) Freeman stated that this woman was schizophrenic and all that could be done was to turn her into a 'veritable household pet’. (Centre) Lobotomy procedure  (Right) Electroconvulsive therapy.

Katie Serena (2022) notes: Rosemary Kennedy JFK’s sister suffered oxygen deprivation during birth. As a child, she was unable to keep up with her siblings. Her lack of inclusion often caused her to experience “fits,” which were later discovered to have been seizures or episodes relating to her mental illness. She was also reportedly causing trouble for the nuns in the American convent. According to them, Rosemary was caught sneaking out at night to go to bars, where she met strange men and went home with them. .Joe Kennedy was grooming his two oldest boys for careers in politics. Because of this, Rose and Joe worried that Rosemary’s behavior could create a bad reputation not just for herself but for the whole family in the future, and eagerly searched for something that would help her. Despite the ominous stories about the lobotomy, Joe needed no convincing to sign Rosemary up for the procedure, as it seemed like this was the Kennedy family’s last hope for her to be “cured.” Years later, Rose would claim that she had no knowledge of the procedure until it had already happened. No one thought to ask if Rosemary had any thoughts of her own. In 1941, when she was 23 years old, Rosemary Kennedy received a lobotomy. During the procedure, two holes were drilled in her skull, through which small metal spatulas were inserted. The spatulas were used to sever the link between the pre-frontal cortex and the rest of the brain. Though it is not known whether he did so on Rosemary, Dr. Freeman would often insert an icepick through the patient’s eye to sever the link, as well as the spatula. Throughout the entire operation, Rosemary was awake, actively speaking with her doctors and even reciting poems to her nurses. The medical staff all knew that the procedure was over when she stopped speaking to them. Immediately after the procedure, the Kennedys realized that something was wrong with their daughter. Not only had the operation failed to cure her intellectual challenges, but it had also left her extremely disabled. Rosemary Kennedy could no longer speak or walk properly. She was moved to an institution and spent months in physical therapy before she regained normal movement, and even then it was only partially in one arm. Her family did not visit her for 20 years while she was shuttered away in the institution. It wasn’t until after Joe suffered a massive stroke that Rose went to go see her daughter again. In a panicked rage, Rosemary attacked her mother during their reunion, unable to express herself any other way.

After 2,500 operations, Freeman performed his final ice-pick lobotomy on a housewife named Helen Mortenson in February 1967. She died of a brain haemorrhage, and Freeman's career was finally over. Freeman sold his home and spent the rest of his days traveling the country in a camper, visiting old patients, trying desperately to prove that his procedure had transformed thousands of lives for the better. Freeman died of cancer in 1972.

By contrast with removing key and essential parts of the brain, electroconvulsive therapy is a psychiatric treatment where a generalised seizure is electrically induced to manage refractory mental disorders. Typically, 70 to 120 volts are applied externally to the patient's head. ECT is used, where possible with informed consent, as an intervention for resistant major depressive disorder, schizophrenia, treatment-resistant catatonia, prolonged or severe mania. A course involves multiple administrations, two or three times a week until the patient no longer has symptoms. Although it is claimed to be an effective treatment for depression, cognitive impairment is noticed after ECT. The American Psychiatric Association acknowledges: "In some patients the recovery from retrograde amnesia will be incomplete, and evidence has shown that ECT can result in persistent or permanent memory loss”, although it is disputed whether it causes permanent brain damage.

Antipsychotics are a class of psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but also in a range of other psychotic disorders, including bipolar disorder, encompassing mania and depression. First-generation (typical) antipsychotics were introduced in the 1950s following on from the discovery of promethazine in the 1940s, which also has antipsychotic properties but is used as a first generation sedative antihistamine. Chlorpromazine, derived from promethazine originally as a sedative, was found to have neuroleptic properties in the early 1950s, and was the first typical antipsychotic. Second-generation (atypical) antipsychotics, were sought in the 1970s to address some of the side effects including mortality risk.

Fig 43: Thorazine (chlorpromazine) advertised both for aggressive mania (in men) “When the patient ashes out against ‘them’ Thorazine quickly puts and end to his violent outburst” and menopausal depression (in women). “To help you relieve the severe emotional upset of the menopausal patient – Thorazine”.  Centre Right: “Hallucinating and delusional? – Consider starting her on Haloperidol”. Right: Quetiapine advert 2009 .“Bipolar depression doesn’t just affect you – IT CAN CONSUME YOU”. Marketed as both an atypical antipsychotic and as an adjunct treatment for bipolar, or just persistent, depression, complete with five pages of legal disclaimers, including: High blood sugar and diabetes, Weight gain, potentially fatal neuroleptic malignant syndrome (fever, rigid muscles, confusion), “tardive dyskinesia (TD) uncontrollable movement of the face, tongue, or other parts of the body” which can become permanent, Cataracts, Suicidal thoughts, increased risk of death, ”Priapism"  2011 Seroquel TV Advert

Research has shown that use of any antipsychotic is associated with smaller brain tissue volumes, including white matter reduction and that this brain shrinkage is dose dependent and time dependent. The use of antipsychotics may result in many unwanted side effects such as involuntary movement disorders, such as tardive dyskinesia, gynecomastia, impotence, weight gain and metabolic syndrome increasing the risk of heart disease, stroke and type 2 diabetes.

To understand how antipsychotics affect receptors in the brain, it is highly informative to examine in detail their receptor binding properties to the major classes of psychoactive receptors.  A key core of antipsychotics involves antagonism at dopamine receptors, believed to be driving psychosis. As shown in detail in fig 41, the prototypical antipsychotic chlorpromazine is an antagonist at all five dopamine receptors D1-5. However, it also antagonises multiple serotonin receptors, all muscarinic acetyl-choline receptors M1-5, histamine H1, and all the α-adrenergic receptors for nor-epinephrine. This is an effect like an elephant sitting on the devil’s keyboard, flattening (a) mood (serotonin) (b) alertness (acetyl choline) (c) motivation (dopamine) (d) wakefulness (histamine) and (e) vigilance (nor-epinephrine). Its introduction has been ironically labeled as one of the great advances in the history of psychiatry.

Other typical antipsychotics are tuned to enhance the focus on antagonising dopamine receptors. Fluphenazine does this strongly with less anticholinergic effects. It is less prone to causing sedation, or low blood pressure but is associated with a higher frequency of movement disorders. Haloperidol does it  even more aggressively, by being an inverse agonist, particularly at D2 as well as D3, D4 (orange squares in fig 41).  However this extreme dopamine suppression causes Haloperidol to be the most prone to the rare neuroleptic malignant syndrome, a life-threatening reaction that can occur in response to antipsychotic medication, due to a sudden drop in dopamine levels, paradoxically causing glutamate over-stimulation. Neuroleptic, originating from Greek: νεῦρον (neuron) and λαμβάνω (take hold of)—thus meaning "which takes the nerve"—refers to both common neurological effects and side effects. Symptoms include high fever, confusion, rigid muscles, variable blood pressure, sweating, and fast heart rate. Complications include rhabdomyolysis, when damaged muscle tissue releases its proteins into the bloodstream, leading to heart and kidney damage or failure. All antipsychotics cause a significant increase in death rates when used for elderly dementia. In comparison with atypical risperidone, haloperidol was associated with a mortality ratio of 2.14 in one study and in another both typical and atypical (risperidone, olanzapine, quetiapine, and aripiprazole) had ratios of 1.6 against placebo, implying a death rate for haloperidol against placebo of over 3 times higher.

The atypical  antipsychotics, perhaps with the exception of risperidone, fare little better, although they were intended to reduce negative side-effects, and display the same warnings about the same spectrum of outcomes. Quetiapine suppresses  the same receptors as chlorpromazine and olanzapine is in addition an aggressive inverse agonist for serotonin receptors 5HT2a, b, & c blanking out emotional mood.

Antidepressants – Brave New World

The history of antidepressants is equally chequered. Monoamine oxidase inhibitors (MAOIs) were the first type of antidepressant developed. Monoamine oxidase is a generalised enzyme which clears the brain of any superfluous monoamine transmitters. Use of MAOIs typically requires diet restrictions and avoiding certain other medications because MAOIs can cause dangerously high blood pressure when taken with certain foods or medications, as noted in serotonin syndrome. MAOIs also affect other neurotransmitters in the brain and digestive system, causing additional side effects.

The next generation of anti-depressants were tricyclics. Imipramine, originally investigated as an antipsychotic, was discovered in the early 1950s, and was the first tricyclic antidepressant, along with amitriptyline. As shown in fig 41, they  inhibit serotonin uptake, although antagonising 5HT2a and c, and although not suppressing dopamine, are still strongly anticholinergic, sedative antihistamines that suppress -adrenergic receptors. Common side effects include sleepiness, sudden weight gain, dry mouth, constipation, nausea, and blurry vision, increased risk of suicide in those under the age of 25, mania, and urinary retention. A withdrawal syndrome may occur if the dose is rapidly decreased.

Tricyclic antipsychotics, antidepressants and antihistamines all have anticholinergic action which has been associated with increases in dementia and mortality (Gray et al. 2015, McMichael et al. 2020) with high use contributing to an approximately 50% increase in both.

Fig 44: Targeting women: (Left) Mother's little helper": Before the current fashion in SSRI antidepressants, benzodiazepines such as valium (diazepam) and serax (oxazepam) were massively marketed to vulnerable women trapped in domestic incarceration until their recreational popularity and withdrawal symptoms became apparent. (Right) Doxepin – sine qua non! "Sinequan helped her save her family life". The Prozac Promise – Confidence, Convenience, Compliance. Zoloft used for the same purpose as serax. Effexor "I got my playfulness back". In another "I got my mummy back"! Petition: Effexor withdrawal Can bring you to your knees!

Subsequent drug development has focussed closely on the serotonin transporter SERT as a way of enhancing mood in a modulated manner. The current round of SSRI and SNRI antidepressants are head and shoulders above the previous ones, although their efficacy and the basis of their action is still debated (Moncrieff et al. 2022, Erritzoe et al. 2022).  Serotonin reuptake inhibition of the serotonin transporter SERT is believed to be responsible for their anti-depressant activity, although longer term neurogenesis has also been reported. The SSRI fluoxetine (prozac) and the SNRI venlafaxine (effexor) thus increase serotonin by reducing the reuptake of serotonin by the serotonin SERT transporter. Common side effects are agitation, nausea, digestive upset, loss of appetite and weight loss dizziness, blurred vision, dry mouth, excessive sweating, insomnia or drowsiness, loss of libido, anorgasmia, erectile dysfunction, dependence and withdrawal symptoms. Severe side effects include increased risk of suicide, mania, and serotonin syndrome. Antidepressant withdrawal syndrome may occur if stopped. Fluoxetine has a less  problematic tendency to antidepressant withdrawal syndrome than venlafaxine and can be used as a stepping stone out.

The effectiveness of antidepressants is still only marginal against placebo, or effective psychological support and they come with problems of long-term dependence potentially as serious as with previous use of benzodiazepines such as “mother’s little helper” valium was. By comparison psychedelic therapy holds great promise because it doesn’t require daily dosing on an indeterminate basis and the transformative nature of the experience can enable the person to reevaluate their life and meaning in the psychedelic context, giving them a new more wholesome accepting perspective on existence, even for people facing terminal conditions. In 2020 around 4000 death in the US were associated with antidepressants.

Reversing the effect of SERT is also believed to be responsible for the serotonin flooding causing the prosocial entactogenic effect of the amphetamine analogue ecstasy or MDMA (3,4-Methylenedioxy-methamphetamine). The insights of MDMA experiences have proved effective in dealing with intractable conditions such as post-traumatic stress syndrome (PTSD) through a refreshed world view again without having to have daily medication. However MDMA can cause neurological oxidative damage and medium term depletion of SERT transporters, and deaths have been recorded. In Australia 62% of deaths were attributed to drug toxicity (48% multiple drug toxicity and 14% MDMA toxicity alone), and 38% to other causes (predominantly motor vehicle accidents) with MDMA recorded as a contributory factor (Roxburgh & Lappin 2020). The more serious adverse effects include hypertension, hyperthermia, serotonin syndrome, seizures, stroke, hyponatremia and cardiac arrest, involving multiple factors such as dancing in high temperatures in crowded spaces.

Serotonin Super-Agonists – Agents of Illumination and Annihilation

The most positive tolerable therapeutic agents are in the serotonin receptor class, the 5HT2a receptor fig 43, is widely distributed across the cortex, receiving inputs from 5HT1a neurons sending ascending pathways from the basal Raphe nucleus widely across cortical areas, where they couple e.g. to 5HT2a receptors on vertically-aligned pyramidal neurons and affect mood. Serotonin receptors are diverse with types 1 - 7, both excitatory and inhibitory, with 5HT1 having five subtypes, 5HT2 three and 5HT3 being ionotropic.

The super-agonist effect of psychedelics differs from that of  both antidepressants and MDMA because it leads instead to the psychedelic state, putatively via exciting a second subcellular G-protein linked pathway modulating the adjacent metabotropic glutamate receptor mGluR2 as illustrated in fig 34(d). It acts primarily as a super-agonist of 5HT2a and 5HT2c but is also a partial agonist of dopamine and nor-epinephrine receptors (green squares) adding motivational drive and vigilance to the experience. LSD has an even broader distribution of activations, giving it the rich quality of experience appreciatively noted by the research chemist Dave Nicholls.

Fig 45: Timothy Leary, Alexander and Anne Shulgin (Alex Gray) and Albert Hofmann (Robert Venosa).

Note however there is also a dark side – overdosing on SSRIs or SNRIs (serotonin norepinephrine reuptake inhibitors), or combining two agents, including a variety of drug combinations from pethidine which is also serotogenic with SSRIs and some psychedelics (mescalin) and monoamine oxidase inhibitors, can cause the potentially fatal condition, serotonin syndrome, involving high body temperature and blood-pressure , agitation, seizures and muscle breakdown.

The natural entheogens, psilocin, DMT and mescaline, are safe and can be highly illuminating, when used in a safe context, as is LSD although extremely potent. Deaths from overdose are unknown and the few deaths to which natural entheogens are attributed are due to accidental misadventure. Maria Sabina, the mushroom benefactress lived to 93 and last time I took peyote with the road man Tellus Goodmorning he was also 93.  Mescaline was first isolated and identified in 1897 by Arthur Heffter and first synthesised in 1919 by Ernst Späth. LSD was first synthesised Nov 16, 1938, by Albert Hofmann, but it wasn’t until 1963 that Hofmann and Troxler reported the synthesis of psilocybin. Starting from mescaline, which although not a serotonin analogue binds to the 5HT2a receptor in the same way as psilocin and DMT, a series of more potent mescaline analogs has been created (Shulgin  1991), such as 2CB, 2CB-Fly and the super-potent  25I-NBOMe. Psilocin also has several psychedelic analogues (Shulgin 1997).

But there are plain bad psychedelics too. Bromo-DragonFLY (BrDF) is a very potent hallucinogen, having around one third the potency of LSD and it has an extremely long duration of action, up to several days and is relatively toxic. It can easily be confused with related less potent agents e.g. 2CB-FLY, which is 20x less potent, 2CB or 2CE which is 100 times less potent. Two young adults died after overdosing on BrDF, which they thought was 2C-E, and several others were hospitalised during the same incident. Because they took a dosage appropriate for 2C-E, those who took the drug received, in some cases, 100x the normal dose. Both deaths followed seizures, vomiting blood, and terrifying hallucinations. A 35-year-old male required amputation of the front part of his feet and several fingers on one hand after taking a massive overdose. The compound acted as a long-acting vasoconstrictor, leading to necrosis and gangrene which became apparent several weeks after the overdose occurred. A 22-year-old male from Copenhagen died after ingesting BrDF. His friend described the trip saying, "It was like being dragged to hell and back again. Many times. It is the most evil [thing] I've ever tried. It lasted an eternity.”

The lesson for me is to trust natural entheogens. Sacred mushroom species such as Psilocybe cubensis have evolved to provide a genetically pure psychedelic experience with no dangerous contaminants. Magic mushrooms are some of the safest recreational drugs around. Out of a survey of more than 12,000 people who did shrooms in 2016, just 0.2 percent said they needed emergency medical care—a rate that was five to six times lower than LSD, cocaine, MDMA, and alcohol, and three times lower than weed. However some wood-loving species Psilocybe azurescens, cyanescens, and subaeruginosa can cause temporary muscle weakness or paralysis.

Cannabinoids

Cannabis plants have a great variety of psychoactive molecules. In particular cannabidiol moderates the effects of the principal psychoactive agent 9-THC to give a more health promoting effect. 11-hydroxy-THC can be formed after consumption of THC from inhalation and oral use, although levels of 11-hydroxy-THC are typically higher when eaten compared to inhalation. The pharmacokinetic equivalency ratio comparing Delta-9-THC with 11-Hydroxy-Δ9-THC means that one milligram of THC in edible form, is equivalent to 5.71 milligrams of THC in smokable form.

Fig 46: (Left) Sadhu attending the Maha Shivaratri festival Nepal marking a remembrance of "overcoming darkness and ignorance" in life and the world on the night before the new moon. (Lower) Some key natural and synthetic cannabinoids. (Upper-left) Scythians used cannabis ritually by heating whole plants in braziers in an enclosed space (Rudgley 1993). The black residue inside the gold vessels dating from the fourth century BC contained opium and cannabis (Curry 2015). (Upper-right). Vessels for heating cannabis resin of the Sogdians, a people of western China and Tajikistan who were Zoroastrians (Ren 2019). A 700-900 BC Israelite temple with active cannabis is shown in fig 140.

Cannabinoid metabotropic receptors have a variety of functions. CB1 occurs widely in the brain and CB2 is expressed on cells of the immune system where it has an immunomodulatory effect, reducing inflammatory response where it plays a role in processes including implantation of the fertilised embryo. CB1 receptors are thought to be one of the most widely expressed G protein-coupled receptors in the brain. This is due to endocannabinoid-mediated depolarization-induced suppression of inhibition, a very common form of short-term plasticity in which the depolarization of a single neuron induces a reduction in GABA-mediated neurotransmission. Interference with working memory, displayed by cannabinoids is believed to result from secondary action of glial astrocytes, which have CB1 receptors, on hippocampal pyramidal, cells. The actions of 9-THC result from partial agonist activity at the cannabinoid receptor CB1 (Ki = 40.7 nM), located mainly in the central nervous system, and the CB2 receptor (Ki = 36 nM), mainly expressed in cells of the immune system, meaning it binds similarly to both.

Anandamide, the principal enodcannabinoid, along with 2-arachidonyl-glycerol, both derived from the prominent fatty acid arachidonic acid which occupies 20% of the fatty component of the brain, was first described (and named) in 1992 by Raphael Mechoulam and co-workers. The group went on to devise far more potent synthetic cannabinoids. HU-210, HU for Hebrew University, synthesised by Mechoulam has 100-800 times the potency of THC which itself is active in quantities of around 1-5 mg.

While natural cannabis is a safe herbal product used for up to five thousand years as a psychoactive substance, and the only deaths attributed to natural cannabis use are associated with other factors such as injuries from vehicle accidents where cannabis is detected, synthetic cannabinoids have exploded on the recreational market, some with serious damaging side effects and deaths. 

A series of potent naphthoylindole cannabinoids, the JWH family named after John W. Huffman, of Clemson University introduced a wide array of new cannabinoids with new structural arrangements ad some with disquieting side effects. JWH-018 is a full agonist of both the CB1 and CB2 cannabinoid receptors and has been associated with unpleasant effects, including seizures, possibly associated with GABA inhibition and dissociative and anxiety episodes. JWH-073 acts as a partial agonist at both the CB1 and CB2 cannabinoid receptors. It is five times more selective for the CB2 subtype. JWH-015 has an affinity for CB2 receptors of 13.8 nM, while its affinity for CB1 is 383 nM, meaning that it binds almost 28 times more strongly to CB2 than to CB1. JWH-081 by contrast is ten times more selective for CB1. Two fluorinated compounds XLR-11 and AM-2201 have recently been associated with acute kidney damage (Murphy et al).

AB-Fubinaca was originally developed by Pfizer in 2009 as an analgesic medication but was never pursued for human use. In 2012, it was discovered as an ingredient in synthetic cannabinoid blends in Japan. In 2016, a "mass casualty event" in Brooklyn, New York, where 33 people ranging in age from 25 to 59 years old were adversely affected by the drug. 18 were hospitalized. All of the victims were described by-standers as “zombielike” and the cause was attributed to closely-related AMB-Fubinaca with a methoxy group instead of an amine. A sudden spate of around 60 deaths in New Zealand, which had never experienced deaths from natural cannabis, accompanied by zombie incidents, were also attributed to the drug, with tested products containing between 32 mg/g and 400 mg/g of the active ingredient, between 2x to 25x stronger than the product involved in the mass casualty event in New York a year earlier.

Deleriants – Devil’s Breath and Witches Brew

There is a long diverse history of use of solanaceous plants from belladonna (deadly nightshade) and mandrakes to Datura and Brugmansia species to induce states of delirious hallucination in which the subject is unable to differentiate their sometimes mundane hallucinations from reality, becoming unable to look after their own affairs, often slumping into unconsciousness and awakening with little memory of what has happened. This is the basis of the witches’ flight on a broom stick, reputedly after rubbing the ointment on their skin and vaginal membranes. It is caused by toxic quantities of scopolamine, which is an undiscriminating muscarinic acetyl-choline antagonist, although also an essential medicine.

Fig 47: Datura stramonium, or devil's trumpet, renowned for the Jimson weed incident named after Jamestown, Virginia, where English soldiers consumed it for food while attempting to suppress Bacon's Rebellion. They spent 11 days in altered mental states of hallucinatory delirium incarcerated for their own protection. Guambioano drawing of a woman under a borachero tree of the evil eagle of toxic flight Brugmansia volcanicola, or angel's trumpet tree Colombian Andes. The Dance of the Sabbath (Gustav Doré). A young Basque witch applying her flying ointment José de la Pena. Atropa belladonna and Henbane Hyoscyamus niger. Ceremonial scopolamine use goes back to the beginning of the first millennium BC (Guerra‐Doce et al. 2023).

Its use in psychoactive quantities, like that of other anticholinergic agents leads, to accumulating brain atrophy. In smaller doses it is used for motion sickness and postoperative nausea and vomiting. Originally used as an anaesthetic and amnesiac in childbirth, it is frequently used to drug victims to induce docility, persuading the victim to release their bank accounts, after which they awaken not remembering what happened. In South America it is sometimes added to hallucinogenic ayahuasca potions containing DMT.

Then Rachel said to Leah, Give me, I pray thee, of thy son’s mandrakes. And she said unto her, Is it a small matter that thou hast taken my husband? and wouldest thou take away my son’s mandrakes also? And Rachel said, Therefore he shall lie with thee tonight for thy son’s mandrakes (Gen 30:14).

NMDA Dissociatives

Ketamine is a dissociative anaesthetic which induces a trance-like state providing pain relief, sedation, and amnesia. At sub-anaesthetic doses it is a recreational drug which induces a profound dissociative trance like experience entirely different from psychedelics and is a promising agent for pain and treatment-resistant depression. It is one of the safest anaesthetics, in contrast with opiates, ether, and propofol, it suppresses neither respiration nor heart rate. Ketamine is an NMDA receptor antagonist which putatively acts by blocking the passage of ions in the ion channel. Related agents are PCP, N₂O, Xenon and dextromethorphan. The psychotropic effects of ketamine range from dissociation and depersonalization. Depending on the setting they can be pleasant or distressing and include a sensation of feeling light, body distortion, absence of time sense, novel experiences of cosmic oneness and out-of-body experiences. PCP has gained notoriety for uncontrolled behaviour, because it stimulates other receptors including D2, notably alleviated in an overdose by Haloperidol’s D2 suppression. By contrast, overdosing Ketamine results in falling into the anaesthetic K-hole.

μ-Opioid Analgesics and κ-Opioid Dissociatives

Opioid receptors are a group of inhibitory G protein-coupled receptors with opioid polypeptides as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract. The opioid receptor class consists of four types δ, κ, μ, ζ and nociceptin – DOR, KOR, MOR, ZOR & NOR. Opiate drugs, such as morphine, act as MOR agonists setting off inhibitory effects, building up tolerance and causing withdrawal symptoms, possibly via NOR. NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates. NOP and KOP do not react with MOP agonists such as α-endorphin, the 16 unit polypeptide Tyr-Gly-Gly-Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr, but dynorphins such as 13 unit dynorphin A – Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys. The opioid receptors appear to maintain a dynamic equilibrium of pain perception, with opiates effect being due to MOP with NOP contributing to tolerance and withdrawal symptoms, with KOP having an alleviating role.

Fig 48: Top row: Poppy Goddess with slit pods (1400–1100 BC Gazi, Crete), Juglet with traces of papaverine unique to the opium poppy Papaver somniferum (Daley 2018), The sacred mushroom benefactress Maria Sabina holding Salvia divinorum.

Opium has been revered as a sacred potion since the dawn of urban culture, with sacred use manifest in the slit poppy pods on the crown of the Minoan Goddess and the presence of opium along with cannabis in the Scythian rituals. Opiates remain core essential medicines playing a key role in the management of pain, but they are also prime targets of dependence, addiction and mortality because of their seductive ability to escape the pain of the mortal coil. This leads to opiates and the ensuing synthetic opioids being primary agents of drug-induced mortality.

As can be seen in the figure above, opioids have beed developed in two ways, firstly by modification of morphine to heroin (diamorphine) , oxycodone and others, and secondly after the discovery of pethidine to arrive at fentanyl and carfentanyl, having exponentiating potencies and risks. The strength of sample opioids relative to morphine is: Codeine 1/10, Pethidine 1/3, Morphine 1, Oxycodone 3/2, Methadone 3, Heroin 3, Fentanyl 100, Carfentanyl 10,000.  Correspondingly the overdose death rates in the US for opioids in 2020 are very high and skewed towards the most potent: Heroin 13,000, Prescription opioids 16,000, Fentanyl 57,000. A significant share of these deaths can be directly attributed to the criminal mass marketing of opioids by the US drug industry.

Similarly to μ-opioid receptor agonists, such as morphine, κ-opioid agonists are potently analgesic, and have been employed clinically in the treatment of pain, however they also produce side effects such as dysphoria, hallucinations, and dissociation, which has limited their clinical usefulness. κ-opioid receptors are extremely widely distributed in the brain, spinal cord, and in peripheral tissues, including high levels in the prefrontal cortex, raphe nuclei (dorsal), ventral tegmental area, substantia nigra, dorsal striatum (putamen, caudate), ventral striatum, amygdala, claustrum, hippocampus, hypothalamus, midline thalamic nuclei, locus coeruleus, spinal trigeminal nucleus, parabrachial nucleus, and solitary nucleus.

They may provide a natural addiction control mechanism, and therefore, drugs that target this receptor may have therapeutic potential in the treatment of addiction. Ibogaine a natural hallucinogen from Africa has seen a wave of popularity as a means to escape addiction and alcohol dependence. There is evidence that distribution and/or function of κ-opioid receptors may differ between sexes. The effects of the κ-opioid agonist salvinorin-A include baffling dysphoric visual spatial experiences quite different from psychedelics, and loss, or inversion of one’s body image to become an external part of the environment, like the walls of the room, or crushed between giant wheels in a huge aircraft hangar. As can be seen in fig 34(h), ibogaine’s unique receptor binding profile involves super-agonism of 5HT2a providing a psychedelic effect, agonism of κ-opioid receptors providing both alleviation of dependence and a salvinorin-like dissociative effect and antagonism of NMDA receptors, akin to Ketamine’s dissociative effect.

Uppers and Downers

Two central drugs of key medical use and recreational and addictive misuse second only to opioids are stimulants, providing euphoriant stimulus and emotional drive, and sedatives, providing obliterating relaxation and somnolence.

Fig 49: Left: Erythroxylum coca providing cocaine. Right: Catha edulis (Khat) providing the stimulant cathinone.

Stimulants

Caffeine, fig  63, present in tea and coffee and multiple plants, is regarded as the world’s most commonly used stimulant. It acts uniquely by being an antagonist for receptors for adenosine, which accumulates in the brain through the day in the use of ATP energy, signalling the onset of fatigue.

Other stimulants act to enhance dopamine levels in various ways. Amphetamine is a strong central nervous system (CNS) stimulant that is a potent full agonist of trace amine-associated receptor 1 (TAAR1) residing inside the dopamine secreting synaptic bulb, which plays a key role, in promoting release of dopamine, as part of a complex feedback process, shown in fig 53k. Methamphetamine is a variant now used primarily as a recreational drug as a euphoriant that at high doses, can induce psychosis, breakdown of skeletal muscle, seizures and bleeding in the brain. Cathinone is a natural amphetamine analogue consumed widely in the middle East as the stimulant khat.

Fig 50: Amphetamine action inside the synapse to release dopamine.

Cocaine – coca from Quechua kúka, is a natural stimulant from Erythroxylum species that has been used for millennia and is ritually and customarily consumed without social harm, by chewing the leaves with lime to free-base it. Cocaine is a purified form of the acid salt that has more capacity for psychological and physical dependence. It binds tightly to the dopamine transporter DAT forming a complex that blocks the transporter's function so that additional dopamine accumulates in the synaptic cleft. Cocaine also blocks the serotonin transporter and norepinephrine transporter, inhibiting reuptake of serotonin and norepinephrine. Effects include intense happiness, sexual arousal, loss of contact with reality, or agitation. Physical effects may include a fast heart rate, sweating, and dilated pupils. Effects begin within seconds to minutes of use and last between five and ninety minutes. Methylphenidate (Ritalin) is also a dopamine and norepinephrine reuptake inhibitor in a 3:1 ratio, used widely for attention deficit syndrome without social harm. A group of cathinone/MDMA analogues, marketed as "bath salts", such as mephedrone and methylone are stimulant/entactogen designer drugs with effects similar to MDMA or cocaine, with a duration of 5–6 hours. Methylenedioxypyrovalerone (MDPV) acts as a norepinephrine–dopamine reuptake inhibitor causing not only a severe anxiogenic effect but also increased aggressive behaviour, resulting in a peak in US emergency admissions in 2011.

Central to the drug wars and the whole criminal enterprise of drug cultivation, manufacture and distribution for illicit profit and second only to opioids as harbingers of mortality, are stimulants.  In the US in 2020, overdose deaths from cocaine are estimated at 19,000, and methamphetamine at 24,000. The only viable solution to undercut the cartels is to treat all recreational and nonprescription drug use as a health issue in a decriminalised environment.

Sedatives

Sedatives act almost universally through modulation of ionotropic GABA-A receptors to increase inhibition of ensuing glutamate excitatory activity. GHB (gamma-hydroxybutyric acid) is a pro-drug of GABA that is therefore an indirect natural agonist of GABAa that causes acute sedation and is sometimes used s a date rape drug. All the other examples cited in the figure are allosteric modulators that result in increased expression of the receptor and central nervous inhibition. Ethanol’s drunkenness and sedation is understood in terms of its activity as such a modulator, although it also has other effects as well (Davies 2003).

The first GABA sedatives were the barbiturates that act as central nervous system depressants. They are effective as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as well as overdose potential and have largely been replaced by benzodiazepines and Z-drugs. Sodium pentothal is a rapid-onset short-acting barbiturate general anaesthetic. It is routinely used for euthanasia and was previously used for most lethal injections in the United States, but the US manufacturer Hospira stopped manufacturing the drug in 2011 and the European Union banned the export of the drug for this purpose. It is still used in some countries as a truth serum to weaken the resolve of a subject and make the individual more compliant to pressure, by decreasing both higher cortical brain function and inhibition. Phenobarbital is used as an anti-seizure medication in epilepsy and occasionally to treat trouble sleeping, anxiety, and drug withdrawal and help with surgery.

The next generation of GABA agents were benzodiazepines which appeared to present fewer problems of toxicity, dependency and withdrawal. Their effects vary from sedation (temazepam) to tranquillisers aggressively marketed to treat anxiety (diazepam or valium) until recreational use led to a realisation of their dependence and withdrawal risks including rebound insomnia and seizures.  Some have a long half life so used for sleep can leave the subject under the influence next day. Non-medical temazepam use reached epidemic proportions in some parts of the world with massive increases in fraudulent prescription resulting in the banning of tis use.  Anecdotal evidence suggests that temazepam may be the most psychologically habit-forming (addictive) benzodiazepine.

Flunitrazepam (rohypnol) among other names is used to treat severe insomnia and assist with anaesthesia, to be prescribed only for short-term use or by those with chronic insomnia on an occasional basis. Adverse effects of flunitrazepam include dependency, both physical and psychological; reduced sleep quality resulting in somnolence; and overdose, resulting in excessive sedation, impairment of balance and speech, respiratory depression or coma, and possibly death. Because of the latter, flunitrazepam is commonly used in suicide. It is known to induce anterograde amnesia in sufficient doses; individuals are unable to remember certain events that they experienced while under its influence, particularly dangerous if it is used to aid in the commission of sexual assault. However, in a 2001 study, the benzodiazepines midazolam and temazepam were the two most common benzodiazepines utilised for date rape.

In 2020 in the US, benzodiazepines accounted for 12000 deaths by overdose or suicide.

The non-benzodiazepine Z-drugs are also positive allosteric modulators of the GABA-A receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex. Many of these compounds are subtype selective, providing novel anxiolytics with little to no hypnotic and amnesiac effects and novel hypnotics with little or no anxiolytic effects. Z-drugs have demonstrated efficacy in treating sleep disorders. There is some limited evidence that suggests that tolerance to Z-drugs is milder and slower to develop than with benzodiazepines. Zolpidem with a short half life of 2-3 hours is reported to result in occasional sleepwalking. Zopiclone has a half-life of 5-7 hours, suitable for inducing and maintaining sleep but without the hangover of temazepam, with a half life of 8-20 hours.

Symbiotic Existential Cosmology Next Section

Footnotes