Neurotransmitters and the Integral Approach to Reality

by JOMS (Creative Commons)

by JOMS (Creative Commons)

This article is by Dr. Neal Goldsmith.


Neurotransmitters and the integral approach to reality: Three types of neurotransmitters and three types of psychedelic

There are three major types of psychedelics that correspond to three of our primary neurotransmitters.

There are acetylcholine ‘psychedelics’ – scopolamine, atropine, and hyoscyamine, found in plants of the Solanaceae (nightshades) family – that although not meaningfully psychedelic in a psychospiritual sense, are capable of creating the illusion that an actual object or person is present, when to the outside observer they are not; they also create a swooning sense of flying and stimulate the mucosa (including the vaginal walls). Not surprisingly, these chemicals comprise the active ingredients in the medieval witches’ hexing herbs – henbane, mandrake root, deadly nightshade (belladonna), hemlock, wolfsbane, and thornapple (datura). When seen through the lens of ‘true hallucinogens’, stories of witches’ brew, flying to a remote coven (on a broomstick used for applying ointments), talking with the devil and having sex with him, begin to become understandable. These chemicals do carry a heavy ‘body load’, however: they are difficult for the body to experience and process. Even so, some kids somewhere in suburbia are always trying to get high on jimson weed (a form of datura), which, unfortunately, can be a lethal mistake (and calls our attention to what can happen when these substances are perceived as illicit and active distribution of objective information is suppressed).

The second major type is the norepinephrine psychedelics, which block, mimic, or enhance the endogenous (internal) norepinephrine system in the body. (Norepinephrine has a stimulating effect and mediates the body’s response to substances such as caffeine, amphetamine, or cocaine.) The norepinephrine psychedelics known as phenethylamines – for example mescaline and MDMA, or Ecstasy – are structurally related to methamphetamine and, as a result, have something of a stimulant action. At high doses, certain amphetamines are considered hallucinogens.

The third major endogenous neurotransmitter system is the serotonin system. That’s the system that’s more influenced by LSD, psilocybin, and the other tryptamines.

Discounting the hexing herbs, then, the two major types of ‘classic’ psychedelic are the phenethylamines, such as MDA and mescaline, and the tryptamines, such as LSD or psilocybin. In fact, there is a lot of overlap in these systems, with varying amounts of these three neurotransmitters triggered by any psychedelic. Mescaline, a phenethylamine, does generate cross-tolerance to both LSD and psilocybin (tryptamines). Tolerance has occurred if you take a psychedelic one day, then try again the next day and find it ineffective. Either the endogenous neurotransmitter is temporarily depleted, or the number of receptor sites died back, in a natural process called downregulation that attempts to effect homeostasis in a system that has been overwhelmed by neurotransmitter stimuli. If response to a different class of drug, such as LSD, also shows tolerance after a prior mescaline experience, then the two drugs are said to exhibit cross-tolerance, meaning that the two substances share a chemical and a functional similarity. Not only do they exhibit cross-tolerance, but in clinical studies it’s impossible for most subjects to distinguish between the mescaline experience and the LSD experience.

by Cheryl (Creative Commons)

by Cheryl (Creative Commons)

The serotonin system

Neurons transmit their electrochemical signal through the nervous system across chains of long, slender neurons arrayed end to end. At the end of each nerve in the series, there is a small gap called the synapse. These gaps are linked through the synaptic fluid; they do not physically touch the next nerve in the chain. When the electrochemical charge comes to the end of a neuron, it stimulates the release into the synaptic fluid of a chemical that will have a particular geometric form. This neurotransmitter then floats across the synapse and, fitting like a key in a lock, is taken up by a reciprocally structured receptor site. If there is a physical fit – a structural opening into which this neurotransmitter can fit electrochemically, at the molecular level – then the new nerve cell is stimulated to relay an electrical signal down to (and across) the next synapse. Once the electrical signal has been sent, the neurotransmitter that triggered the second neuron to fire is released from the receptor site and sent back into the synaptic fluid – where, ultimately, it is taken up again by the original neuron, to be reused the next time a signal comes down the neuronal path to trigger its release into the synapse.

This is the system Prozac interacts with as a selective serotonin reuptake inhibitor (SSRI). Prozac fits into – and blocks – the reuptake sites in the first neuron, where the serotonin is meant to be reabsorbed and reused. When the serotonin is released by the receptor site and floats back through the synaptic fluid to the first neuron, it finds the reuptake site blocked by the Prozac. As a result, that serotonin bounces back into the synaptic fluid, remaining available and eventually finding its way to the second neuron’s receptor site, stimulating that nerve to fire again. Essentially, Prozac works by keeping more serotonin in play and available to trigger more neuronal firing at serotonin receptor sites.

Psychedelics tend to either mimic or enhance (acting as agonists) or block or diminish (acting as antagonists) the release of neurotransmitters such as serotonin. If you look at structural drawings of the psychedelics, you’ll notice that these substances are structurally quite similar to the neurotransmitters with which they’ve been associated.

The ‘church organ’ metaphor

We must match the effect to the purpose. Familiarity with the particular substance, its action, its usual constellation, and its arc of effects are crucial to a successful experience.

All non-ordinary states of consciousness are similar, by definition, in that they are different from our consensual reality. Many first-time psychedelic users are surprised, sometimes frightened, by the experience and the realization that states of consciousness other than our default, waking state exist at all.

Plant-based or laboratory-conceived psychoactive chemicals mimic or block the operation of neurotransmitters (chemical messengers in the nervous system that influence perception and mood). The numerous neurotransmitters – serotonin, norepinephrine, dopamine, acetylcholine, and the like – act by triggering or blockading the firing of corresponding receptor sites in our brain. The neurotransmitters fit into the receptor sites like keys into locks. The receptor sites associated with each neurotransmitter come in an array of subtypes. For example, serotonin (5-hydroxytryptamine, or 5-HT) has approximately 14 receptor site subtypes. To make this even more complex, most psychedelics operate on more than one neurotransmitter system (for example, peyote interacts with the dopamine and serotonin systems, among others).

One way to get one’s mind around this complexity is to think of structure–activity relationships – the way neurotransmitters trigger (agonize) or blockade (antagonize) receptor sites – using the metaphor of a large church pipe organ with multiple keyboards. Imagine that each keyboard represents a different neurotransmitter system: serotonin on one keyboard, dopamine on the next, and so on. Next, imagine that the white keys represent the release (agonism) of a neurotransmitter and the black keys represent the suppression (antagonism) of a neurotransmitter. Finally, let’s think of chords as the complex interweaving of agonism and antagonism of receptor-site subtypes involved with a particular drug’s mode of action. Using this model, when a subject experiences LSD, for example, serotonin is the neurotransmitter most heard, but ‘chords’ on the dopamine, norepinephrine, and other keyboards are also played. Furthermore, LSD is likely to play a different chord on the 5-HT keyboard than 5-HT itself (because even at the level of individual receptors, the binding action of LSD is not identical to the binding action of 5-HT), adding yet another level of complexity to the mechanism of action. This rich mix of interactions helps explain how each drug, while based on the same building blocks, will often have dramatically different effects.

Tribal societies have a very purposive and articulated natural psychopharmacopia. Living in an entirely natural environment is like living inside a drug store (and grocery store, and hardware store, and church!). Moreover, tribal knowledge gained over millennia makes living in nature’s pharmacy somewhat akin to the pharmacist who has worked in one shop for 40 years and doesn’t have to think about where each item is kept or even about how to combine them into prescribed admixtures.

For example, the active ingredient in the ayahuasca used in the Amazon, dimethyltryptamine (DMT), most commonly comes from the leaves of Psychotria carthagenensis or P. viridis. However, DMT is not active orally, because it is broken down in the gut by monoamine oxidase (MAO) enzymes. As such, tribal users long ago learned to add a separate chemical, a monoamine oxidase inhibitor (MAOI) – most commonly harmine from a vine, Banisteriopsis caapi. Although these are the most commonly used mixtures and all ayahuascas combine some source of DMT (or the closely related 5-MeO-DMT) with some source of MAOI, there are many recipes, and the natives have different names for the various types and strengths of ayahuasca. It is said that when asked how they came to find this exact combination of active substance and activating substance, among the millions of potential combinations of plant leaves, bark, root, or wood, prepared in any number of boiling, grinding, and filtration preparation methods, and then combined with one or more additional substances with similarly complex arrays of potential selection and preparation, Amazonian natives replied, ‘The plants told us’.

While this story may be apocryphal, it is clear that native experimental methods have been effective. Pre-agricultural cultures did not have our formal, institutionalized scientific methods, yet experimental designs were used. For example, systematic comparisons must be made among different types of leaves for their ability to be shaped into a drinking vessel, or among different bones for their tensile strength and ability to hold a sharp edge. Without our institutional science, but with generations of time and traditions, a kind of ‘serial’ experimental control would have been used – a systematic, directed process of trial and error. That is, rather than testing a variety of conditions simultaneously, as we do with experimental treatments and controls, native innovations evolved serially, over time, as prior knowledge was improved upon, trial by trial. This new knowledge was then incorporated into the tribal armamentarium to be maintained and passed down through religious ritual and other, culturally rooted daily behaviors and oral traditions.

While we want to benefit from the tribal perspective, we must not idealize it. Both the tribal and integral worldviews share a unitary philosophy, yet they are distinguished by more than simply differing degrees of organization and technology. There is a difference between the simple unitary view that the environment and self are all part of an underlying, unifying energy, and the more complex experiential unification and integration of previously disparate –sometimes diametrically opposite – elements of a greater whole. The tribal perspective accommodates the material and the spiritual by never splitting the two in the first place. The material world is seen as a fundamentally spiritual place. The integral perspective accommodates the material and the spiritual, already split by modernity, by reuniting them through a transcendence of their duality – an integral perspective, not just a unitary one.

Conclusion: An integral approach to reality

Every worldview contains the seeds of its own eventual dethroning, contradictions that will be explained only by the superseding worldview. Today, it is the integral that is supplanting modernity and postmodernity – the dualism of Descartes being replaced by a worldview that accommodates and integrates opposites: of technology and art, self and other, spirit and flesh. We might refer to this integral approach as a ‘poetry science’ – not the science of poetry, nor poetry about science, but a higher-order worldview that positions modern, industrial, extractive science within a broader, poetical, undergirding context of cosmology, creativity, spirituality, and community.

This integration of seeming opposites seems counterintuitive only when viewed from a Newtonian perspective. When we think of the cosmic level of the universe as a whole, counterintuitive, non-Newtonian concepts such as the Big Bang, time dilation, or a ‘finite yet boundless’ universe are now accepted as normal. Likewise, at the subatomic level of quantum mechanics, we accept seemingly counterintuitive behavior (such as matter springing into existence, or particles communicating instantly over great distances) as the new normal. Yet despite this wonderful insight into nature at the extremes of the subatomic and the cosmic, we still insist that at the human scale, reality is linear, logical, predictable, and mechanistic.

An integral science that can theorize alternate universes can (and must) also accommodate alternate ways to understand living on Earth. How do states of mind differ from the action of neurotransmitters – and how do both differ from spirituality? It is from an integral perspective that we can finally see that even at the human scale, reality is not fundamentally Newtonian. This integral, human-scale perspective is more consistent with the perspectives of quantum mechanics, relativity, and cosmology that supplanted Newton.

An integral science is post-postmodern. That is, after the extractive, power orientation of modernity, after the existential void of postmodern deconstruction, we are now moving toward an integral approach to reality, one that integrates seeming opposites – such as tribal and scientific – and makes us whole again. This perspective is based on a nondual, natural philosophy that sees the universe at times as counterintuitive, but never supernatural. We must also apply that idea to viewing the mind: nothing supernatural – just complex and holistic with emergent properties, such as intelligence and consciousness or self-awareness. The same argument can be applied to the universe as a whole: it is emergent, so what some refer to as ‘miraculous’ is still a fully natural gestalt process. The seemingly miraculous or supernatural is just the nature of the universe itself – a gestalt process fully in effect by which the whole is greater than the sum of the parts.

This is a holistic, spiritual perspective, but also a scientific one. The integral worldview must successively pass through both spiritual and scientific sieves to reveal its fundamental convergent validity. This requires a holistic approach high enough in perspective to recontextualize and with broad enough inclusiveness to embrace the range of what we’ve been referring to as the ‘spiritual’.

Many thinkers describe a complex universe – alive at essence, fundamentally, with consciousness (and, ultimately, love) – as an emergent property of this complexity. A poetry science sees global mind as the emergent property of life on Earth, spiritual wisdom as simply the fully blossomed endpoint of normal human development, and the planet as a Gaian organism, embedded in a Gaian universe – and sees all this not as supernatural, but simply as the normal state of nature. Over the course of my personal and professional development, I have observed three different perspectives on psychospiritual development:

  1. A material view of visionary plants as containing psychoactive chemicals, often extracted or re-created in a laboratory as pharmaceutical drugs, that are seen to interact with endogenous neurotransmitter receptor sites. From this perspective on our personal (and societal) development process, we are conceptually, experientially, and phenomenologically separate from our true self and from everyone else’s true self, or soul.
  1. A psychological perspective oriented toward healing medical ‘pathology’. In this view, we connect with our true underlying self to provide love for our process of personal development, but we still feel separate from others – feeling empathy and compassion for our inner child, yet still cursing the person in the car in front of us who cuts us off on the highway on the way to our job caring for the sick.
  1. A spiritual view of us as incarnated energy, best conceptualized as love or care for others. In this perspective, we are finally connected both to our own true self and to that of all others. Our personality has become transparent and is no longer calling us, distracting us from our underlying true nature. We see the fundamental unity of reality, of all souls, and radiate spiritual love for everyone and everything.

There have been important tools that have helped me to see these perspectives: psychedelics, such as psilocybin and the Mother Vine ayahuasca, that open the heart and illuminate the soul; ayurvedic and tantric philosophy; guided visualization techniques; and daily meditation and yoga, each of which I have found to be effective, nonpsychedelic practices for experiencing transcendence and catharsis in the loving balance so crucial to transformative psychospiritual development.

My fervent hope is that by reading this article, you have been brought along on the path of my own journey in such a way as to better understand and release your own personality, to reidentify with your own true, underlying self – your soul – and that your own life journey will now be clearer, facilitated by, and bathed in, the love of self and others that I believe to be our truest nature.

Acknowledgement: This article is adapted from Neal Goldsmith’s book Psychedelic Healing: The Promise of Entheogens for Psychotherapy and Spiritual Development (Inner Traditions, 2011).

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