In 1957, psychiatrist Humphry Osmond wrote in a letter to Aldous Huxley:
To fathom Hell or soar angelic
Just take a pinch of psychedelic.
Osmond coined the word psychedelic, from Greek root words psyche (breath, life, spirit, mind) + delos (clear, manifest) to refer to a class of drugs that he had been conducting research on; a class of drugs which was thought to make consciousness visible. The psychedelic drug is a psychoactive hallucinogen, i.e., a drug that crosses the blood-brain barrier to induce altered states of consciousness. Classical psychedelics such as LSD, magic mushrooms, mescaline, and DMT (as opposed to other hallucinogens such as dissociatives,e.g., ketamine; and deliriants,e.g.,datura) are also known as serotonergic psychedelics. These serotonergic psychedelics are known as such because they are 5-HT2a agonists, explanation follows.
Serotonin, a neurotransmitter (a chemical that transmits signals from one brain cell to another), activates the serotonin receptors, also known as the 5-HT receptors. The 5-HT receptors modulate the release of various neurotransmitters and hormones. These receptors play a role in biological and neurological processes, such as appetite, cognition, mood, and sleep. An agonist is a chemical that binds to a receptor and activates that receptor.
Essentially, classical psychedelics activate the 5-HT receptors, and more specifically, the 5-HT2a receptors (though some activate additional receptors). The 5-HT2a receptor is expressed throughout the central nervous system, with high concentrations in the prefrontal (brain region considered responsible for the organization of thoughts in accordance with goals, among other responsibilities), parietal (integrates sensory information), and the outer layer of the cerebral cortex (associated with, not exclusively, memory, attention, thought, language, and consciousness). The 5-HT2a receptor modulates learning, anxiety, behavior, and neuronal excitation in the central nervous system.
The molecular structure of many psychedelic drugs is very similar to that of serotonin. This may account for the psychedelic drugs’ affinity for the serotonin receptor. Serotonin has been likened to a “key,” by Franz Vollenweider, in which the receptors are the lock. If the “key” is slightly different, it may still go in the lock, but it won’t quite fit, and will make modifications to the neural process. Given that the areas in which the 5-HT2a receptors are the most dense are associated with cognition and perception (the posterior cingulate cortex), and where the receptors are the least dense are associated with motor control (the primary motor cortex), it makes sense that subjective accounts of psychedelic drug use find that motor skills are not generally impaired, whereas consciousness is greatly altered.
The theory that psychedelic drugs interact with serotonin receptors is widely accepted; largely because of work by Dr. Franz Vollenweider demonstrating that the hallucinogenic effects of psilocybin can be blocked by a 5-HT2a receptor antagonist like ketanserin. However, the serotonergic system is complex; while the drugs may begin in the 5-HT2a receptor, they go on to change intracellular signalling pathways, and possibly alter gene expression. How these drugs create changes in the brain, through their role as serotonin agonists, is becoming basic to the understanding of their processes; but finding out what those changes are, and what they mean to cognition and behavior is still in early stages of research.
Franz Vollenweider, Director of the Heffter Research Institute in Zurich, has over 80 publications, most of which investigate the mechanisms of psychostimulants and hallucinogens in humans. In 1997, Vollenweider employed the functional imaging technique, Positron Emission Tomography (PET), to view the brain under the influence of psilocybin. The hypothesis was that excessive activation of serotonin receptors by psilocybin will result in a “sensory overflow of the frontal cortex associated with the sensory flooding and cognitive fragmentation seen in psilocybin and naturally occurring psychosis. »
Ten volunteers with no drug experience were chosen from hospital and university staff. They were administered 15-20mg of psilocybin (depending on the weight of the volunteer) orally, via capsules, 90 minutes before the FDG injection (fluorodeoxyglucose – a substance necessary to the PET scan process). Vollenweider devised methods for plotting subjective data in order to compare it with objective readings from the PET scan, and reach working conclusions about the areas in the brain responsible for various processes – and how those processes are altered by psilocybin. He compared findings from the psilocybin scans to known information on the mechanisms of psychotic states. Vollenweider found that psilocybin, “variously increased absolute cerebral metabolic rates of glucose in most of the brain regions examined…Whole brain glucose metabolism was increased in all subjects” and that the increases significantly correlated with the amount of psilocybin administered.
Results were as expected, namely that psilocybin “leads to hyperfrontal metabolic pattern associated with acute psychotic symptom formation. » However, it was noted that patients were able to recognize their altered consciousness as abnormal and attribute it to the drug. The findings are said to be in line with studies done on mescaline, and LSD testing in rats.
The conclusion reached by Vollenweider was that an increase in metabolic activity in the frontal cortices of the brain might contribute to ego disintegration and derealization phenomena. It was also speculated that functional integrity, or the communication between brain regions was compromised by psilocybin.
Functional connectivity under psychedelics is an idea explored in a study by Dr. Robin Carhart-Harris et al., Broadband Cortical Desynchronization Underlies the Human Psychedelic State, 2013. Post-doctoral researcher Dr. Robin Carhart-Harris at the Centre for Neuropsychopharmacology, Imperial College London, has conducted a number of clinical trials studying the effects of psychedelic drugs on the human brain. This is the first study to use the neuroimaging technique magnetoencephalography (MEG) to look at the brain under the influence of psilocybin. The MEG records magnetic fields produced by naturally occurring electrical currents in the brain. For this study, 15 volunteers with previous psychedelic drug experience, though not in the last 6 weeks, were administered 2mg of psilocybin intravenously. When administered this way, the drug takes hold within seconds. Similar in some ways to the results of the Vollenweider study, the functional connectivity of the brain was compromised. Meaning that areas of the brain which normally operate in conjunction, were no longer. There was a general collapse of the normal rhythmic structure of cortical activity. Particularly affected are key structural hubs within the brain; the medial prefrontal cortex (implicated in planning and personality) and the posterior cingulate cortex (implicated in emotion, autobiographical memories and awareness) significantly decreased in positive coupling under psilocybin.
The MEG study also replicated the results of a number of other fMRI and EEG studies conducted by Carhart-Harris et al. Namely that psychedelics decrease cerebral blood flow in high-level association regions and important connector hubs.
It should be noted that many of the studies by Carhart-Harris have aspects that contradict those undertaken by Vollenweider and team. Whereas Vollenweider found increased activity in the brain,particularly in the frontal cortex, Carhart-Harris found that psilocybin caused a decrease in brain activity. However, the recent study by Carhart-Harris in conjunction with Suresh Muthukumaraswamy et al., reports the findings as entirely consistent with related research as “excitation of deep-layer pyramidal cells is consistent with decreased brain activity. » Essentially, the cells that are excited by the presence of the psychedelic in turn decrease functional connectivity in high-level brain regions.
Carhart-Harris has presented the most accessible model of the psychedelic effect on the brain, however reliable. His paper The Entropic Brain takes the current research a step further by updating Freudian psychoanalysis to reflect findings in neuroscience. He presents a theory of the brain which consists of two states: primary and secondary. The primary state is one of high entropy – disorganization – likened to that found in infancy, in dreams,in psychosis, and in the psychedelic state. The secondary state is one of low entropy – high organization – and likens an entropy-free brain to one of complete rigidity, as seen in sedation, seizure, OCD, depression, and addiction. His theory, based on sound neuroscience, though interpreted with certain enthusiasm, may be a way of understanding mental illness.
The Default Mode Network is a central hub in the brain which organizes brain regions responsible for high-level thought (self-reflection, autobiographical memory, daydreaming). It is when this network is relatively suppressed and entropy is limited, that we are able to view a stable reality as opposed to one informed by wishes, fantasies and fears.
Brain scans using fMRI of long term practitioners of meditation have found both long and short term differences within the main nodes of the Default Mode Network: the medial prefrontal and the posterior cingulate cortex. Namely, that the mPFC and the PCC are “less active in meditators. » But interestingly, there is an increase in DMN connectivity, suggesting that the reduced mental activity during meditation is mediated by an increase in connectivity of networks controlling internal attention. The mind of the meditator is essentially trained, able to focus on internal processes without the negative rumination indicative of depression.
Individuals with depression are thought to have overactive DMNs (specifically in the medial prefrontal cortex), i.e., to be low in entropy, which is somewhat of an antithesis to the psychedelic state. A drug like psilocybin has the ability to suppress the over-active Default Mode Network, allowing for disorganization; for well-tread paths to grow over; if only long enough that one can have a glimpse of a world outside of themselves.
It has also been indicated in early studies with psilocybin and LSD that psychedelics are effective in treatments for Obsessive Compulsive Disorder. The entropy theory rates OCD high on a scale of entropy suppression and rigidity, making it a candidate for the DMN suppressing qualities of psychedelic drugs, and in fact, research suggests positive results:
“…a study showing that psilocybin given on four different occasions at escalating doses (ranging from sub-hallucinogenic to hallucinogenic doses) markedly decreased OCD symptoms (by 23%-100%) on the Yale-Brown obsessive compulsive scale in patients with OCD who were previously treatment resistant. »
Like depression and OCD, the Default Mode Network and its associated brain regions may have some role to play for those with addictions.
An analysis of data regarding LSD and the treatment of alcoholism over the past 40 years compiled by researcher Teri Krebs and clinical psychologist Pål-Ørjan Johansen finds a significant beneficial effect of LSD on alcoholism in the short and medium term. A total of 6 trials and 536 patients were analyzed. Participants were all involved in alcohol treatment programs, 38% of which showed improvement without LSD; 59% of which showed improvement after receiving between 210 and 800 micrograms. Given the results, the paper states that it is “puzzling why this treatment approach has been largely overlooked. »
In fact treating alcoholics with LSD was one of the earliest clinical uses of the drug. In 1952 Dr. Abram Hoffer and Dr. Humphrey Osmond began investigating LSD as treatment for alcoholism. Preliminary research was positive, and the word began to spread. Author Gerald Heard, friend and mentor to Alcoholics Anonymous co-founder Bill Wilson introduced Bill to writer Aldous Huxley. Huxley is known for his experiments with psychedelic drugs and suggested to Wilson that he work with Hoffer and Osmond. Apparently, Wilson was initially “unthrilled” by the idea, but later found great value in their work. Of Wilson’s experience, Huxley has written:
A friend of mine, saved from alcoholism, during the last fatal phases of the disease, by a spontaneous theophany… has taken lysergic acid two or three times and affirms that his experience under the drug is identical with the spontaneous experience which changed his life…There is, obviously, a field here for serious and reverent experimentation.
– Aldous Huxley to Father Thomas Merton, 10 January 1959
Of psychedelics, pharmacologist Dr. David E. Nichols states that the feature which distinguishes them from other classes of drugs is their capacity to induce states of altered perception that are not otherwise experienced except in times of dreams or religious exaltation. A drug that can induce exaltation, epiphany, profundity, is by definition, in a class by itself. The study of these drugs is essential to the understanding of consciousness and psychiatric disorders. If not for the panicked response by the US DEA and FDA (as well as analogous organizations in other countries) to suppress 1960s counter-culture and control irresponsible psychedelic drug use by over-regulating professionals and ignoring high-level government experimentation (CIA), psychedelic drug research may be farther along today. With applications from alzheimer’s to autism, psychedelic drug research is incredibly important to the future of cognitive neuroscience.