This article involves addressing the neurobiological mechanisms of psychedelic drugs, the resulting changes in brain activity and integration of traditional viewpoints. Science is still at the early stages of understanding psychedelic molecular mechanisms and even further from understanding the psychedelic state as any scientist who has experienced it is aware.
Current Classification of Psychedelics?
The field of psychedelic neuroscience has witnessed a recent renaissance following decades of restricted research due to their legal status. As this is a relatively new field, there are incongruences in the literature related to terminology, classification, content, and effect of the various psychedelics.
- The term “psychedelic” means mind-revealing and psychedelics have exceptional anti-amnesic effects and are able to “make conscious” that which was previously unconscious through changes in brain “state,” but also there is growing evidence which demonstrates the role of epigenetic mechanisms. This supports traditional therapeutic use of psychedelics to heal ancestral trauma. Details of these mechanisms are provided along with suggestions for further research.
Currently, psychedelics are grouped according to their neuro-receptor affinities into classic and atypical psychedelics, each with individual treatment potentials and abilities to elicit potent acute experiences and long-lasting changes in neurobiology through concurrent activation of several neuro-modulatory systems. The presently accepted classification of psychedelics includes classic psychedelics and atypical/non-traditional/non-classical psychedelics.
- Classic psychedelics are the phenethylamines such as 3,4,5-trimethoxy-phenethylamine (mescaline, derived from Cactaceas plant family including peyote cactus), tryptamines such as 5-methoxy-dimethytryptamine (5-MeO-DMT; which can be synthetically produced, but also found in Bufo alvarius toad venom and several plants including Anadenanthera peregrina, derivative colloquially referred to as Amazonian yopo snuffs), N,N-dimethyltryptamine (N,N-DMT; found in ayahuasca a brew made with Banisteriopsis caapi vine and other ingredients), N,N-dimethyl-4-phosphoryloxytryptamine (Psilocybe genus of mushrooms) and ergolines such as lysergic acid diethylamide (LSD; derived from lysergic acid extracted from ergot fungus).
- Atypical psychedelics can be further divided into dissociative psychedelics (N-methyl-d-aspartate receptor-NMDA antagonists), e.g., phencyclidine (PCP; original synthesis was toward an anesthetic), ketamine (an amnesic surgical anesthetic) and ibogaine (derived from Apocynaceae family of plants), as well as cannabinoid agonists (e.g., Δ9-tetrahydrocannabinol (Δ9-THC) from cannabis), muscarinic receptor antagonists (e.g., scopolamine initially synthesized for anesthesia), and entactogens (e.g., 3,4-methylendioxymethampheamine-MDMA-“ecstasy”).
Problems within the Field of Psychedelic Neuroscience
Problematic in the field, perhaps more so than in other fields, is the issue of conflicting results, likely due to the limited research. For example, there is conflicting evidence as to whether or not the low 5HT2A affinity of ibogaine has any functional relevance – one study found that the 5HT2A receptor antagonist, ketanserin, blocked the effect of noribogaine on structural plasticity yet both ibogaine and noribogaine failed to induce head-shake response in rats, a behavior which is seen to be comparable to hallucinations in humans and mediated by 5HT2A activation suggest that this result supports the subjective experiences in humans, where ibogaine does not produce the typical interferences in thinking, identity distortions, and space–time alteration, which are produced by the classic psychedelics.
- A second example, where there is confusion is the literature regarding 5-MeO-DMT. 5-MeO-DMT is described as being a constituent of ayahuasca, while it is evidenced that ayahuasca holds a high concentration of N,N-DMT, 5-MeO-DMT concentration is either non-existent or negligible in most brews and the ayahuasca psychedelic experience bears little to no resemblance to an experience with 5-MeO-DMT.
Then cannabis research is possibly the best example of conflicting psychedelic research. As reviewed, evidence as to whether cannabis use is associated with adverse effects to mental health or cognition in humans is equivocal. There are also many divergent results in the functional human neuroimaging studies. Indeed, this is a new and growing field of research, and more research is required to uncover the various psychedelic drugs, their active components and neurobiological effects.
Neurobiology of Psychedelic Therapy for Depression and Addiction
Classic psychedelics and dissociative psychedelics are known to have rapid onset antidepressant and anti-addictive effects, unlike any currently available treatment. Randomized clinical control studies have confirmed antidepressant and anxiolytic effects of classic psychedelics in humans. Ketamine also has well established antidepressant and anti-addictive effects in humans mainly through its action as an NMDA antagonist. Ibogaine has demonstrated potent anti-addictive potential in pre-clinical studies and is in the early stages of clinical trials to determine efficacy in robust human studies.
Psychedelics are not only known to have rapid onset, but their effects persist long after their acute effects; this includes changes in mood and brain function. These effects are suggested to result from their unique receptor affinities which affect neurotransmission via neuro-modulatory systems which then serve to modulate brain activity, i.e., neuroplasticity. These lasting effects are reported to promote cell survival, be neuroprotective, and modulate neuroimmune systems of the brain. The mechanisms which lead to these long-term neuro-modulatory changes have been linked to epigenetic modifications and gene expression changes. These psychedelic drug effects, previously under-researched, may potentially provide the next generation of neurotherapeutics, where treatment resistant diseases, e.g., depression and addiction, may become treatable with attenuated pharmacological risk profiles.
Further, it is acknowledged that classic psychedelics have an extremely low potential for abuse, and it is suggested that stimulation of 5HT2C receptors limits their potential for addiction and that their therapeutic effects are mediated by acute 5HT2C receptor stimulation followed by sustained downregulation of 5HT2A and 5HT1A receptors. Investigation into the complex mechanisms of action of classic psychedelics which lead to its anti-depressant and anti-addiction properties via the serotonergic system continues to gain momentum, e.g., minimal research has investigated the role of 5HT7 activation by psychedelics, but has been suggested to play a role in classic psychedelic anti-addiction properties, specifically 5-MeO-DMT in alcohol use disorder.
Neurobiology of the Psychedelic Experience
The psychedelic experience can produce eyes-closed and eyes-open imagery. The imagery can be clear and visual, or it can have a dream-like quality with strong emotions and insights. There is also often heightened memory retrieval where long-forgotten memories are retrieved with exceptional clarity and detail. A common experience on ibogaine, for example, is that one’s life flashes before their eyes as clear as if they were watching a movie about their life. The neurophysiological mechanisms that facilitate the psychedelic experience are largely unknown, but progress is being made in understanding how the neurochemical profile of psychedelics elicits this effect, bringing that which was previously unconscious to the conscious mind.
The differences in the psychedelic state elicited by the various classic and atypical psychedelics hold promise in differentiating the exact neuroreceptor-mind interactions. Neuroreceptors are coded by individual genes and extensive genetic variation exists in the population for these neuro-modulatory systems. Variation in the neuroreceptor-mind interactions, thus, holds further promise for psychiatric neuro-genomics research as it will uncover how individual genetic variation in the neuro-modulatory systems affects different psychedelic states and changes in neurobiology.
The serotonergic system’s involvement in the psychedelic state has received the most research attention and has provided new insights related to the neurochemical mechanisms underlying changes in brain network activity and perfusion. Serotonin is involved in many neurological (e.g., epilepsy) and psychiatric (e.g., depression) diseases. Serotonin receptors may directly or indirectly depolarize or hyperpolarize neurons by changing the ionic conductance and/or concentration within the cells and is able to change excitability within brain networks.
- For example, pharmacological magnetic resonance imaging (phMRI) in rats indicates that psilocin induces brain signal increases in olfactory and limbic areas and brain signal decreases in somatosensory and motor cortices. 5-MeO-DMT disrupts cortical activity and low frequency cortical oscillations in the frontal cortex of rats with alternating activity in frontal and visual areas associated with psychedelic effects.
Studies point toward not only brain network activity changes but also significant increases in hemodynamics. Increased cerebral blood flow has been reflected in temperature record of different brain areas with administration of MDMA, increased blood flow to the cortex correlated with increased neuronal activity as expected, however within the thalamus increased blood flow negatively correlated with increased neuronal activity.
- A psilocybin study reported decreased local field potentials to sensory stimuli while hemodynamic response was enhanced. These data support a brain “state” change, but also require us to challenge our knowledge of the nature of this differential activity, neural versus hemodynamic, and their interplay which leads to the psychedelic experience.
Human brain imaging studies are limited, the neurophysiological underpinnings are largely speculative while the findings are interesting and need to be further investigated. For example, an LSD functional MRI (fMRI) study found increased hemodynamic activity within brain areas rich in 5HT2A receptors and globally, the authors conclude that this reflected increased functional connectivity and that this increased activity led to ego dissolution. Then a psilocybin fMRI study found decreased hemodynamic activity within the thalamus and anterior and posterior cingulate cortices, where the decreased activity in the anterior cingulate correlated with the psychedelic experience.
The Link Between Psychosis and Psychedelics
A population study which investigated psychedelic use in Norway, in 2013, reported that from their 21,967 respondents, 13.4% reported lifetime psychedelic use, and found no significant association with mental health outcomes; in fact, there were several instances where psychedelic use was associated with lower rate of mental health problems. The use of psychedelics, such as cannabis, when psychosis does develop and persists, is suggested to result from an interaction of genes and the environment, as an example; multiple natural genetic variations interact with cannabis and other environmental factors (stress) to increase the risk of developing psychosis. Ergo, psychedelics alone do not produce psychosis or psychotic disorder, as an individual needs to be genetically predisposed or carry a greater risk profile or susceptibility to developing psychosis.
More research needs to focus on psychedelic “microdosing,” as it is known in the field. As mentioned by Murnane, sub-psychedelic doses of psychedelic compounds have been found to assist with certain disorders or conditions which is common practice within the psychedelic communities; however, there is only one human study in the literature which demonstrated that microdosing psilocybin had a positive effect on creativity. Additional controlled studies in this area could be of tremendous value in the field.
Another area that requires further research is combination psychedelic therapy. Traditional practitioners often use psychedelics in combination and have been doing so for many generations. Researchers propose a theory as to how 5-MeO-DMT and ibogaine used in sequential administration would be more effective in treating addiction than either one on its own. The combined neurotransmitter profile of the two compounds would likely have an augmented effect when used in combination but as this is the first study of its kind assessing combined psychedelic therapy, more research is needed to uncover poly-psychedelic pharmacology.
Additionally, the neuroimaging and electrophysiological research that has been performed clearly reports that there are changes in brain “state” and authors suggest that this may be related to de-coupling of certain brain networks, yet to be fully identified.
Lastly, the identification of non-psychedelic compounds with similar serotonergic and glutamatergic receptor affinities as psychedelics has been proposed to be an important area for future research, with view to potential anti-neuroinflammatory properties.