University of Groningen
Through ketamine fields
Viana Chaves, Tharcila
DOI:10.33612/diss.107955714
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Publication date: 2019
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Viana Chaves, T. (2019). Through ketamine fields: pain and afterglow. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.107955714
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Chapter 1
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Chapter 1
From the dance floor to the mainstream scientific research
We are living a psychedelic renaissance. It is characterised by the use of psychedelic substances to treat different types of disorders (such as depression, drug dependence, chronic pain, and post-traumatic stress disorder - PTSD) under medical surveillance and based in growing scientific evidence. In this thesis, the focus is on ketamine. However, several other psychedelic substances are showing striking results in managing different sort of disorders. In order to illustrate it, two examples are essential: (a) psilocybin (the main psychoactive compound of the so-called “magic mushrooms”, i.e. mushrooms from the biological genus Psilocybe, among others) for the treatment of depression and (b) MDMA (3,4-methylenedioxymetamphetamine) for PTSD management.Psychedelic drugs have been used by several cultures all around the world for millennia. The use of peyote (active compound: mescaline), iboga (ibogaine), ayahuasca (N,N-Dimethyltryptamine - DMT), and other naturally occurring plants can be traced back to ancient history (1, 2). Psilocybin is a naturally occurring alkaloid found in some specific mushrooms. Controlled, double-blind clinical trials in healthy volunteers show that, under supportive conditions, psilocybin can cause deeply personally meaningful experiences. Psilocybin is a classic psychedelic with a history of use in psychotherapy because it aids emotional insight by lowering psychological defences (3-5). A recent clinical trial that tested the use of psilocybin for the management of treatment-resistant depression (TRD) showed that tolerability to psilocybin is good, with large effect sizes and symptom improvements that appeared rapidly and remained significant six months post-treatment (3).
Petri et al. (2014), presenting a new method to analyse brain networks called “homological scaffolds”, compared the resting-state functional brain activity in fifteen healthy volunteers after intravenous infusion of placebo or psilocybin. The results show that the structure of the brain’s functional patterns undergoes a dramatic change post-psilocybin, as represented by figure 1.1.
According to Petri et al. (2014), “the homological scaffolds represent a new measure of topological importance of edges in the original system […]”. They applied this method to a functional magnetic resonance imaging dataset comprising a group of subjects injected with placebo and another injected with psilocybin. Their findings imply that the brain does not simply become a random system after psilocybin injection, but instead retains some organisational features, albeit different from the normal state. This supports the idea that psilocybin disrupts the normal organisation of the brain with the emergence of strong, topologically long-range functional connections that are not present in a normal state (6).
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than fixed structural ones as may be the case for acquired synaesthesia [52]. Broadly consistent with this, it has been reported that subjects under the influence of psilocybin have objectively worse colour perception performance despite subjectively intensified colour experience [53].
To summarize, we presented a new method to analyse fully connected, weighted and signed networks and applied it to a unique fMRI dataset of subjects under the influence of mushrooms. We find that the psychedelic state is associ-ated with a less constrained and more intercommunicative mode of brain function, which is consistent with descriptions of the nature of consciousness in the psychedelic state.
7. Methods
7.1. Dataset
A pharmacological MRI dataset of 15 healthy controls was used for a proof-of-principle test of the methodology [54]. Each subject was scanned on two separate occasions, 14 days apart. Each scan consisted of a structural MRI image (T1-weighted), followed by a 12 min eyes-close resting-state blood oxygen-level-dependent (BOLD) fMRI scan which lasted for 12 min. Placebo (10 ml saline, intravenous injection) was given on one occasion and psi-locybin (2 mg dissolved in 10 ml saline) on the other. Injections were given manually by a study doctor situated within the scan-ning suite. Injections began exactly 6 min after the start of the 12-min scans, and continued for 60 s.
7.1.1. Scanning parameters
The BOLD fMRI data were acquired using standard gradient-echo EPI sequences, reported in detail in reference [54]. The volume repetition time was 3000 ms, resulting in a total of 240 volumes acquired during each 12 min resting-state scan (120 pre- and 120 post-injection of placebo/psilocybin).
functional data to the middle volume of the acquisition using the FMRIB linear registration motion correction tool, generating a six-dimension parameter time course [55]. Recent work demon-strates that the six parameter motion model is insufficient to correct for motion-induced artefact within functional data, instead a Volterra expansion of these parameters to form a 24 parameter model is favoured as a trade-off between artefact cor-rection and lost degrees of freedom as a result of regressing motion away from functional time courses [56]. fMRI data were pre-processed according to standard protocols using a high-pass filter with a cut-off of 300 s.
Structural MRI images were segmented into n ¼ 194 cortical and subcortical regions, including white matter cerebrospinal
fluid (CSF) compartments, using FREESURFER(http://surfer.nmr.
mgh.harvard.edu/), according to the Destrieux anatomical atlas [57]. In order to extract mean-functional time courses from the BOLD fMRI, segmented T1 images were registered to the middle volume of the motion-corrected fMRI data, using bound-ary-based registration [58], once in functional space mean time-courses were extracted for each of the n ¼ 194 regions in native fMRI space.
7.1.3. Functional connectivity
For each of the 194 regions, alongside the 24 parameter motion model time courses, partial correlations were calculated between all couples of time courses (i,j), non-neural time courses (CSF, white matter and motion) were discarded from the resulting functional connectivity matrices, resulting in a 169 region corti-cal/subcortical functional connectivity corrected for motion and additional non-neural signals (white matter/CSF).
7.2. Persistent homology computation
For each subject in the two groups, we have a set of persistence
diagrams relative to the persistent homology groups Hn. In this
paper, we use the H1 persistence diagrams of each group to
construct the corresponding persistence probability densities
Figure 6. Simplified visualization of the persistence homological scaffolds. The persistence homological scaffolds Hplap (a) and Hpsip (b) are shown for comparison.
For ease of visualization, only the links heavier than 80 (the weight at which the distributions in figure 5a bifurcate) are shown. This value is slightly smaller than the bifurcation point of the weights distributions in figure 5a. In both networks, colours represent communities obtained by modularity [49] optimization on the placebo persistence scaffold using the Louvain method [50] and are used to show the departure of the psilocybin connectivity structure from the placebo baseline. The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration. A labelled version of the two scaffolds is available as GEXF graph files as the electronic supplementary material. (Online version in colour.)
rsif.r oy alsocietypublishing.org J. R. Soc. Interfa ce 11 :20140873 8
Figure 1.1: Simplified visualisation of the homological scaffolds: (left) placebo and (right) psilocybin scaffolds. The width of the links is proportional to their weight and the size of the nodes is proportional to their strength. Note that the proportion of heavy links between communities is much higher (and very different) in the psilocybin group, suggesting greater integration (6).
Another substance that has been showing interesting results in the management of some mental disorders is MDMA. It is different than psilocybin in regard to its non-natural origin. From its roots as an agent to assist psychotherapy in the 1970s and 80s, to its wide scale popularity as the recreational drug “ecstasy” in the rave scene of the 90s, to its contemporary re-emergence as a potential tool for treating PTSD, the controversy around the medical use of MDMA is so big that the debate about its risks and safety is steeped in political issues that threaten to undermine the basic principles of evidence-based medicine. MDMA is emerging as the leading drug in announcing this new form of medical treatment: psychedelic drug-assisted psychotherapy for the treatment of anxiety-based disorders (1).
Psychiatrists and psychotherapists in the United States (in the 1970s until 1985) and Switzerland (between 1988 and 1993) used MDMA legally as a prescription drug to enhance the effectiveness of psychotherapy (7). But it was not until 2010 that Michael Mithoefer, working with the Multidisciplinary Association for Psychedelic Studies, would publish the world’s first randomised controlled study testing MDMA-assisted therapy against placebo, without any evidence of harm (8). MDMA has been researched for its potential role in treating PTSD, a severe anxiety-based psychiatric
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Chapter 1
disorder, with a high level of treatment-resistance, and high rates of mortality from suicide (1).
Finally, this psychedelic revival also brings ketamine, which has proven to be useful for the rapid relief of depressive symptoms, for providing an acute interruption of suicidal intent, and for the control of agitated suicidal and aggressively psychotic individuals in the emergency room setting (9). It is the first modern legal psychedelic medicine in use. It has been used as an anaesthetic since the 1960s. Ketamine hydrochloride was invented in 1962 by the American pharmacist Calvin Stevens at the Wayne State University, in the United States. Like all the arylcyclohexylamines (the chemical group that ketamine belongs to), it blocks N-methyl-D-aspartate (NMDA) receptors, preventing them from being activated by the neurotransmitter glutamate (10). More about its mechanism of action is presented in chapters 2, 3 and 5.
In 1964, ketamine was given to a human being for the first time by Edward Domino (11). It was found to be a potent psychedelic drug, and the effects were described as trance-like. In 1966, ketamine was patented by Parke-Davis for use as an anaesthetic in humans and other animals. In 1970, the United States Food and Drug Administration (FDA) approved it for use in children and the elderly. By the end of the 1970s, the FDA was worried about ketamine on the streets. In the following years, ketamine has moved to the mainstream with the consolidation of a dance culture, connected to rave parties, night clubs, and the underground scene (10). Although ketamine is an anaesthetic, it can be a powerful stimulant at lower doses, and it is usually used in combination with other drugs (see chapters 4 and 6). The album “Dig your own hole” (figure 1.2), by the electronic music duo The Chemical Brothers, gives a good example of how the dance and drug cultures are connected: its ninth track is entitled “Lost in the K-hole” (12); “K” is a common nickname for ketamine, while the “K-hole” is a state of deep introspection, filled with hallucinations, and even out-of-the body sensations, caused by ketamine.
Figure 1.2: Cover of the classic electronic music album “Dig your own hole” by The Chemical Brothers (12).
Aims and outline of this thesis
This thesis aims to provide a wide analysis about the use of ketamine as a depression, PTSD and chronic pain medicine, from the users’ point of view to brand new scientific data. Furthermore, the exploration of the accidents and fatalities that recreational and medical uses of ketamine can cause is also an objective of this thesis.
Chapter 2 introduces the review article entitled “Oral ketamine for the treatment of pain and treatment-resistant depression”, published in the British Journal of Psychiatry (13). Appendices 1, 2 and 3 also contain information gathered by this study.
The third chapter presents the piece “Special features of special K: applications for pain and depression treatments”, referring to ketamine through another nickname: special K. It is published in the book “Breaking Convention: psychedelic pharmacology for the 21st century”. The Breaking Convention is the largest and most relevant psychedelic science conference in Europe.
Following the need for more information regarding the consequences of ketamine use, chapter 4 presents the article “The use of ketamine to cope with depressive symptoms: a qualitative analysis of the discourses posted on a popular online forum”, where the qualitative method was applied in order to perform a
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Chapter 1
content analysis in the discourses of Bluelight members. Bluelight is an online drug forum, with precious information about self-medication with ketamine.
On chapter 5, “Ketamine as a new management tool for persistent physical and mental pain” discusses the development of central nervous system sensitisation (also known as “central sensitisation”) in the aggravation of chronic physical pain, its relationship to depression, and how ketamine can be useful to treat both.
Chapter 6 introduces a systematic review about overdoses and deaths connected not only to ketamine, but also to its analogues (e.g. phencyclidine and methoxetamine). “Overdoses and deaths related to the use of ketamine and its analogues: a systematic review” examines several cases reported in the scientific literature and brings a relevant discussion about the dangers of ketamine use, in medical and non-medical settings.
Lastly, chapter 7 provides a general discussion on the topic, including future perspectives and recommendations for upcoming research.
References
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hallucinogenic powers. Rochester: Healing Arts Press; 1996.
3. Carhart-Harris RL, Bolstridge M, Day CMJ, Rucker J, Watts R, Erritzoe DE, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology. 2018;235(2):399-408.
4. Carhart-Harris RL, Leech R, Williams TM, Erritzoe D, Abbasi N, Bargiotas T, et al. Implications for psychedelic-assisted psychotherapy: functional magnetic resonance imaging study with psilocybin. British Journal of Psychiatry. 2012;200(3):238-44. 5. Griffiths RR, Johnson MW, Richards WA, Richards BD, Jesse R, Maclean KA, et al.
Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors. Journal of Psychopharmacology. 2018;32(1):49-69.
6. Petri G, Expert P, Turkheimer F, Carhart-Harris R, Nutt D, Hellyer PJ, et al. Homological scaffolds of brain functional networks. Journal of The Royal Society Interface. 2014;11(101):20140873.
7. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD). Journal of Psychopharmacology. 2013;27(1):40-52.
8. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of ±3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of Psychopharmacology. 2011;25(4):439-52.
9. Wolfson P. Introduction to “The ketamine papers”. In: Wolfson P, Hartelius G, editors. The ketamine papers: science, therapy, and transformation. Santa Cruz: Multidisciplinary Association for Psychedelic Studies; 2016. p. 1-23.
10. Jansen K. Ketamine: dreams and realities. Santa Cruz: Multidisciplinary Association for Psychedelic Studies; 2000.
11. Domino EF, Domino EF. Taming the ketamine tiger - 1965. Anesthesiology. 2010;113(3):678-84.
12. The Chemical Brothers. Dig your own hole. London: Orinoco Studios; 1997.
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