The altered state of consciousness induced by Δ9-THC
Introduction
Altered states of consciousness (ASC) represent an acute and marked deviation in subjective experience from normal/waking consciousness (Dittrich, 1998, Studerus et al., 2010). ASC arise through diverse induction mechanisms including psychoactive drugs, breathing and meditative techniques, or sensory deprivation. Despite these differences, ASC contain shared features or characteristics (Schmidt and Berkemeyer, 2018, Studerus et al., 2010, Watts, 1968). Therefore, the experimental induction of ASC has become a topic of interest in the field of cognitive neuroscience toward relating changes in phenomenological states to underlying biophysical mechanisms (Schmidt & Berkemeyer, 2018). The identification of neurobiological substrates underlying both health (e.g., mindfulness) and disorder (e.g., psychosis) is an important goal for neuroscience and psychiatry.
Δ-9 tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, is one compound that may reliably induce ASC (Earleywine et al., 2021, Zaytseva et al., 2019). Despite shifts in the global policy landscape related to cannabis use, very little is known empirically about the nature of subjective effects induced by cannabis or THC, including which effects may be mediated by THC alone or THC in combination with other compounds within the cannabis plant (LaVigne et al., 2021, Morgan et al., 2018). Case reports on the subjective effects of cannabis have detailed robust alterations of cognition and perception (Barrett et al., 2018, Keeler et al., 1971, Perna, 1969) resulting in early classifications for cannabis as a “hallucinogen” (Keeler et al., 1971). Specifically, early questionnaires probed respondents for alterations that had occurred “while under the influence of marijuana.” 90% of respondents endorsed seeing “colors or objects as more intense,” ∼50% endorsed “hallucinating colors or designs” and about a third “felt closer to God, nature, mankind, or felt better able to understand the meaning of the universe.” (Keeler et al., 1971). More recent placebo-controlled studies in laboratory settings have found that the magnitude of subjective effects elicited by THC alone are roughly comparable to those elicited by cannabis containing the same doses of THC (Wachtel et al., 2002).
In the brain, THC activates cannabinoid (CB1) receptors predominately expressed throughout the cortex, cerebellum, hippocampus, amygdala and striatum (Mackie, 2005). In these regions, CB1 receptor activation directly regulates the release of inhibitory (GABA) and excitatory (glutamate) neurotransmitters and indirectly regulates the release of neuromodulators including dopamine and serotonin (Araque et al., 2017). Primarily, CB1 receptors regulate the release of GABA from inhibitory interneurons in the cortex, thereby facilitating or disinhibiting excitatory output from projection neurons to activate brain regions (Fortin et al., 2004, Kiritoshi et al., 2016, Kovacs et al., 2012). Neuroimaging studies consistently show increased cerebral blood flow after THC indicating greater activation of the frontal cortex, insula, and cingulate (for review see (Bloomfield et al., 2019)), brain regions critical for self-awareness, consciousness and cognition (Craig, 2009, de Souza et al., 2014, Hadland et al., 2003, Huang et al., 2021, Miller et al., 2002). Acute THC administration also affects neural networks, including blocking the deactivation of the rest-related default-mode network during intended task engagement (Bossong et al., 2013). THC similarly affects neural oscillations by blocking reductions in the rest-related alpha wave during intended task engagement, analogous to the default-mode network findings (Murray et al., 2022).
Serotonin (5-HT)2A receptor agonists, also known as classical psychedelics, are more often associated with ASC than CB1 agonists (Liechti et al., 2017). The past decade has seen a resurgence of clinical studies with compounds that activate the 5-HT2A receptor, including psilocybin and lysergic acid diethylamide (LSD) (Davis et al., 2021, De Gregorio et al., 2021, Nutt et al., 2020, Tullis, 2021). The subjective effects of these compounds may be instrumental in mediating therapeutic outcomes (Preller et al., 2017, Yaden and Griffiths, 2021), and more broadly, may aid in empirical studies of consciousness (Bayne and Carter, 2018, Yaden and Griffiths, 2021). 5-HT2A receptors are present throughout the cortex, and their activation has been shown to promote diverse network connectivity, or “entropy,” across the brain (Carhart-Harris and Friston, 2019, Carhart-Harris et al., 2014) in part through facilitating the release of the excitatory neurotransmitter glutamate from thalamocortical nerve fibers (Aghajanian and Marek, 2000, Beique et al., 2007, Nichols, 2016, Preller et al., 2019). Unlike CB1, 5-HT2A activation impacts all frequency bands of brain waves by reducing the power, or amplitude, of these neural oscillations at rest (Muthukumaraswamy et al., 2013). Notably, this occurs even after the administration of “microdoses” (i.e., 13 and 26 µg LSD) below the threshold of intoxicating effects, yet not after high doses (15 mg) of THC, indicating that broadband reductions in oscillatory power, which may be associated with therapeutic outcomes, are not a necessary biophysical feature of ASC (Murray et al., 2022, Murray et al., 2021). To what extent the phenomenological features of ASC induced by 5-HT2A agonists compare to the CB1 agonist THC is a major aim of the current study.
In addition to 5-HT2A and CB1 receptor systems, ASC may be induced by other pharmacological and non-pharmacological means, including dissociative drugs such as ketamine, entactogens such as 3,4-methylenedioxymethamphetamine (MDMA), continuous exposure to visual and auditory stimulation (Bartossek et al., 2021, Schmidt et al., 2020), or various meditative techniques (Milliere et al., 2018). While some neurophysiological and phenomenological commonalities have been reported between meditative and drug-induced states, including the dissolution of the sense of self (Milliere et al., 2018), the variety of meditation techniques and contemplative practices makes broad generalizations here difficult. For an in-depth review of the neurobiology and phenomenology of meditative states as compared to classical psychedelics, see work by Millere and colleagues (Milliere et al., 2018).
How are ASC phenomena studied? In recent years, researchers have developed systematic approaches to evaluate the features of ASC across induction mechanisms. These approaches include psychometrically validated questionnaires and natural language processing (NLP) of speech or text content generated during ASC. The present study leverages both approaches, examining THC ASC through the lens of closed-ended questionnaires and open-ended self-reports. One questionnaire that has gained prominence in recent years is the altered states of consciousness rating scale (11D-ASC). The 11D-ASC comprises 11 dimensions or subscales including Experience of Unity, Complex Imagery, and Insightfulness (Studerus et al., 2010). This questionnaire was developed to test the hypothesis that ASC contain shared features, independent of their means of induction, toward a taxonomy of ASC. Studies with the 11D-ASC have shown that compounds including psilocybin, ketamine, and MDMA, and non-pharmacological techniques involving sensory stimulation, are indeed sensitive to the subscales (Carbonaro et al., 2018, Kometer et al., 2012, Liechti et al., 2017, Pokorny et al., 2017, Preller et al., 2016, Schmidt and Prein, 2019), with some expected differences in the magnitude of subscale ratings. For instance, ketamine is highly sensitive to Disembodiment, whereas MDMA is highly sensitive to Blissful State, and psilocybin to Elementary Imagery. To date, the 11D-ASC has not been used to assess ASC during meditation, although reports from meditative-like states, including autogenic training, were used in the development of the questionnaire (Dittrich, 1998).
The 11D-ASC enables a detailed assessment of ASC, however, it is not designed to be exhaustive, or encompass all features that may accompany ASC. Thus, the current study employs two complementary rating scales, one assessing mind-wandering, and the other, mindfulness, in addition to NLP assessments of open-ended self-report. Mind-wandering is assessed with a 1–10 rating scale administered immediately following a behavioral task, such as a working memory task. Increases in mind-wandering are related to decreases in task performance. The level of mind-wandering after drug administration, or during meditative states, is dependent on both drug type and meditation technique (Adam et al., 2020, Milliere et al., 2018). Rating scales have also been developed to assess states and traits of mindfulness. The state of mindfulness generally refers to a state of greater awareness of one’s sensations, emotions, and thoughts, with a non-judgmental attitude. In our analysis, we used the State Mindfulness Scale, designed to capture both traditional Buddhist and contemporary scientific models of mindfulness (Tanay & Bernstein, 2013). To our knowledge, only one study has explored changes in state mindfulness after drug administration, finding non-significant increases after psilocybin (315 μg/kg; oral) (Smigielski et al., 2019).
Complementary to psychometric questionnaires, natural language processing enables an analysis, not only of the content of ASC, but also of how that content is expressed through language. These analyses might help identify shared features between drug effects and states of mental health or disorder to guide diagnoses and treatments (Tagliazucchi, 2021). NLP has been used to quantitatively evaluate open-ended self-reports after classical psychedelics including LSD, psilocybin, ayahuasca, and N,N-dimethyltryptamine (DMT), in addition to MDMA, ketamine, and antidepressants (Hase et al., 2022, Sanz et al., 2021). In a large dataset of available online reports (N = 2947), relative to antidepressants, language content after MDMA was highly emotional, whereas Ayahuasca and DMT linguistic markers were highly associated with mystical experiences. In placebo-controlled studies with MDMA (1.5 mg/kg), MDMA resulted in greater semantic proximity to the concepts of friend, support, intimacy, and rapport (Bedi et al., 2014) and an increase in use of social and sexual words (Baggott et al., 2015). In a placebo-controlled study examining LSD’s effects on language, Sanz and colleagues identified increases in the entropy of verbally communicated topics, which paralleled prior findings of greater neural entropy after LSD (Sanz et al., 2021). To our knowledge, NLP has not been applied to cannabis or THC intoxication, or to non-pharmacological techniques of ASC induction, including acute meditative states.
The purpose of our study was to examine the subjective effects of THC through surveys and natural language to enable a “window into the intoxicated mind” (Baggott et al., 2015, Bedi et al., 2014) and facilitate comparison with 5-HT2A receptor agonists through a CB1 receptor-based ASC induction mechanism. Our central hypothesis was that THC induces ASC that mimic classical psychedelic states. Here, we assessed the acute effects of THC (7.5 and 15 mg) vs placebo in healthy men and women that were not regular cannabis users and with little to no prior experience with classical psychedelic substances. Ratings of mind-wandering and written self-reports of THC or placebo effects were collected near the anticipated peak drug effect. Ratings of mindfulness and altered states of consciousness were collected retrospectively at the end of sessions. NLP was performed on text transcribed from written self-report and included measures of language entropy, sentence perplexity, and classification to predict THC or placebo reports. This work is a sub-analysis of a larger study that included behavioral and neurophysiological assessments in the same set of participants, with one additional participant included here that did not participate in the neurophysiological measures (Murray et al., 2022).
Section snippets
Study design
Healthy adults (N = 25) participated in three 5-hour sessions in which they received capsules containing THC (7.5 or 15 mg) or placebo. THC was administered under double-blind and randomized conditions. Dependent measures included surveys of mind-wandering, state mindfulness (SMS), altered states of consciousness (11D-ASC), and natural language processing of self-reported effects.
Subjects
Participants (N = 25) were healthy adult males and females (either aged 18–20 or 30–40 years) who had used cannabis
Demographic characteristics
Participants were 25 years of age on average and reported minimal current or prior substance use. In addition to meeting inclusion criteria of <20 total lifetime cannabis use and 0 use in the last 30 days, participants reported an average of 5 months since last cannabis use, and less than one lifetime or total classical psychedelic experience (Table 1).
Self-report measures
On subjective ratings, both doses of THC (7.5 and 15 mg) increased ratings of marijuana-like effects (ARCI Marijuana) over the course of
Discussion
Our goal was to investigate the subjective effects of oral THC in infrequent cannabis users to determine whether these effects include features of altered states of consciousness that are characteristic of other ASC induction mechanisms, including classical psychedelics. We found that THC dose-dependently increased most subscales of the 11D-ASC in addition to increasing language entropy, findings that have been reported after LSD and psilocybin (Kometer et al., 2015, Liechti et al., 2017, Sanz
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We thank Zhengyi Huang for technical assistance during laboratory sessions and Harriet de Wit for funding acquisition and facilitating this work through the University of Chicago Human Behavioral Pharmacology Laboratory.
Funding
This research was supported by the National Institutes of Health [DA02812] to Harriet de Wit. Conor H. Murray was supported by the National Institutes of Health [T32DA043469].
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