Abstract
Cannabis and classic psychedelics are controlled substances with emerging evidence of efficacy in the treatment of a variety of psychiatric illnesses. Cannabis has largely not been regarded as having psychedelic effects in contemporary literature, despite many examples of historical use along with classic psychedelics to attain altered states of consciousness. Research into the “psychedelic” effects of cannabis, and delta-9-tetrahydrocannabinol (THC) in particular, could prove helpful for assessing potential therapeutic indications and elucidating the mechanism of action of both cannabis and classic psychedelics. This review aggregates and evaluates the literature assessing the capacity of cannabis to yield the perceptual changes, aversiveness, and mystical experiences more typically associated with classic psychedelics such as psilocybin. This review also provides a brief contrast of neuroimaging findings associated with the acute effects of cannabis and psychedelics. The available evidence suggests that high-THC cannabis may be able to elicit psychedelic effects, but that these effects may not have been observed in recent controlled research studies due to the doses, set, and settings commonly used. Research is needed to investigate the effects of high doses of THC in the context utilized in therapeutic studies of psychedelics aimed to occasion psychedelic and/or therapeutic experiences. If cannabis can reliably generate psychedelic experiences under these conditions, high-THC dose cannabis treatments should be explored as potential adjunctive treatments for psychiatric disorders and be considered as an active comparator in clinical trials involving traditional psychedelic medications.
Introduction
Despite decades of research suggesting potential therapeutic use in the 1950s and 1960s, classic psychedelics such as lysergic acid diethylamide (LSD) and psilocybin are regulated as controlled, dangerous substances with no allowance for therapeutic use in most legal jurisdictions. Recent research is building momentum toward what some call a renaissance in psychedelic science. Striking results from clinical trials have resulted in classic psychedelics being heralded as key components of breakthrough treatments for treatment-refractory psychiatric illnesses, which has triggered immense interest in the therapeutic potential of psychedelic therapies (Eschner, 2022). Recent studies have demonstrated potential utilization of psychedelics in managing a variety of pathologies, including depression and anxiety related to a terminal illness (Griffiths et al., 2016; Grob et al., 2011; Muttoni et al., 2019; Ross et al., 2016), major depressive disorder (Carhart-Harris et al., 2016a, 2021; Davis et al., 2021; D’Souza et al., 2022; Goodwin et al., 2023), tobacco use disorder (Johnson et al., 2014, 2017), alcohol use disorder (Bogenschutz et al., 2015, 2022; Krebs and Johansen, 2012), obsessive-compulsive disorder (Moreno et al., 2006), and opioid use disorder (Jones et al, 2022; Savage and McCabe, 1973). Despite these results and an increase in interest, the exact mechanism(s) underlying the benefits of classic psychedelics remain largely uncertain. Although it is accepted that classic psychedelic drugs are agonists at serotonin 2A (5HT2A) receptors, their binding to this receptor does not, in and of itself, explain their therapeutic effects (Hesselgrave et al., 2021; Moliner et al., 2023; Nardou et al., 2023).
Cannabis has followed a similar trajectory to classic psychedelics with respect to public opinion and clinical research findings. Like classic psychedelics, cannabis is a controlled substance in many jurisdictions, but recent research has demonstrated promise in studies and case reports as a treatment for psychiatric disorders such as major depressive disorder (Li et al., 2020), alcohol use disorder (Mikuriya, 2004), opioid use disorder (Hurd et al., 2019), posttraumatic stress disorder (Ragnhildstveit et al., 2023), and anxiety related to public speaking (Linares et al., 2018). In all, 36 US states and several countries have legalized the medicinal use of cannabis for a variety of health conditions (Anderson and Rees, 2023). Moreover, pharmaceutical formulations of the phytocannabinoids cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) have been approved by many large regulatory agencies (e.g., US Food and Drug Administration) for managing chemotherapy-induced nausea, spasticity related to multiple sclerosis, and certain forms of epilepsy (Drug Enforcement Administration [DoJ], 2017; Rubin, 2018; Wise, 2018).
Like classic psychedelics, the pharmacological mechanism(s) by which cannabis exerts therapeutic effects for individuals with psychiatric disorders is unclear (note that, currently, the term “cannabis” encompasses a wide variety of products that range with respect to the intended route of administration (e.g., inhaled, ingested, topically applied), chemical composition (amount and ratio of phytocannabinoids present), formulation, and level of quality control). In this review, unless otherwise specified, the term “cannabis” refers to varieties of botanical cannabis or processed cannabis-derived products in which delta-9-THC is the predominant chemical constituent. Endogenous cannabinoid receptors can modulate the release of serotonin, gamma-aminobutyric acid, and glutamate—three neurotransmitters implicated in depression and anxiety (Rey et al., 2012; Russo et al., 2005). However, the effect of cannabis on these neurotransmitter systems is complex, differs across brain regions, and appears to vary based on the dose and specific cannabinoid(s) (e.g., THC vs other phytocannabinoids) administered (Langlois et al., 2021; Sharpe et al., 2020).
The similarities between classic psychedelics and cannabis appear to extend beyond their contemporary roles as exploratory treatments for mental health and substance use disorders, as historical records indicate that both have been used to attain an altered state of consciousness or for other spiritual purposes across cultures. Both substances were used as sacraments during religious ceremonies in ancient cultures (Ferrara, 2021; Johnson et al., 2019; Johnstad, 2020). Philosopher Alan Watts included cannabis as one of the “five principal psychedelics” (the other four being LSD, mescaline, psilocybin, and dimethyl-tryptamine (DMT)) in his attempts to reach a “cosmic consciousness” defined by “concentration in the present,” “awareness of polarity,” “awareness of relativity,” and “awareness of eternal energy,” ultimately finding that LSD and cannabis “suited [his] purposes best” (Watts, 1968). In addition, cannabis was observed to induce similar behaviors to LSD and bufotenine (a psychedelic analog of DMT that naturally occurs in the venom of the bufo toad species) in a preclinical study of mouse behaviors in response to psychedelics (Siegel and Poole, 1969). This information suggests that cannabis may hold properties akin to classic psychedelics.
The purpose of this review is to aggregate and evaluate extant scientific publications that provide evidence related to the acute effects of cannabis that traditionally are associated with classic psychedelics. Outcomes of interest include perceptual disturbances, aversiveness or challenging experiences, and mystical experiences. A brief section contrasting neuroimaging findings of acute cannabis use versus classic psychedelic use has also been included. The review concludes with a discussion of future directions in research that are needed to better understand the psychedelic effects of cannabis, as well as the clinical and scientific implications of such work.
Perceptual changes
The seminal publication Psychedelic Drugs Reconsidered defined a “psychedelic” as a “drug which. . . more or less reliably produces thought, mood, and perceptual changes otherwise rarely experienced except in dreams, contemplative and religious exaltation, flashes of vivid involuntary memory, and acute psychosis” (Grinspoon and Bakalar, 1979). Psychedelics are now recognized as having functions beyond just altering perceptions— which may be why the term “hallucinogen” has fallen out of favor (Nichols, 2016)—yet it remains an important attribute to consider when identifying psychedelic effects in other substances.
Two case series describe cannabis-induced perceptual changes, including visual hallucinations and thought distortions. The first report centered on 200 adults from India who had a psychotic experience following cannabis use. Confusion, emotional lability, and visual hallucinations represented the most frequently reported symptoms (Chopra and Smith, 1974). The second case series involved eight Israeli men seeking treatment for cannabis detoxification who reported experiencing visual disturbances following the use of highly concentrated cannabis (the exact dose was not mentioned in the article). These disturbances persisted as “flashbacks” up to 6 months after use and were perceived as benign occurrences by the participants. The authors of the latter study explicitly suggest that these cannabis-induced responses could have a similar mechanism to the perceptual changes seen with classic psychedelics: “The chronic and persisting effects of LSD, hallucinogen persisting perception disorder (HPPD), and flashbacks. . .may closely resemble the previous hallucinogenic experience, implying that a mechanism related to the original one may be involved” (Lerner et al., 2011). HPPD—a disorder in which individuals continue to experience visual illusions and hallucinations long after the use of hallucinogens and commonly associated with the use of classic psychedelics like LSD—was also suspected as a response to cannabis in a case study of a 15-year-old male (Ellison-Wright and Sessa, 2015). However, the authors of this case study acknowledged confounding factors that could have contributed to this response, including the possibility that the cannabis was contaminated with a psychedelic drug.
Another case of perceptual changes following cannabis use occurred during a double-blind research study in which a participant demonstrated sedation and disorientation after receiving vaporized cannabis containing 25 mg of THC (Barrett et al., 2018). As the participant’s ability to effectively communicate with staff returned, the participant recalled having experienced a dissociative state, auditory and visual hallucinations, nausea, dizziness, and tingling sensations down the arms and legs. Unlike the aforementioned case studies, researchers had the opportunity to evaluate the participant’s experience using a psychometric measure—in this case the Hallucinogenic Rating Scale, a scale designed to assess the acute subjective effects of psychedelics (Strassman et al., 1994). Results on the Hallucinogen Rating Scale from this participant were compared to data obtained from other controlled studies of classic and atypical psychedelic drugs (psilocybin, dextromethorphan (DXM), and Salvinorin A) at the same laboratory. Results indicated that the participant’s experience was associated with significantly elevated scores in the domains of intensity and perception (similar in magnitude to comparison study drugs except for DXM), somaesthesia (similar in magnitude to comparison study drugs except for psilocybin), and volition (similar in magnitude to all comparison study drugs). The participant’s cannabis experience was also associated with Affect and Cognition scores that were significantly lower than those from psilocybin doses. The participant’s experience was not probed for any sense of meaning or other elements related to a mystical experience. From the report, the authors concluded that this participant’s experience was unlikely to have arisen from a mechanism akin to that of classic psychedelics given that there were several differences in effect profile between this case and historical data from psilocybin studies. It is notable, however, that this experience occurred in a healthy adult volunteer who was not expecting a psychedelic or mystical experience and who had undergone cannabinoid administration in a research context not designed to induce such effects (e.g., the person was upright in a brightly lit room and was repeatedly asked to perform cognitive tasks, answer questionnaires, and provide biospecimens vs going through the drug experience laying down with eyes closed, listening to classical music).
Outside of these case studies, a review of the literature identifies only two human studies aimed at evaluating psychedelic effects after acute cannabis exposure. In a retrospective self-report study, researchers administered a 13-item questionnaire to American undergraduates that probed perceptual disturbances and emotional reactions during cannabis use. Of the 42 individuals who confirmed they had previously smoked cannabis, 88% reported having experienced at least one “minor” perceptual effect (either identifying colors as more intense or noticing that objects appeared sharper) and 50% reported having at least one “major” perceptual effect (seeing colors or designs with eyes opened. or noticing objects that appeared to have a distorted shape). The context and/or setting in which cannabis was used was not described in this study and was likely to have varied widely across participants, so it is unclear how such factors could have impacted the results. Based on these findings, the authors concluded that cannabis could be classified as a hallucinogen. Although the authors also inquired about LSD and mescaline use using the same questionnaire, they did not compare rates of hallucinatory experiences between cannabis use and the use of psychedelics (Keeler et al., 1971).
The other study involved the controlled, separate experimental administration of cannabis and cocaine to regular users of these substances across two study centers to determine the influence of trait impulsivity on subjective feelings of intoxication. Psychedelic effects represented one of the main outcomes of this study and were assessed using the Bowdle Visual Analog Scale (B-VAS), a rating scale for psychedelic experiences in which most questions evaluate sensory changes (Bowdle et al., 1998). Cannabis use was associated with significant increases in the B-VAS score for all questions compared to placebo. Researchers noted that participants at one of the study centers received higher amounts of THC than participants at the other center. These differences in concentration had no significant effect on the magnitude of the measured psychedelic effects in this study (Van Wel et al., 2015).
Challenging and aversive experiences
The recent surge in research on classic psychedelic drugs has elucidated additional traits of psychedelics outside of their ability to yield perceptual changes. Challenging or aversive experiences—in which subjects encounter negative affective experiences such as fear, grief, paranoia, and a feeling of isolation—represent a key feature observed with the use of classic psychedelics (Carbonaro et al., 2016). The identification of this response pattern helped lead to the development of the Challenging Experience Questionnaire (CEQ), a psychometric scale with validity in assessing clinical response to psychedelic treatments (Barrett et al., 2016; Herrmann et al., 2022). Indeed, a recent survey study on individuals with strong responses to psychedelics indicates that challenging experiences could be associated with more meaning and insight (Nikolaidis et al., 2023).
Cannabis use can likewise lead to paranoia and anxiety, if not complete psychosis, which could explain why such experiences have largely not been evaluated for clinical benefit (Johns, 2001; Mangot, 2013). Yet, one recent survey study indicates that cannabis can yield challenging, yet meaningful, experiences (Farmer et al., 2019). Of the 172 individuals responding to a survey on adverse experiences with edible cannabis, 63% felt that their aversive experience with cannabis had at least some meaning and 8% defined the experience as one of the most meaningful experiences of their lives. Authors suggest that the aversiveness from cannabis (or at least edible cannabis) may resemble the unpleasant effects that can occur with challenging psilocybin experiences, although the proportion of psilocybin users describing the experience as one of the most meaningful in their lives (34%) in a different study (Carbonaro et al., 2016) far exceeded that of those using cannabis (8%) in this one (Farmer et al., 2019). It would be disingenuous to conclude from the Farmer et al. study that the challenging experiences with cannabis are equivalent to the challenging experiences with classic psychedelics without direct comparison involving more formal psychometric measures.
Mystical experience
The mystical experience serves as arguably the most clinically pertinent feature of classic psychedelics, as its presence has been linked to its therapeutic effects (Garcia-Romeu et al., 2014; Griffiths et al, 2016; Ross et al., 2016). Mystical experiences have been defined by seven traits: (1) a sense of unity facilitated by the eradication of a sense of boundaries between all people and things, (2) deeply felt positive mood, (3) transcendence of space and time, (4) ineffability that renders complete description in words near-impossible, (5) sacredness, (6) a sense that the experience allows for a connection to ultimate reality, and (7) paradoxicality, or the coexistence of mutually exclusive states (Stace, 1960). These features helped form the basis of the Mystical Experience Questionnaire (MEQ), a psychometrically validated tool for the evaluation of mystical experiences occurring in the context of classical psychedelic use (Barrett et al., 2015).
Cannabis’ mystical effects were suggested in studies that were previously discussed in this review. In the aforementioned case series of Indian adults who had psychotic symptoms following cannabis use, study authors observed that the hallucinations were tied to religious themes such as the “realization of God” and the “mysteries of life” (Chopra and Smith, 1974). Furthermore, the survey study performed by Keeler and colleagues investigating the hallucinogenic effects of cannabis included two questions related to mystical effects: “Have you felt closer to God, nature, or mankind?” and “Have you felt better able to understand the meaning of the universe?” 40% of the respondents indicated that under the acute effects of cannabis, they felt closer to God, nature, or mankind or were better able to understand the universe (Keeler et al., 1971).
In a prospective survey study of individuals using classic psychedelics with and without cannabis (Kuc et al., 2021), a significant, positive linear relationship was observed between the dose of cannabis used and results on the MEQ, as well as the Ego Dissolution Inventory (EDI) and visual subscales of the Altered States of Consciousness Questionnaire (ASC-Vis). The relationship between the psychedelic dose and scores on the MEQ, ASC-Vis, CEQ, EDI, and Emotional Breakthrough Inventory was also positive and linear but was not statistically significant. The study authors suggest these results illustrate a synergistic relationship between cannabis and classic psychedelics on mystical experiences, possibly due to agonism of THC at CB1/5HT2A heteromers (Viñals et al., 2015) or inverse agonism by high doses of CBD at 5HT1A receptors that can disinhibit 5HT2A action (Martínez-Aguirre et al., 2020). Although not explicitly mentioned by the authors, metabolic interactions between these drugs might potentiate psychoactive effects when used simultaneously versus separately.
In another study (Earleywine et al., 2021), cannabis users retroactively rated peak drug effects associated with cannabis exposure using the MEQ. A “complete” mystical experience, which has been previously defined as scoring >60% of the maximum score on each of the four factors of the MEQ (Barrett et al., 2015; MacLean et al., 2012), was endorsed by approximately 20% of the study participants. Although the rate of “complete” experiences observed in studies involving high-dose psilocybin had exceeded 70% in some studies (Griffiths et al., 2006, 2011), the study authors countered that the reduced rate of mystical experiences with cannabis could be related to its less frequent use in therapeutic settings (Earleywine et al., 2021). Mystical experiences with psilocybin are also dose dependent, with 0, 6%, 11%, 44%, and 56% of participants achieving a mystical experience after administration of 0, 5, 10, 20, and 30 mg/70 kg psilocybin, respectively (Griffiths et al., 2011). The doses of cannabis needed to reliably evoke a mystical experience may be much higher than those commonly used in casual settings. The dose-effect function of cannabinoid-evoked mystical experiences is currently unknown and is a target area for future research.
Cannabis-associated mysticism was again observed in a within-subjects functional magnetic resonance imaging (fMRI) study of the acute effects of smoked cannabis (Zaytseva et al., 2019). Shortly after smoking an amount of cannabis of their choosing, participants underwent fMRI and completed a questionnaire evaluating their experiences. The questionnaire included measures related to the 5D-ASC’s Oceanic Boundlessness subscale, which correlates closely with the MEQ and can serve as a proxy for measuring mystical experiences (Liechti et al., 2017). Analysis of the imaging data identified a transient state of high connectivity that was only seen after acute cannabis use and was thus identified as a potential imaging marker for acute cannabis use. The authors observed a significant correlation between the time spent in this transient state and scores on the Oceanic Boundlessness item of the Altered States questionnaire. This link between a neural state mediated by acute cannabis use and higher scores on the Oceanic Boundlessness subscale further supports the idea that cannabis use may yield mystical experiences when administered at appropriate settings and doses.
Neuroimaging findings
Comprehensive reviews on neuroimaging studies of acute cannabis and classic psychedelic use indicate that both substances can elicit a wide range of structural and functional brain changes (Bloomfield et al., 2019; De Vos et al., 2021). There are currently no studies directly comparing the neuroimaging findings of acute cannabis use and the use of classic psychedelics. However, there have been studies that have separately explored the acute effects of cannabis use or classic psychedelic use on specific neural networks. Contrasting such studies suggests that while there could be potential overlap, the available evidence is too inconsistent to make strong conclusions about the similarities between the effects of cannabis and classic psychedelics on neural networks and structures.
One proposed mechanism by which classic psychedelics are thought to yield their effects is via destabilization of the thalamocortical loops responsible for filtering information. A weakening of top-down control of thalamic filters of sensory information would lead to a sensory overflow that could lead to perceptual alterations and cognitive changes seen with classic psychedelics (Doss et al., 2022; Vollenweider and Preller, 2020). Decreased thalamic connectivity was observed in connection to cannabis use in both the previously discussed fMRI study (Zaytseva et al., 2019) and another fMRI study of the influence of cannabis and cocaine on cognitive impulse control and corticostriatal connectivity (Ramaekers et al., 2016). The challenge with this interpretation is that the most recent and rigorous analyses suggest that psychedelics (both psilocybin and LSD) increase thalamic connectivity (Avram et al., 2022; Gaddis et al., 2022). So even if decreased thalamic connectivity is found to reliably occur with acute cannabis use, it remains unclear whether this neural change would drive any acute effects associated with classic psychedelic use.
Destabilization of the default mode network (DMN)—a higher-level network involved in episodic memory, theory of mind, and self-referential processing—represents another popular theory regarding classic psychedelics’ mechanism of action (Carhart-Harris et al., 2012, 2016b; Carhart-Harris and Friston, 2019), although evidence from psychedelic studies for this mechanism has been mixed (Doss et al., 2022). The effects of cannabis on the DMN have likewise been inconsistent: two fMRI studies observed an increase in connectivity within the DMN (Ramaekers et al., 2022; Zaytseva et al., 2019). However, other brain imaging studies have demonstrated reduced connectivity in the DMN after acute cannabis administration (Wall et al., 2019; Whitfield-Gabrieli et al., 2018). Differences in the route of administration and time between the dosing of the study drug to brain scans could account for divergent results.
Based on the available evidence, it is premature to make any strong conclusions about the neural bases of the experiences associated with cannabis or classic psychedelics. Further studies—particularly ones directly comparing the effects of cannabis and classic psychedelic use—are needed to confirm any similarities, or lack thereof, between the neural changes seen with acute cannabis use and classic psychedelic use.
Conclusion and future directions
A body of evidence exists supporting the notion that THC-dominant cannabis use may be able to yield effects and experiences more commonly associated with psychedelics. Several case reports and studies involving the use of psychometric scales suggest that cannabis use can lead to perceptual changes, aversiveness, and mysticism inherent to the psychedelic experience. Some neuroimaging features may be common to both acute cannabis use and classic psychedelic use, although mixed results make it difficult to draw firm conclusions. There are deficits in the literature that are worth noting: most of the involved studies are retrospective and thus liable to self-report and recall biases. There is also no thorough exploration of the dose effects of THC or other cannabinoids on the presence and intensity of psychedelic experiences; it is possible that the apparent link between cannabis use and the development of psychotic disorders (Ganesh and D’Souza, 2022) has prevented the development of such studies. Thus, one cannot yet firmly conclude that cannabis can reliably produce psychedelic effects from the available studies. Randomized controlled trials where responses to cannabis use can be observed in monitored and psychedelic-supportive settings will be necessary to explore this possibility.
Demonstrations of cannabinoid-induced psychedelic effects would have implications in several different scientific and clinical arenas. To start, such studies could provide insights into the cannabis use patterns that could be associated with psychedelic effects. As many of the studies cited in this review did not involve standardized doses, study participants could very well have been using cannabis at levels too low to generate a psychedelic experience. This supposition is supported by a recently published study of cannabis users’ beliefs regarding cannabis-guided psychotherapy (Earleywine et al., 2022). Results illustrated an expectation that cannabis could produce psychedelic effects when administered at an unspecified “ideal dose.” Differences in the patterns of therapeutic use between cannabis and classic psychedelics—with classic psychedelics typically administered over the course of a few intensive therapy sessions and cannabis used more frequently and independent of therapy sessions—may also explain why cannabis has not been more frequently associated with psychedelic experiences (Johnstad, 2020). Clarifying the regimen for generating psychedelic effects from cannabis could support further research on its treatment potential in areas currently being explored as targets for psychedelic therapies, as well as posit it as a potential active comparator in future clinical trials involving psychedelic drugs.
Studies investigating cannabis’ psychedelic properties could also provide information on the importance of set (expectancy) and setting (context) in psychedelic studies. As mentioned previously, psychedelics are taken less frequently and typically in more therapeutic settings than cannabis. The laboratory settings in which psychedelics are typically administered are typically structured in a way that may better elicit mystical experiences. Notably, laboratory studies of the behavioral and neural effects of cannabinoids have not been conducted following guidelines for the safe administration of psychedelics in research contexts, which carefully control set and setting in a specific manner (e.g., lying down, with eyeshades, listening to a predetermined playlist of evocative music, and in the presence of a guide) (Johnson et al., 2008). A blinded study that randomized participants to receive either a classic psychedelic or cannabis while they underwent guided therapy could reinforce not only the notion that cannabis can act as a psychedelic but also the importance of the environment for generating breakthrough experiences.
Furthermore, the incorporation of imaging into these studies could help clarify the neurobiological mechanisms by which mystical experiences occur. Identifying neural changes seen with the use of cannabis and psychedelics could yield useful information regardless of cannabis’ capacity to yield psychedelic effects. For instance, if cannabis does not produce a mystical experience, then any neurologic similarities to classic psychedelics would not be pertinent to the etiology of psychedelic effects. But should cannabis use be found to produce these experiences, then there could be a yet to be determined overlap between the mechanisms of cannabis and classic psychedelics despite their very different apparent pharmacologies (with THC primarily functioning as a cannabinoid receptor agonist and classic psychedelic drugs acting as 5HT2A receptor agonists).
There are many reasons to believe that cannabis and psychedelics will continue to be studied as a possible treatments for difficult-to-treat or intractable psychiatric disorders. An understanding of how these drugs yield such effects will be critical for optimizing any therapeutic benefits while preventing adverse outcomes and may provide insights into the pathophysiology underlying these disorders. Such research could have a substantial impact on the studies of psychoactive substances, laying the foundation for subsequent work exploring the behavioral pharmacology of cannabis and classic psychedelics and the therapeutic applications of these drugs that have inspired so much interest in the medical and scientific communities.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
