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Cannabis Dopaminergic Effects Induce Hallucinations in a Patient with Parkinson’s Disease 1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, “Hallucinations” Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral

Cannabis Dopaminergic Effects Induce Hallucinations in a Patient with Parkinson’s Disease

1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA; [email protected] (K.P.); [email protected] (N.D.T.-P.); [email protected] (A.M.); [email protected] (N.A.)

David Thacker

2 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA; [email protected] (D.T.); [email protected] (J.T.)

Nicole Del Toro-Pagán

1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA; [email protected] (K.P.); [email protected] (N.D.T.-P.); [email protected] (A.M.); [email protected] (N.A.)

Abeer Hanna

3 Viecare Butler, Program of All-Inclusive Care for the Elderly (PACE), Butler, PA 16001, USA; [email protected]

Jacques Turgeon

2 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA; [email protected] (D.T.); [email protected] (J.T.)

4 Faculty of Pharmacy, Université de Montréal, Montréal, QC H3C 3J7, Canada

Adriana Matos

1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA; [email protected] (K.P.); [email protected] (N.D.T.-P.); [email protected] (A.M.); [email protected] (N.A.)

Nishita Amin

1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA; [email protected] (K.P.); [email protected] (N.D.T.-P.); [email protected] (A.M.); [email protected] (N.A.)

Veronique Michaud

2 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA; [email protected] (D.T.); [email protected] (J.T.)

4 Faculty of Pharmacy, Université de Montréal, Montréal, QC H3C 3J7, Canada

1 Office of Translational Research and Residency Programs, Tabula Rasa HealthCare, Moorestown, NJ 08057, USA; [email protected] (K.P.); [email protected] (N.D.T.-P.); [email protected] (A.M.); [email protected] (N.A.)

2 Tabula Rasa HealthCare, Precision Pharmacotherapy Research and Development Institute, Tabula Rasa HealthCare, Orlando, FL 32827, USA; [email protected] (D.T.); [email protected] (J.T.)

3 Viecare Butler, Program of All-Inclusive Care for the Elderly (PACE), Butler, PA 16001, USA; [email protected]

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Abstract

Cannabis products that contain the tetrahydrocannabinol (THC) cannabinoid are emerging as promising therapeutic agents for the treatment of medical conditions such as chronic pain. THC elicits psychoactive effects through modulation of dopaminergic neurons, thereby altering levels of dopamine in the brain. This case report highlights the complexity associated with medicinal cannabis and the health risks associated with its use. A 57-year-old male with Parkinson’s disease was experiencing worsening tremors and vivid hallucinations despite therapy optimization attempts. It was discovered that the patient took cannabis for chronic back pain, and a pharmacogenomics (PGx) test indicated the presence of variants for the COMT and HTR2A genes. These variants could increase dopamine levels and predispose patients to visual hallucinations. Once the cannabis was discontinued, the patient’s hallucinations began to slowly dissipate. Cannabis use continues to expand as it gains more acceptance legally and medicinally, but cannabis can affect the response to drugs. This patient case suggests that cannabis use in combination with dopamine-promoting drugs, especially in a patient with genetic variants, can increase the risk for vivid hallucinations. These conditions support the importance of considering herb–drug interactions and PGx data when performing a medication safety review.

1. Introduction

The use of medical cannabis has steadily gained popularity over the last several years. Cannabis has demonstrated therapeutic effects with different cannabinoids derived from the cannabis plant, specifically tetrahydrocannabinol (THC) and cannabidiol (CBD), which are being utilized for several medical conditions by providing analgesic, antispasmodic, and antiemetic properties [1,2,3]. While the role of cannabis in medicine continues to expand, it is imperative to consider cannabis effects and potential drug interactions. Research has demonstrated that THC and CBD are substrates of the cytochrome P450 (CYP) enzymes CYP2C9 and CYP2C19, and thus, will increase the risk for drug–drug interactions [4]. Additionally, THC has been shown to elicit its psychoactive effects through modulation of dopaminergic neurons, thereby altering levels of dopamine in different areas of the brain [5].

Appropriate dopamine levels are vital, as the nervous system utilizes dopamine for the regulation of several physiological functions (e.g., mood, motor, cognitive) [6]. Enzymes and transporters, such as the catechol-O-methyltransferase (COMT) enzyme and dopamine transporters, help regulate the level of dopamine in the synapses [6]. The COMT gene is responsible for producing the COMT enzyme, which acts as a metabolizing enzyme for dopamine [6]. Therefore, genetic alterations of COMT and other relevant genes affecting dopamine can potentially alter how an individual responds to THC [7].

Low levels of dopamine in specific brain regions have been found to be associated with certain conditions, such as Parkinson’s disease (PD). PD is a neurodegenerative disease caused by the death of dopamine-producing neurons in the substantia nigra, which is a part of the midbrain responsible for coordinating movement [8]. Neuronal death in this region results in low dopamine concentrations; therefore, treatment strategies for PD often involve initiating medications (e.g., carbidopa-levodopa, ropinirole, entacapone) that result in increased concentrations of dopamine to improve movement control [8]. Concomitant intake of cannabis and drugs used in the treatment of PD can significantly modulate dopamine concentrations. The case described herein demonstrates the importance of considering the pharmacokinetic and pharmacodynamic effects of cannabis and an individual’s pharmacogenomic (PGx) data when evaluating a patient’s medication regimen for therapeutic response and/or adverse drug events.

2. Case Presentation

A 57-year-old male with a past diagnosis of PD began treatment with a new primary care physician (PCP). In addition to PD, the patient’s past medical history includes spinal stenosis, vitamin D deficiency, frequent falls, a history of nicotine and alcohol dependence, mild kidney disease, and chronic neck, back, and shoulder pain. The patient had spinal surgery approximately two years ago, during which he developed complications (i.e., delirium) from anesthesia, causing him to remain hospitalized for an additional month. During his initial meeting with the PCP, the patient reported experiencing worsening tremors, body pain, and vivid visual hallucinations encompassing small children and flying objects, which the patient claimed to have been seeing for over two years. This patient was also prescribed rivastigmine, as Lewy body dementia was recently included as a differential diagnosis due to the presence of these hallucinations. Upon evaluation of the patient’s past medical history and medications, changes were made to his drug regimen to better control his symptoms, which included increasing the doses for carbidopa-levodopa and rivastigmine ( Figure 1 ). The patient’s tremors began to slowly diminish with his new medication regimen; however, his vivid hallucinations were still present. Upon further inquisition at a subsequent visit, the PCP discovered that approximately two years ago the patient had been advised to chronically use cannabis to manage his chronic back pain. On average, the patient reported smoking approximately 3 g of cannabis per week. The new PCP promptly recommended the cessation of cannabis, as its use with other medications could be contributing to his vivid hallucinations. The patient’s interdisciplinary team continued to evaluate his hallucinations and tremors after discontinuation of cannabis, which was confirmed with a negative drug screen. The patient reported that his hallucinations began to diminish slowly over time. As more time elapsed, his hallucinations of children and flying objects changed to seeing only floating dots. Considering the improvement in hallucinations was observed following discontinuation of cannabis, rivastigmine was discontinued as it was determined that the patient’s hallucinations were likely not due to Lewy body dementia. During a follow-up encounter two months later, the patient reported that his hallucinations had disappeared, and control of his tremors had improved further. The clinical pharmacist recommended dose increases of carbidopa-levodopa to help control his tremors still present early in the morning ( Figure 1 ).

Drug and Symptom Change Timeline. 1 Shaded area in the chart represents when hallucinations were experienced by the patient. Shades of gray are associated with the presence of vivid or fewer hallucinations and which medications are administered at that time. 2 Period when tremor symptoms were experienced by the patient. Abbreviations: QD: once a day, BID: twice a day, TID: three times a day, QID: four times a day, HS: at bedtime.

A PGx test was also ordered to help determine if a genetic component could explain why this patient experienced such vivid hallucinations from cannabis. Upon reception of the PGx results ( Table 1 ), the pharmacist observed that the patient was homozygous for the COMT variant (rs4680 AA (Met/Met); this variant is associated with low enzyme (COMT) activity due to a decreased production of the enzyme. Such a decrease in COMT activity is associated with higher levels of catecholamines (i.e., dopamine) in the brain.

Table 1

Patient’s Pharmacogenomics Test Results.

Gene Genotype Phenotype
CYP1A2 1 *1F|*1F Possible Normal
Metabolizer
CYP2B6 *1|*1 Normal Metabolizer
CYP2C9 *1|*1 Normal Metabolizer
CYP2C19 *1|*1 Normal Metabolizer
CYP2D6 *1|*4 Intermediate Metabolizer
CYP3A4 2 *1|*1 Undetermined
CYP3A5 *3|*3 Poor Expresser
Metabolizer
COMT rs4680 AA (Met/Met) Low Activity
DRD2 rs1799978 AA Normal Receptor
Expression
HTR2A rs7997012 GG Altered Receptor Function

1 Common variants in CYP1A2 gene reflect its inducibility. CYP1A2 genetic variations, without the presence of induction (e.g., smoking, concomitant CYP1A2 inducers), have not been demonstrated to clinically alter the activity of CYP1A2 [9]. 2 CYP3A4 gene shows some genetic variations and most variants have not been demonstrated to clinically alter the activity of CYP3A4. Many of the variants are extremely rare, making it difficult to derive a phenotype based on genetic results [10].

To manage his chronic pain (after cessation of cannabis), the patient was prescribed celecoxib and lidocaine topical patches for back, neck, and shoulder pain. However, his PCP determined that additional medication for pain control was warranted. Given that patient was identified as a CYP2D6 intermediate metabolizer ( Table 1 ; CYP2D6*1/*4), the clinical pharmacist recommended prescribing an opioid that does not utilize the CYP2D6 pathway (e.g., morphine) to decrease the risk of pharmacotherapy failure and/or possible adverse drug events.

3. Discussion

The use of cannabis products for medical purposes continues to expand as research develops. The patient under consideration in this case report was initially recommended cannabis for analgesia due to chronic back pain. Guidance is currently available regarding medical cannabis use for the treatment of chronic pain, suggesting that cannabis-based drugs can be considered when all other treatment options have failed [1]. CBD and THC are the two most prominent cannabinoids found in cannabis and have been used to treat multiple sclerosis spasms, neuropathic and cancer pain, nausea, and insomnia [4]. CBD has been utilized as an anxiolytic and the U.S. Food and Drug Administration has approved the CBD oral solution (Epidiolex ® ) as a treatment option for epilepsy [4,11]. While research has provided guidance on managing chronic pain with cannabis, guidance is not available regarding use in other conditions. However, research has shown that cannabis use can cause hallucinations in patients with PD, thus the appropriateness of cannabis use should be evaluated [1,12].

THC is the main psychoactive cannabinoid in cannabis as both the parent molecule and its 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) metabolite produce euphoric effects [13]. THC does not provide analgesic effects, but its 11-carboxy-delta-9-tetrahydrocannabinol (11-COOH-THC, psychotropically inactive) metabolite possesses anti-inflammatory and analgesic properties [13]. The non-psychoactive analogue of THC, CBD, another cannabinoid found in cannabis, has also shown analgesic and anti-inflammatory effects [14].

THC is metabolized by CYP enzymes in the liver, particularly CYP3A4 and CYP2C9 [4,15]. CBD is mainly metabolized by CYP3A4 and CYP2C19, and at higher oral doses (5 mg/kg/day), can inhibit CYP2C9 and to a lesser extent CYP1A2 [8,11,16]. Concomitant administration of prescribed medications with cannabis engenders a risk of potential herb–drug CYP450 interactions ( Figure 2 ). Therefore, any drug with a stronger affinity for the CYP2C9, CYP2C19 or CYP3A4 enzymes than THC or CBD, if administered at the same time, could affect their disposition and result in an herb–drug interaction [4,17]. These interactions could lead to increased CBD or THC concentrations and possibly lower concentrations of THC’s metabolites [4,17]. Furthermore, CYP2C9 and CYP2C19 are both polymorphic enzymes with differing functions that could modulate cannabis exposure if genetic variants are present (which was excluded as a contributing factor for this case) ( Table 1 ) [15,18].

Summary of Affinity and CYP Metabolic Pathways. 1 Treatment with celecoxib began after the cessation of cannabis. Abbreviations: CBD: cannabidiol, CYP: Cytochrome P450, THC: tetrahydrocannabinol.

Although studies investigating the use of cannabis for pain demonstrated mixed results, there is emerging evidence supporting the benefit of cannabis for pain [19,20,21]. Numerous factors can explain discrepancies between study results such as pain models, healthy subjects vs. patients, routes of administration (inhalation vs. oral), and sources of the product [19,20,21]. The utility of cannabis use remains under debate as there is no approved indication, formulation, or dosage for pain. Further research is needed to better understand the efficacy, dose–response effects, routes of administration and side-effect or safety profiles associated with such products. In general, inhaled cannabis (smoking and vaping) is associated with a quicker onset of action, while oral administration of cannabis has a slower or delayed onset of action, and it is exposed to the intestinal-hepatic first-pass effect [4]. Side effects and safety profiles should be considered for both routes of administrations.

PD is characterized by the death of dopamine-producing neurons, specifically in the substantia nigra, which impacts an individual’s ability to control their movements [8]. Treatment strategies to combat PD motor symptoms include drugs such as dopamine precursors (e.g., carbidopa-levodopa), dopamine agonists (e.g., ropinirole), COMT inhibitors (e.g., entacapone), and monoamine oxidase B inhibitors (e.g., rasagiline) [8]. Additionally, visual hallucinations are a common non-motor symptom observed in patients with PD, and they typically result from long-term use or dose increases of PD drugs [8]. The cause of these particular hallucinations can be multifactorial but there is evidence attributing them to high levels of dopamine [22]. In this patient’s case, the medical team considered the patient’s PD medication regimen and disease progression when attempting to identify the cause of hallucinations while managing worsening tremors. The clinical presentation suggested that the patient was not receiving enough dopamine from his medications to control his tremors supporting the proposed increased dose of carbidopa-levodopa. In addition, the dose of rivastigmine was increased to improve cognitive and functional abilities and diminish visual hallucinations [23]. These pharmacotherapy interventions improved his tremors; however, his vivid hallucinations were not alleviated which warranted further consideration.

The endocannabinoid system (ECS) is an essential regulator of dopamine levels [4,24]. The ECS is a neuromodulatory system able to regulate several neurons (e.g., dopamine) [4,24,25]. THC acts as a receptor agonist for receptors in the ECS, known as cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R) [4,5,24]. CB1Rs are found predominately in the brain and are located on many neurons presynaptically, as well as postsynaptically [26]. In regards to dopamine neurons, inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) act on dopamine neurons to regulate and reduce dopamine release into the synapses [5,24,25]. When CB1Rs on presynaptic neurons are activated, inhibitory neurotransmitter levels are reduced and dopamine levels increase [5,24,25]. When THC binds in the striatum and cortex, the euphoric feeling associated with THC occurs; however, abnormal levels of dopamine in the striatal and limbic regions of the brain have been observed in patients experiencing psychotic symptoms, including hallucinations [5,24,27].

A small percentage of people have been shown to experience psychotomimetic effects with low-dose THC in the presence of genetic polymorphisms [7]. The COMT gene is responsible for producing the COMT enzyme, which acts as a metabolizing enzyme for dopamine [6]. The COMT enzyme demonstrates the importance of dopamine regulation within the prefrontal cortex, as there are fewer available dopamine transporters in this region of the brain [28]. In COMT, a common polymorphism can occur due to a change from the amino acid valine (Val) to a methionine (Met) [Val158Met], which results in a reduction in dopamine metabolism [29]. Therefore, carriers of the Met variant experience higher dopamine concentrations in synapses [29]. Studies in healthy individuals with the COMT wild-type have been shown to metabolize dopamine up to four times faster than those with COMT Met/Met, deeming individuals homozygous for Met as having low COMT enzyme activity [28]. Interestingly, the patient’s PGx results ( Table 1 ) reported a genotype for COMT Met/Met, therefore higher levels of dopamine in his synapses would be expected.

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Research has been conducted to evaluate the effects of the COMT Val158Met polymorphism and the use of cannabis on the risk for psychosis [28,30]. In healthy individuals, there is an observed correlation between cannabis use in those with COMT Val/Val and increased risk for psychosis [28,30]. This genotype is also associated with lower levels of prefrontal dopamine; therefore, this observation is thought to be due to higher levels of phasic dopamine transmission, which aids in the development of psychotic symptoms [28]. Additionally, a previous study evaluated patients with PD and their subsequent reactions to cannabis use, reporting that one out of five patients experienced hallucinations [12]. Given these studies and considering THC can also increase dopamine levels, extra care should be exercised in carriers of the Met variant in regards to cannabis use [31].

Furthermore, this patient was reported to have a single nucleotide polymorphism on the HTR2A gene, resulting in altered serotonin 2A (5-HT2A) receptor function ( Table 1 ). While there is a lack of clinical studies with the 5-HT2A receptor and cannabis, research has demonstrated that the CB1R is expressed on serotonin neurons; therefore, the binding of THC to this receptor increases neuronal firing [32]. In pre-clinical studies, the CB1R and 5-HT2A have been shown to form a heteromer that could be responsible for altered homeostasis of the serotonin system [33]. This type of serotonin receptor is commonly found in the prefrontal cortex and evidence has suggested that alterations in receptor function have demonstrated association with mood disorders and psychosis [25]. Several studies have proven that cannabinoids affect the serotonergic system; however, the data regarding the relationship between cannabis and HTR2A and its subsequent effects are limited [25].

The PGx test results identified the patient as a CYP2D6 intermediate metabolizer, which is heavily involved in the metabolism of several opioid drugs utilized for pain (e.g., codeine, tramadol, hydrocodone, oxycodone) [34]. Guidelines are available for CYP2D6 and select opioids, which state that individuals with CYP2D6 intermediate metabolizer status may experience altered effects (e.g., possible adverse drug events, increased risk for pharmacotherapy failure) when compared to CYP2D6 normal metabolizers [34]. Given this patient’s genetic results, guidelines, and current pain status, the clinical pharmacist suggested morphine as an alternative, as it does not utilize CYP2D6 for metabolism [34]. Studies have been conducted evaluating pain sensitivity in individuals with COMT genotype Val/Met and Met/Met, reporting that those with this polymorphism have an increased pain sensitivity [35]. In addition, low COMT activity has demonstrated association with increased opioid analgesia and opioid side effects (e.g., nausea, vomiting) [35]. Considering these studies and the patient’s COMT genotype, if an opioid were to be prescribed, starting a low dose opioid and monitoring for any medication-related side effects would be suggested. There are additional genetic polymorphisms proven to affect an individual’s reaction to THC, such as the Taq1A polymorphism in the dopamine receptor gene; however, these data were not available for the patient at the time of these interventions. [7].

4. Conclusions

Cannabis use has been demonstrated to have an impact on dopamine concentrations in the brain, resulting in side effects like hallucinations. In a condition like PD, many interactions and their subsequent side effects can occur when combining cannabis with dopamine-promoting drugs and the genetic variants that affect dopamine. This patient case demonstrates the importance of considering cannabis use when evaluating for potential drug–drug and drug–gene interactions in an individual’s regimen. Considering all drug-use (e.g., prescribed, recreational, over-the-counter drugs), along with an individual’s PGx results when evaluating a patient allows for a safer and more accurate approach when completing comprehensive assessments.

Acknowledgments

The authors want to thank Katie Meyer for her assistance. The authors would also like to thank Pamela Dow and Dana Filippoli, for their comprehensive review and comments on this manuscript.

Author Contributions

Conceptualization, N.D.T.-P., D.T., A.M. and V.M.; writing—original draft preparation, K.P., N.D.T.-P. and D.T.; writing—review and editing, K.P., N.D.T.-P., D.T., A.H., V.M. and J.T.; supervision, D.T., A.M., N.A., V.M. and J.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Articles from Medicina are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

“Hallucinations” Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs

Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland.

* Address correspondence to: Frederick S. Barrett, PhD, Behavioral Pharmacology Research Unit, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 5510 Nathan Shock Drive, Baltimore, MD 21224, E-mail: [email protected]

This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Introduction: Cannabis has been historically classified as a hallucinogen. However, subjective cannabis effects do not typically include hallucinogen-like effects. Empirical reports of hallucinogen-like effects produced by cannabis in controlled settings, particularly among healthy research volunteers, are rare and have mostly occurred after administration of purified Δ-9 tetrahydrocannabinol (THC) rather than whole plant cannabis.

Methods: The case of a healthy 30-year-old male who experienced auditory and visual hallucinations in a controlled laboratory study after inhaling vaporized cannabis that contained 25 mg THC (case dose) is presented. Ratings on the Hallucinogen Rating Scale (HRS) following the case dose are compared with HRS ratings obtained from the participant after other doses of cannabis and with archival HRS data from laboratory studies involving acute doses of cannabis, psilocybin, dextromethorphan (DXM), and salvinorin A.

Results: Scores on the Volition subscale of the HRS were greater for the case dose than for the maximum dose administered in any other comparison study. Scores on the Intensity and Perception subscales were greater for the case dose than for the maximum dose of cannabis, psilocybin, or salvinorin A. Scores on the Somaesthesia subscale were greater for the case dose than for the maximum dose of DXM, salvinorin A, or cannabis. Scores on the Affect and Cognition subscales for the case dose were significantly lower than for the maximum doses of psilocybin and DXM.

Conclusion: Acute cannabis exposure in a healthy adult male resulted in self-reported hallucinations that rated high in magnitude on several subscales of the HRS. However, the hallucinatory experience in this case was qualitatively different than that typically experienced by participants receiving classic and atypical hallucinogens, suggesting that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action. This type of adverse event needs to be considered in the clinical use of cannabis.

Introduction

Cannabis, containing the psychoactive constituent Δ-9 tetrahydrocannabinol (THC), was historically classified as a hallucinogen, possibly due to the observation of powerful psychoactive effects. Early case reports that documented the subjective effects of cannabis 1,2 included experiences of anxiety, physiological distress, spiritual or mystical effects, and alterations to perception, awareness, and insight. These case reports provided support for characterizing cannabis as a hallucinogen. 2 Currently, it is uncommon for cannabis to be categorized as a hallucinogen, but, as policy changes regarding the medicinal and nonmedicinal (i.e., “recreational”) use of cannabis are rapidly being implemented, revisiting this potential effect of cannabis is warranted.

Hallucinations may be elicited by a variety of psychoactive drugs, with variable pharmacology. That said, hallucinations are consistently observed, and, arguably, the defining feature of a subset of drugs. The primary subjective effects of classic hallucinogens (e.g., psilocybin, lysergic acid diethylamide, and dimethyltryptamine [DMT]) are altered perception and cognition, 3 mystical or spiritual experiences, 4,5 and occasional anxiety and physiological distress, 6 and the molecular mechanism of action of hallucinogens is understood to be 5HT2A receptor agonism. 7,8 A set of pharmacologically diverse atypical hallucinogens, including κ-opioid agonists (e.g., salvinorin A) 9 and N-methyl-D-aspartate (NMDA) antagonists (including ketamine and dextromethorphan [DXM]), 10 are also known to consistently produce effects similar to, but distinguishable from, those of classic hallucinogens. THC is a partial agonist of cannabinoid receptor type-1 (CB1) and type-2 (CB2) receptors. Neither THC, nor minor cannabinoids, nor the terpenoids present in cannabis plant material have known direct effects at the 5HT2A, κ-opioid, or NMDA receptor. 11

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Most case reports describing hallucinations following acute cannabis exposure involve individuals with current psychosis or a family history of psychosis, populations that are known to have an atypical response to cannabis. 12 A growing literature continues to explore the relationship between cannabis use and development of psychosis among individuals with an underlying vulnerability for psychosis. 13–16 While perceptual alterations in healthy individuals during the acute effects of THC have been described, 17,18 empirical reports describing hallucinogen-like effects of cannabis and cannabis constituents in controlled settings and in healthy participants without a family history of psychosis are quite rare.

Peer-reviewed reports that do detail hallucinogen-like experiences in healthy adults predominantly come from research studies involving the administration of purified THC 16 or case reports of individuals who experience adverse reactions following use of synthetic cannabinoids (often full CB1 agonists with greater potency than THC), 19 rather than whole plant cannabis. This distinction is worth noting as it points to exogenous CB1 receptor agonism as a potential mechanism for inducing hallucinations, and also because it has been postulated that phytocannabinoids such as cannabidiol (CBD) 20 or terpenoids 11 that are present in the cannabis plant may mitigate some of the deleterious effects of THC.

The following report presents the case of an atypical response to cannabis that included self-reported “hallucinogen-like” effects after inhalation of vaporized cannabis containing THC, but nominal levels of CBD in a controlled laboratory study. To qualitatively investigate the phenomenology of this hallucinogen-like experience, we conducted cross-sectional comparisons of data from this case with archival data obtained from controlled behavioral pharmacology studies of cannabis, the classic hallucinogen psilocybin, and the atypical hallucinogens DXM and salvinorin A.

Methods

Approach

In the context of a double-blind, placebo-controlled laboratory study investigating the effects of smoked and vaporized cannabis, we present the details of an adverse reaction to inhalation of vaporized cannabis containing 25 mg THC (the “case dose”) in a healthy male research participant (H.C.). Ratings of subjective drug effects provided by H.C. during the case dose are compared with subjective data obtained from other participants in the same study, as well as subjective effects reported by participants in separate self-administration studies that evaluated acute dose effects of oral cannabis, psilocybin, 5 DXM, 10 and salvinorin A. 9,21

Study methods

All research studies were conducted at the Johns Hopkins Behavioral Pharmacology Research Unit (BPRU). Across investigations, research participants were enrolled if they were medically healthy adults who screened negative for current Axis I psychiatric disorders, denied a personal or family history of psychosis (i.e., first or second-degree relative), did not meet formal diagnostic criteria for substance use disorders (other than caffeine or tobacco), and were not taking medications that could interact with study drugs. Urine drug tests verified abstinence from drugs of abuse before all experimental sessions.

Cannabis studies

Subjective effects data from 31 healthy adult participants were collected across two cannabis self-administration studies; one experiment (N=17) evaluated acute doses of orally ingested cannabis in brownies that contained 0, 10, 25, and 50 mg THC, and a second study (N=14), in which H.C. was a participant, examined acute doses of smoked, and vaporized cannabis containing 0, 10, or 25 mg THC. Cannabis plant matter was sourced from and certified by the Drug Supply Program of the National Institute on Drug Abuse (NIDA) to contain 13.4% THC and 0.03% CBD. Dried cannabis was weighed and dispensed in a quantity that was calculated to contain the target dose of THC (e.g., 186.6 mg of cannabis would be vaporized to deliver 25 mg THC). Participants endorsed a history of cannabis use and denied use of cannabis for at least 30 days before study enrollment. Participants were not dependent on or seeking treatment for cannabis or other psychoactive drugs. A minimum of 1 week separated each dose condition to allow for a full washout of doses, and washout was biochemically verified with quantitative urine and blood toxicology tests.

Psilocybin study

Eighteen healthy adult participants, 17 who were hallucinogen-naive, completed five experimental sessions involving administration of 0, 5, 10, 20, and 30 mg/70 kg psilocybin doses in a controlled and supportive laboratory setting. 5 Drug administration sessions were separated by ∼1 month. Data collected during the 5 mg/70 kg dose is not included in this report.

DXM study

Twelve healthy adults with histories of hallucinogen use were administered up to eight doses of DXM (100–800 mg/70 kg), two doses of the sedative–hypnotic drug triazolam (0.25 and 0.5 mg/70 kg), and placebo under blinded conditions using an ascending dose run-up design. 10 A minimum of 48 h separated each drug administration session. All participants received at least the first four doses of DXM (100, 200, 300, and 400 mg/70 kg), but the study was halted before the 800 mg/70 kg dose for 10 participants due to adverse effects at lower doses. For the current comparison, we present data from placebo, 200 mg, the second highest (penultimate) dose, and the maximum dose administered to each participant.

Salvinorin A study

Eight healthy adults with previous lifetime use of a classic hallucinogen and at least one instance of salvia divinorum use in the past 5 years inhaled up to 16 ascending doses of vaporized salvinorin A (0.375–21 μg/kg). 9 A minimum of 24 h separated each drug administration session. Data from placebo, 9, 15, and 19.5 μg/kg doses were used for comparison in this study, as these doses of salvinorin A roughly corresponded to low, moderate, and high doses of psilocybin 5 on ratings of drug effect intensity.

Hallucinogen effects assessment

Participants across studies completed the Hallucinogen Rating Scale (HRS). 22 The HRS has been widely used to investigate the effects of a range of classic hallucinogens, including DMT, 23–26 psilocybin, 4,5 2C-B, 27 and 3,4-methylenedioxy-N-ethylamphetamine. 28 The HRS contains 59 items that are rated using a 5-point scale (0—not at all, 1—slightly, 2—moderately, 3—very much, 4—extremely) and scored with subscales indicating the degree of change that occurs during an acute drug experience from a more typical everyday experience across six dimensions (with example items for each dimension): Intensity (“high,” “a rush”), Somaesthesia (“change in body temperature,” “electric/tingling feeling”), Affect (“panic,” “euphoria”), Perception (“change in distinctiveness of sounds,” “change in brightness of objects in room”), Cognition (“change in rate of thinking,” “change in quality of thinking”), and Volition (“in control,” “able to move around if asked to”). Subscale scores were calculated as the average rating on all items that load onto each subscale.

Analyses

Average scores from the HRS were computed for each drug condition in each study, and plotted along with the HRS scores from responses for each dose and route of administration reported by H.C. A one-sample Student’s t-test was used to compare HRS scores from each drug condition in each study to the HRS scores for H.C. during the experimental session (vaporized cannabis containing 25 mg THC) in which he self-reported experiencing hallucinations.

Results

Case description

H.C. presented as a medically and psychiatrically healthy 30-year-old Caucasian male. He denied a history of significant health and psychiatric conditions and denied a family history of psychosis. He endorsed prior cannabis use, denied a history of any significant adverse effects associated with prior use, and he disclosed that 6 years had passed since he last used cannabis. He reported weekly use of alcohol and caffeine and denied use of nicotine/tobacco products and illicit drugs. He endorsed use of over-the-counter medication as needed for seasonal allergies. During the first three study sessions, he smoked cannabis that contained 0, 10, or 25 mg THC through hand-held pipe. Dose-related subjective drug effects, cardiovascular effects, and impairment on cognitive performance assessments were observed as expected. On the fourth experimental session (as with other experimental sessions), baseline assessments were within normal limits and urine drug screening (for common drugs of abuse) and breath alcohol tests were negative. After consuming a standard low-fat breakfast, the participant self-administered vaporized cannabis that contained 25 mg THC within 10 min (per protocol). Acute drug effects escalated in magnitude for the first 20 min following inhalation. He had difficulty responding to staff inquiries, was unable to complete self-report questionnaires, had difficulty keeping his head up, and appeared to periodically fall asleep or lose consciousness despite encouragement by research staff to stay awake and continue. He was unable to maintain a balanced, steady gait when he walked.

H.C. displayed behavior consistent with heavy sedation. The volunteer had difficulty maintaining consciousness and, at times, would not respond to verbal inquiries by study staff. He was under direct supervision of medical staff and neither his vital signs nor his behavior required medical intervention. He was able to complete a self-reported drug effect questionnaire, but had extreme difficulty completing cognitive performance assessments in the first 90 min following drug exposure. When he did speak, he reported feeling faint, dizzy, nauseated and that he was experiencing tingling sensations in his arms and legs and pain at the base of his neck.

Quantitative analysis (LC/MS/MS) of whole blood collected 10 min after the completion of cannabis administration (peak level measured in this study) showed 16 ng/mL THC, 3 ng/mL 11-OH-THC, and 17 ng/mL THC-COOH for H.C. These are consistent with mean values (14 ng/mL THC, 2 ng/mL 11-OH-THC, and 7 ng/mL THC-COOH) observed for all participants in this study at that time point and dose of vaporized cannabis. 29 Analysis of whole blood collected 10 min after the completion of cannabis administration in the smoked condition for the same dose level for H.C. (25 mg THC) showed 1 ng/mL THC, 1 ng/mL 11-OH-THC, and 4 ng/mL THC-COOH, and these values are consistent with mean values observed for all participants in this study at that time point and dose of smoked cannabis. 29

Three hours after drug administration, his symptoms began to decrease in severity. He indicated that he had experienced a dissociative state and altered perceptions of auditory and visual stimuli at the time of peak drug effect. He reported a hypersensitivity to voices at that time, which he described as if he was more aware of conversations around him, but was unable to hear or understand distinct words. He described visual distortions in the form of the environment and floor sinking away and the appearance of patterns moving on the carpet and chairs in the room. Additionally, he reported an “out-of-body” experience characterized by the feeling of being removed from his body, existing above it in space, and feeling that his surroundings were sinking away from him, which was also accompanied by a feeling of paralysis. He reported having had a similar experience when administered ketamine before surgery for a broken leg. Four hours after drug administration, and after eating lunch, H.C.’s symptoms of nausea, faintness, dissociation, and auditory, visual, and perceptual alterations had almost completely subsided. Five hours after drug administration, he appeared more alert and was able to complete all study-related tasks.

At the end of the experimental session, H.C. was prompted to recount his experience. He reported feeling overwhelmed that it was an uncomfortable, scary, and unpleasant experience akin to what he would expect an overdose or anxiety attack may feel like, and he indicated he never wanted to have the experience again. He expressed the sense that he thought he would “never come out of this” and that he would always feel the adverse effects. Within 8 h of acute drug administration, measures of cognitive performance, subjective mood and drug effects assessments, and vital signs had returned to baseline levels. The study medical team determined that there was no significant health risk with continued study participation and H.C. completed two remaining experimental sessions (lower dose and placebo cannabis) without significant discomfort.

Comparison of Hallucinogen Rating Scale scores

Comparison of HRS scores across studies. (A) HRS Intensity score, (B) HRS Somaesthesia score, (C) HRS affect score, (D) HRS perception score, (E) HRS cognition score, and (F) HRS volition score. Each (A–F) compares the scores for the indicated scale of the HRS (ordinate) at each of four dose conditions for each drug (abscissa) for each of the studies identified within the legend. Pen=average of ratings provided after the second-highest (penultimate) dose of DXM that a given participant received. 10 Max=average of ratings provided after the highest dose of DXM that a given participant received. 10 “Cannabis THC dose” refers to the amount of THC contained in dried cannabis that was administered. Smoked cannabis and vaporized cannabis studies are not yet published. HRS, Hallucinogen Rating Scale; THC, tetrahydrocannabinol.

Discussion

The legalization of cannabis for medicinal and nonmedicinal use is rapidly expanding. The development of novel routes of administration and technologies for delivering cannabis raises concerns about the adequacy of available data to inform dosing recommendations and complete disclosure of potential adverse consequences. In a controlled research study, a 30-year-old healthy male research participant (H.C.) experienced an adverse reaction to an acute dose of vaporized cannabis containing 25 mg of THC self-administered over the course of 10 min. H.C.’s response appeared somewhat remarkable in that he reported distortions in visual and auditory perception, cognition, and volition. These effects are not typical in controlled laboratory studies of healthy adults who do not report prior adverse reactions to cannabis or family history of psychosis. He reported large changes on the Intensity, Somaesthesia, Perception, and Volition subscales of the HRS, domains associated with classical hallucinogen drug effects, but relatively low ratings on the Affect and Cognition subscales compared with HRS ratings obtained in controlled laboratory studies of other hallucinogenic drugs. The case dose was greater in Intensity and Perception subscales of the HRS compared with mean scores obtained following administration of high doses of psilocybin and salvinorin A, but was comparable to Perception scores following the maximum tolerated dose of DXM. 10 This is consistent with the participant’s report of a ketamine-like experience, given that DXM is a dissociative hallucinogen/anesthetic with a similar mechanism of action to ketamine (NMDA antagonism). The participant’s scores on the Somaesthesia subscale were similar to those observed after administration of a high dose of oral psilocybin (30 mg/70 kg), 5 both of which were greater than scores observed following DXM and salvinorin A administration. Scores on the Affect and Cognition subscales of the HRS for the case dose were low, consistent with scores provided by other participants in acute cannabis dosing studies, and were not consistent with the most intense reported experiences with psilocybin, DXM, or salvinorin A.

Given that changes in affect and cognition are core features of experience with classic hallucinogens, 3 it is difficult to attribute the reported case as an experience similar to that of a true classic hallucinogen. Curiously, Intensity scores for the case dose were equal to the Intensity score for H.C. after self-administration of smoked cannabis containing the 25 mg THC dose. H.C. did not report any hallucinations during the 25 mg THC smoked cannabis session. Also, scores on the Volition subscale for all vaporized drug conditions, including placebo, were greater than for sessions involving smoked cannabis for H.C., and were higher than those observed in archival study comparisons.

A number of case reports have been recently published that indicate psychotic or hallucinogen-like effects after ingestion of synthetic cannabinoids in both adults 19,30,31 and adolescents. 32,33 In many cases, these individuals, like H.C., were otherwise healthy, had negative toxicology screens for other substances of abuse, and were typically free of personal or family history of psychosis. 31 Unlike H.C., cases reported after consumption of synthetic cannabinoids included seizures, agitation or violent behavior, and frank psychosis, 19 or psychiatric syndromes persisting for days or longer after consumption of synthetic cannabinoids. 31 One study reported development of hallucinogen persistent perceptual disorder (HPPD) after synthetic cannabinoid use in otherwise healthy adults who had no prior history of natural or synthetic hallucinogen use 30 ; however, H.C. encountered no persisting effects, either HPPD or other, which were related to the case dose in this report. While THC is a partial agonist of the CB1 receptor, synthetic cannabinoids tend to be full CB1 agonists with high potency and high affinity for the CB1 receptor. These factors may contribute to a greater likelihood (compared with cannabis) of negative and hallucinogen-like effects after consumption of synthetic cannabinoids, and may suggest that CB1 agonism may underlie hallucinogen-like effects of cannabinoids. 34 While H.C.’s experience was atypical for a response to cannabis or THC, it does not seem that his experience is consistent with published case reports of “hallucinogenic” effects following consumption of synthetic cannabinoids.

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Although the subjective effects that H.C. reported exhibited some similarities to the effects of classic and atypical hallucinogens ( Fig. 1 ), the overall profile of subjective effects as characterized by the HRS indicates that his experience was not wholly consistent with what would be expected for a classic hallucinogen, an NMDA antagonist dissociative hallucinogen (DXM, similar in effects to ketamine), or κ-opioid agonist (salvinorin A). Thus, it appears that the hallucinatory effects of cannabis, taken as a whole, may be qualitatively different than those of other hallucinogens, which suggests that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action.

Potential mechanisms of hallucinatory effects of cannabis

Although cannabis constituents do not have high affinity for direct pharmacological effects at 5HT2A, NMDA, or κ-opioid receptors, they may interact with the serotonin and glutamatergic systems. Multiple preclinical studies have demonstrated an impact of exogenous cannabinoid administration on 5-HT receptor expression and function3. CBD has been shown to alter psychological response to ketamine, 35 and subchronic administration of PCP (an NMDA antagonist) has been shown to change the effects of exogenous cannabinoids on prefrontal brain function. 36 However, existing studies suggest that the administration of exogenous cannabinoids does not modulate the κ-opioid receptor system. 37–39 While speculative, it is possible that hallucinatory effects of cannabinoids may be due to effects of exogenous cannabinoid on 5-HT or NMDA receptors; however, studies explicitly evaluating cannabinoid effects in brain areas associated with hallucinations are lacking.

Potential factors contributing to individual differences in cannabinoid response

Blood cannabinoid levels measured after the case dose were comparable to means observed in other study participants for vaporized administration of cannabis containing the same dose of THC (25 mg). Similarly, blood cannabinoid levels measured for H.C. after smoked administration of cannabis containing a dose of THC equal to the case dose were far lower than those measured after the case dose, consistent with means observed in other study participants. This is consistent with suggests that H.C. was not exposed to a greater amount of THC than other study participants. Given H.C.’s history of a strong reaction to a psychoactive and potentially hallucinogenic drug (ketamine) in a clinical setting, this suggests that H.C. may possess some unique sensitivity to psychoactive drugs.

Additional research is needed to help understand the neurobiological underpinnings of hallucinations that are sometimes occasioned following high-dose cannabis administration. For example, there may be genetic differences between individuals who experience and those who do not experience rare and atypical effects of cannabinoids that account for these effects. Although we did not sample and cannot address the genetic profile of H.C., it is possible that genes implicated in cannabis-induced psychosis (such as the DRD2, BDNF, AKT1, and COMT genes) 40 are also involved in the type and degree of experience that was encountered in this case. In addition, individual differences in sensitivity to CB1 agonists (potentially mediated by the CNR1 gene) may predict individual differences in response to exogenous cannabinoids. As mentioned previously, there are hypotheses that cannabis constituents other than THC (e.g., CBD, other phytocannabinoids, or terpenoids) may mitigate some of the adverse effects of THC. The cannabis used in the present study contained a high concentration of THC (13%) and low concentrations of CBD (<1%) and CBN (<1%). While an extreme ratio of THC to these minor phytocannabinoids may increase the likelihood of adverse events such as the hallucinations observed in this report, there is insufficient empirical data on the interaction between THC and other constituents of the plant to confidently draw that conclusion at this point. It is also important to note that most research evaluating the cannabinoid profile of commercial cannabis and related products indicate that very high THC and very low CBD products are predominant in the current retail market. 41–43

Limitations

The current report describes perceptual alterations and dissociative symptoms of a type that have been sparsely described previously as resulting from acute cannabis exposure. There is a substantial literature pointing to cannabinoid-induced psychosis in those with a personal or family history of psychosis. This particular susceptibility to psychosis was nominally ruled out in the case of H.C. in the medical and psychiatric history collected during screening, but the participant may have misreported or there may be a latent family history of which he was unaware. The current article is also limited in that cross-study comparisons with respect to the qualitative and quantitative characteristics of hallucinations across drug types was conducted with archival data across subjects rather than prospective evaluation within the same individuals. Additional research on the comparative effects of these drugs, especially those that incorporate genetic and neuroimaging components, is needed to extend the present observations.

Conclusion

In this article, we highlighted a rare but clinically significant response to acute cannabis dosing. The participant was functionally incapacitated for about 90 min and experienced strongly aversive and disorienting effects. It is unclear how frequently this type of reaction occurs in healthy adults without a family history of psychosis. H.C. did not have any health screening information that would have predicted this effect, indicating that this type of reaction should be considered in decision making regarding cannabis use. This case also demonstrates the importance of considering dose and route of administration in decision making regarding cannabis use as this individual did not exhibit similar effects at lower vaporized doses or smoking the same dose of cannabis.

Abbreviations Used

BPRU Behavioral Pharmacology Research Unit
CB1 cannabinoid receptor type-1
CBD cannabidiol
DMT dimethyltryptamine
DXM dextromethorphan
HPPD hallucinogen persistent perceptual disorder
HRS Hallucinogen Rating Scale
NIDA National Institute on Drug Abuse
NMDA N-methyl-D-aspartate
THC tetrahydrocannabinol

Acknowledgments

The research described here was funded by research contracts from the Substance Abuse and Mental Health Services Administration (SAMHSA; cannabis studies), National Institute on Drug Abuse (NIDA) grants R01-DA003889 (DXM and salvinorin A studies) and R01-DA-19151 (salvinorin A study), and grants from the Heffter Research Institute, the Betsy Gordon Foundation, and the Council on Spiritual Practices (psilocybin study). In addition, N.J.S. received salary support from NIDA postdoctoral training grant T32-DA07209, and F.S.B. was partially supported by NIH grant R03DA042336. The authors also thank the individuals at the NIDA Drug Supply Program for their support in conducting this research.

Author Disclosure Statement

Dr. Vandrey has received consulting fees or honoraria from Zynerba Pharmaceuticals, Insys Therapeutics, Battelle Memorial Institute, and several small businesses that cultivate, process, and/or dispense cannabis under state medical cannabis access programs. All other authors have no conflicts of interest to report.

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References

Cite this article as: Barrett FS, Schlienz NJ, Lembeck N, Waqas M, Vandrey R (2018) “Hallucinations” following acute cannabis dosing: a case report and comparison to other hallucinogenic drugs, Cannabis and Cannabinoid Research 3:1, 85–93, DOI: 10.1089/can.2017.0052.

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