Introduction
Cannabis use in adolescence has been demonstrated on multiple occasions to increase the risk of developing acute psychotic symptoms and contributes significantly to the future risk of schizophrenia (Caprari et al. Reference Caprari, Ferri, Vandelli, Citti and Cannazza2024; Ferland et al. Reference Ferland and Hurd2020; Marconi et al. Reference Marconi, Di Forti, Lewis, Murray and Vassos2016; Pourebrahim et al. Reference Pourebrahim, Ahmad, Rottmann, Schulze and Scheller2025; Volkow et al. Reference Volkow, Swanson, Evins, DeLisi, Meier and Gonzalez2016). Delta-9-tetrahydrocannabinol (Δ9-THC) is the primary psychoactive compound of cannabis (Montoya et al. Reference Montoya and Weiss2018), functioning as a partial agonist at the cannabinoid receptor CB1 (Oliver et al. Reference Oliver, Chesney, Cullen, Davies, Englund and Gifford2024), and is responsible for the characteristic ‘high’ of cannabis intoxication (Ashton et al. Reference Ashton2001).
CB1 receptor density increases significantly during adolescence, contributing to the neural development and the genetic regulation of brain maturation (Iversen et al. Reference Iversen2003; Rubino et al. Reference Rubino and Parolaro2008), with these receptors playing a central role in regulating excitatory and inhibitory neurotransmission during this sensitive period. Evidence from long-term human neuroimaging research and animal studies indicate that cannabis consumption, especially when use is frequent or involving high concentrations of THC, can interfere with normal adolescent brain development and associated behavioural processes, including synaptic and neuronal alterations that highlight the vulnerability of the developing brain (Hurd et al. Reference Hurd2025; Renard et al. Reference Stringfield and Torregrossa2021). Exposure to THC in adolescence has been proposed to interfere with the interplay of inhibitory (Gamma-aminobutyric acid) and excitatory (glutamate) neurons of the prefrontal cortex, impacting maturation of these circuits, which, with prolonged use, increase the risk of developing psychosis or schizophrenia (Bossong and Niesink Reference Bossong and Niesink2010). This finding is supported by meta-analytic data that demonstrates that cannabis use during this critical adolescent period is linked to a significantly increased risk of developing psychosis later in life, and an earlier onset of psychotic symptoms (Kiburi et al. Reference Kiburi, Molebatsi, Ntlantsana and Lynskey2021). Ingested cannabis contains increasingly potent THC (Freeman et al. Reference Freeman, Craft, Wilson, Stylianou, ElSohly and Di Forti2021), with incidence rates of psychosis strongly correlated with frequent high potency THC consumption (r = 0.8) (Di Forti et al. Reference Di Forti, Quattrone, Freeman, Tripoli, Gayer-Anderson and Quigley2019). Conversely, cannabidiol (CBD), the main non-psychoactive component, has been purported to have anxiolytic and potentially anti-psychotic effects; albeit further research is required to clarify the same (Englund et al. Reference Englund, Oliver, Chesney, Chester, Wilson and Sovi2023).
While most research examining clinical presentations to date focuses on Δ9-THC-dominant cannabis, evidence from synthetic cannabinoid receptor agonists highlights the potential for severe psychiatric presentations, including acute psychosis, agitation, affective disturbance, and behavioural dysregulation (Altintas et al. Reference Altintas, Inanc, Oruc, Arpacioglu and Gulec2016; Sweet et al. Reference Sweet, Kim, Martin, Washington and Brahm2018). However, direct comparisons of clinical symptomatology across different cannabinoid classes remain limited. These substances, synthetic cannabinoids, are being increasingly detected in Europe, with prevalence rates of such substances in adolesceEMCDDAnts reported to be as high as 5.1% (EMCDDA 2023).
Hexahydrocannabinol (HHC;6a,7,8,9,10,10a-hexahydro-6,6,9-trimethyl-3-pentyl-6Hdibenzo[b,d]pyran-1-ol), initially identified in 1940 (Adams et al. Reference Adams, Hunt and Clark1940) is categorised as semi-synthetic, as synthesised from CBD usually derived from low-THC cannabis (hemp) (Dillon et al. Reference Dillon, Galvin, Guiney, Lyons and Millar2025), rather than being fully synthetic, as it is not synthesised de novo. By binding to CB1 and CB2 receptors in the brain, HHC potentially produced effects similar to those of Δ9-THC (Radwan et al. Reference Radwan, Chandra, Gul and ElSohly2021; Nasrallah et al. Reference Nasrallah and Garg2023).
Recently, HHC has attracted attention as an alternative to Δ9-tetrahydrocannabinol (THC), initially in the United States and shortly thereafter spreading to Europe (EMCDDA 2023). In May 2022, HHC was detected in Denmark in a food product marketed as a hypnotic (Pitterl et al. Reference Pitterl, Pavlic, Liu and Oberacher2024). By the end of 2022, HHC was placed under heightened surveillance by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA 2023).
Hexahydrocannabinol (HHC) has recently been banned in Ireland. On the 29th of July 2025, it was classified as a Schedule 1 controlled drug under the Misuse of Drugs Act 1977. This classification renders the import, export, production, possession, sale, or distribution of products containing HHC illegal (Department of Health 2025). Prior to being banned, HHC was marketed in multiple forms including vape pens, oils, edibles, and herbal mixtures, along with colourful, eye-catching packaging, which raised concerns about its appeal to adolescents who might perceive it as a safer or more accessible alternative to traditional cannabis. Data from a recent European wide online survey of adult recreational drug users indicated that over one-third of Irish respondents reported HHC use in the previous year (Mongan et al. Reference Mongan, Killeen, Millar, Matias, Keenan and Galvin2025); although self-reported, these findings suggest widespread exposure. Among Irish respondents reporting HHC use, adverse psychological effects were commonly endorsed, particularly among higher-frequency users, including anxiety, paranoia, and hallucinations (Mongan et al. Reference Mongan, Killeen, Millar, Matias, Keenan and Galvin2025).
An initial case series reported two cases of HHC-induced psychosis in an adult psychiatric unit (O’Mahony et al. Reference O’Mahony, O’Malley, Kerrigan and McDonald2024), with a subsequent recent retrospective review over a 21-month period identifying a 13% prevalence of HHC use among patients admitted with psychosis to an acute psychiatric inpatient unit, including 34% of those admitted with a first episode of psychosis (O’Mahony et al. Reference O’Mahony, Lanigan, Lally, O’Malley, Smyth, McDonald and Hallahan2025). No literature to date has specifically investigated the effects of HHC use on adolescents. Here, we present two cases of HHC-induced psychosis in adolescents within a child and adolescent inpatient psychiatric setting, discussing the link with aetiopathogenesis and potential intervention strategies that could be considered to counteract this risk in the future.
Case 1
We present the case of a 16-year-old boy, who presented with his parents on two occasions to the Emergency Department (ED) over 48 hours due to experiencing “racing thoughts”, suicidal ideation (denied a clear plan to end his life) and feeling agitated. On his second visit to the ED, he additionally described several perceptual abnormalities, including running commentary, second- and third-person auditory hallucinations and visual hallucinations where he described seeing spiders and snakes, in close proximity to him. These visual hallucinations “terrified” him, and he believed they were causative in his feeling acutely anxious and suffering severe insomnia. These symptoms had been present with increasing intensity for approximately one week. He consented to inpatient admission at this time.
His initial treatment consisted of fluoxetine 10 mg once daily for the management of anxiety symptoms and quetiapine 25 mg nocte. He was prescribed a low dose of quetiapine initially to manage insomnia as he was neuroleptic naïve. The dose of quetiapine was up-titrated to 100 mg nocte and 25 mg once daily over a 4-day period. Two weeks after his admission date, the dose of fluoxetine was increased to 20mg; however, he described increased agitation and suicidal ideation after this treatment change and engaged in an episode of self-harm (i.e. laceration of the arm with a sharp implement) two days after this treatment change. Fluoxetine was discontinued, and diazepam was commenced (2 mg bd).
On admission, he disclosed utilization of HHC vapes on at least a weekly basis for a period of seven months (approximately 2 ml per week). He denied any other psychoactive substance use, and urine toxicology was positive for THC but no other psychoactive substances. He had a history of anxiety symptoms, prior to utilization of HHC; however, these symptoms were not sufficiently severe to meet operational diagnostic criteria for an anxiety disorder or require any interventions. He had no prior history of psychotic symptoms or engagement in self-harm and no first-degree family members who had a psychiatric history, albeit one second-degree family member was treated for major depressive disorder (without psychotic symptoms). He had no history of utilising other psychoactive substances, including cannabis.
Mental state examination on admission noted him to be agitated and guarded. His speech was clear. Subjectively, he felt “low and stressed,” and objectively, he was dysthymic. There was no evidence of formal thought disorder, and the thought stream was within normal parameters. No clear persecutory or referential delusions were evident. He was orientated to time, person, and place. He described some ongoing perceptual abnormalities, including second- and third-person auditory hallucinations and visual hallucinations. He displayed minimal insight into the cause of his symptoms, but he was agreeable to take psychotropic medications.
His perceptual abnormalities resolved one week after treatment with the increased dose of quetiapine (approximately 11 days post-admission and 13 days since his last use of HHC). Agitation and insomnia persisted, however, with suicidal ideation of varying intensity present for 6 weeks. He described experiencing thoughts of self-harm in the context of significant anxiety, agitation, and distress secondary to perceptual abnormalities (during the initial part of his admission). During his 8-week inpatient admission, he engaged in anxiety management and additional coping skills. He was gradually weaned off diazepam, with escitalopram commenced and the dose increased to 20 mg over a period of 1 week, with no adverse sequelae. He remained on quetiapine 100 mg nocte. On discharge, he denied all psychotic and anxiety symptoms and presented as euthymic, with no suicidal ideation. He was advised to remain on the above medication regimen for 3–6 months prior to a titrated discontinuation of his treatment if he remained symptom-free in collaboration with his treating team.
Case 2
We present the case of a 17-year-old boy who presented to the ED after running away from home. He absconded shortly after arrival at the ED, and police were alerted and subsequently brought him back to the hospital ED, where he was reviewed. He described three days of insomnia, during which he reported feeling confused and mistrustful of his family, believing that his family members wanted to cause him harm. He felt that his life was at risk, and consequently, he left his house abruptly without any provisions. He appeared perplexed, was intermittently guarded, and restless. He found it difficult to remain seated during consultations, pacing in the room where he was interviewed (and leaving the room on occasion), and was also noted to be pacing in the ED.
On admission, he reported using HHC vapes for the previous 9 months (including for three months after they were no longer legally available), at a dose of 2 ml per week for the four months prior to admission, with lower amounts utilised prior to this. He also reported very occasional use of a similar compound, Hexahydrocannabihexol (HHC-H) (a derivative of HHC), and his urine toxicology test was positive for THC, but no other psychoactive substances. He described an ongoing ease of access in attaining HHC vapes despite them becoming illegal in July 2025.
He had no prior history of psychotic symptoms or engagement with mental health services and had no first-degree family members with a psychiatric history. He had previously utilised Lysergic acid diethylamide on one occasion approximately one month prior to admission and described nausea but no disorders of thought content or perceptual abnormalities subsequent to use. He denied any lifetime use of any other psychoactive substances.
Mental state examination on initial review noted him to be agitated, perplexed, and guarded, presenting with incongruous smiling on several occasions. His speech was clear with normal tone and volume, with no evidence of neologisms. His rate of speech was variable, with significant pauses at times, which impeded history taking. Subjectively, he felt “stressed,” and objectively, his mood was labile, with both dysphoria and euphoria evident at different times. His affect was incongruous at times, but reactive. He demonstrated formal thought disorder, with tangentiality, circumstantiality, and derailment evident (abrupt changes in train of thought at times with no connection between thoughts), resulting in illogical speech at times. His thought stream was variable during the interview, and a reduced flow of thoughts was notable on occasions. He described persecutory delusions. His thought content also included religious ideation (out of character for him), but no clear religious delusions were elicited. He was orientated in time, person, and place, but had reduced concentration levels. No perceptual abnormalities were exhibited. He displayed minimal insight into the cause of his symptoms and requested to leave the hospital. Consequently, an Order for Detention under the Mental Health Act 2001 Section 25(6) was attained, and he was admitted involuntarily to hospital.
On admission, he was commenced on olanzapine at a dose of 5 mg daily to treat his psychotic symptoms, with the dose increased over 7 days to 12.5 mg, which he continued for the remainder of his inpatient admission. He was prescribed lorazepam (up to 2 mg per day) to manage agitation, which was required for the first two weeks of his admission. His persecutory delusions dissipated three weeks after treatment with 12.5 mg of olanzapine. His affect also became congruent and reactive, and his mood became normothymic. His thought form resolved more slowly, with difficulties attending to tasks and reduced concentration evident for approximately another six weeks. His detention order was revoked 10 weeks after admission, with no evidence of derailment or tangentiality, and improved concentration evident at this stage. He was discharged home the following day and community mental health services follow-up arranged. His treatment on discharge consisted of olanzapine 12.5 mg nocte, and it is expected that this treatment will be required for approximately 6 months prior to a titrated discontinuation if he is symptom-free. He will also attain ongoing metabolic monitoring (no abnormalities for any metabolic parameter have been noted to date).
Discussion
These two cases demonstrate a temporal association between HHC use and the emergence of first psychotic episodes in two adolescents. Both cases had no prior psychiatric history or engagement with mental health services, or a family history of psychosis. Both cases demonstrated severe symptoms requiring inpatient admission to an acute psychiatric CAMHS inpatient unit for more than six weeks. These findings are consistent with earlier reports in adults of HHC-induced psychosis (O’Mahony et al. Reference O’Mahony, O’Malley, Kerrigan and McDonald2024; O’Mahony et al. Reference O’Mahony, Lanigan, Lally, O’Malley, Smyth, McDonald and Hallahan2025), including FEP. In addition to this, a recent Irish survey found that 3.9% of people who used HHC in the past year had self-reported “psychosis or hallucinations” after use (Mongan et al. Reference Mongan, Killeen, Millar, Matias, Keenan and Galvin2025). Despite the lack of confirmatory toxicology testing for HHC, both patients gave a very clear description of their HHC utilisation and the temporal association between HHC use and onset of symptomatology.
HHC, due to its neuropharmacological similarity to Δ9-THC likely induces psychotic symptoms through CB1 receptor agonism. Acute administration of THC has been demonstrated to increase dopamine activity within the striatum (Bossong et al. Reference Bossong, Mehta, van Berckel, Howes, Kahn and Stokes2015), whilst chronic use is linked with blunted dopaminergic signalling (Bloomfield et al. Reference Bloomfield, Morgan, Egerton, Kapur, Curran and Howes2014; Bloomfield et al. Reference Bloomfield, Ashok, Volkow and Howes2016; Solinas et al. Reference Solinas, Justinova, Goldberg and Tanda2006). Thus, HHC likely stimulates dopamine release brain regions frequently been associated with psychotic disorders (i.e. medial temporal lobe, ventral tegmentum, striatum) (Bhattacharyya et al. Reference Bhattacharyya, Fusar-Poli, Borgwardt, Martin-Santos, Nosarti and O’Carroll2009; Gunasekera et al. Reference Gunasekera, Diederen and Bhattacharyya2022).
The detection and monitoring of HHC use present significant challenges. Depending on the assay used, standard toxicology screens may fail to detect HHC or may produce false positive results for THC (EMCDDA 2023). In these two cases, urine toxicology screens were both positive for THC, despite no usage by either patient of THC. This, along with limited awareness among clinical staff, likely contributes to the under-recognition of HHC in psychiatric assessments (O’Mahony et al. Reference O’Mahony, Lanigan, Lally, O’Malley, Smyth, McDonald and Hallahan2025). Due to its structural similarity to Δ9-THC, HHC can cause cross-reactivity in immunoassays that cannot distinguish between tetra- and Hexahydrocannabinol (Helander et al. Reference Helander, Johansson, Villen and Andersson2024; Wolf et al. Reference Wolf, Pokhai, Poklis and Williams2023). Definitive identification requires more advanced techniques like gas or liquid chromatography-mass spectrometry (Pitterl et al. Reference Pitterl, Pavlic, Liu and Oberacher2024). Although immunoassay screening is not sufficient to reliably differentiate between cannabis related compounds, the cross-reactivity it provides can serve as a preliminary flag for otherwise undetectable novel cannabinoids (Helander et al. Reference Helander, Johansson, Villen and Andersson2024).
The National Drug Treatment Reporting System began to record HHC as a substance of concern in 2024, alongside vaping as a method of administration. From January 1st, 2024, to July 25th, 2025, a total of 221 cases were reported where HHC was identified as either the primary or an additional problem drug. Most individuals treated for HHC use were male and under 19 years of age (Department of Health 2025). Supporting this finding, research from Galway University Hospital reported HHC as the second most common substance utilised among adults admitted with psychotic symptoms (all patients are ≥ 18 years of age), between May 1, 2023, and December 31, 2024; with patients having a mean age of 24 years (SD = 8) (O’Mahony et al. Reference O’Mahony, Lanigan, Lally, O’Malley, Smyth, McDonald and Hallahan2025).
Although Ireland banned HHC in July 2025 following a UN decision based on WHO recommendations in March 2025, this move came two years after France’s ban and over a year after Irish psychiatrists raised concerns. Whilst the ban aligns Ireland with broader European and international initiatives, legal prohibition alone is unlikely to eliminate the entire use. Although the Garda Síochána has urged shops to surrender their remaining stock, early signs suggest that the substance remains accessible, particularly among young people. This ongoing availability is probably due to leftover stock in shops and delayed enforcement. This could lead to “clearance” sales, discreet discounts or new supply routes forming to encourage short-term use before enforcement fully takes effect. However, detailed data on how shops are responding remains limited.
Following the HHC ban, the further risk remains that young people may turn to chemically similar compounds, such as Hexahydrocannabinol-O-acetate (HHC-O) or Hexahydrocannabihexol (HHC-H) to fill the regulatory gap. Following the classification of HHC and Hexahydrocannabiphorol (HHC-P) as narcotics in Sweden on 11 July 2023, these substances mostly disappeared from both street and online markets (Helander et al. Reference Helander, Johansson, Villen and Andersson2024). However, other unregulated substitutes, including Hexahydrocannabinol-O-acetate (HHC-O) and Tetrahydrocannabiphorol (THC-P), subsequently supplanted them (Helander et al. Reference Helander, Johansson, Villen and Andersson2024). These analogues may possess different potencies or pharmacological effects (Adams et al. Reference Adams, Smith and Loewe1941; EMCDDA 2023). Although peer-reviewed toxicological data are lacking, the pattern of emerging substitutes following bans is well-documented in the context of synthetic cannabinoids and novel psychoactive substances (van Amsterdam et al. Reference van Amsterdam, Burgess and van den Brink2023).
In this context, the Irish experience with head shops in 2010 is particularly instructive. Compared to international norms, Irish youth reported particularly high levels of new psychoactive substances (NPS) use, most commonly synthetic cannabinoids and cathinones. This trend coincided with the rapid expansion of head shops on Irish high streets, which widely sold these substances (Symth Reference Smyth2023). When a specific substance was banned, retailers quickly replaced it with NPS, sustaining the cycle of use (Smyth et al. Reference Smyth, Daly, Elmusharaf, McDonald, Clarke, Craig and Cullen2020). This pattern was ultimately halted by the Criminal Justice (Psychoactive Substances) Act (2010), which banned the sale of all psychoactive substances and resulted in the nationwide closure of head shops and a resultant reduction in drug-related psychiatric admissions in Ireland (Symth et al. Reference Smyth, Daly, Elmusharaf, McDonald, Clarke, Craig and Cullen2020), suggesting that targeting suppliers did not simply displace drug sales into underground markets. It is unclear whether recent legislation addressing HHC use in Ireland will have a similar impact on HHC availability, and whether future studies on the prevalence of HHC use, particularly among adolescents and young adults, are required. Prior to the recent prohibition of HHC, O’Mahony et al. (Reference O’Mahony, Lanigan, Lally, O’Malley, Smyth, McDonald and Hallahan2025) highlighted that its continued sale in Ireland revealed shortcomings in the Criminal Justice (Psychoactive Substances) Act (2010), with implications for future responses to novel psychoactive substances.
The effectiveness of the HHC ban will depend not only on legal enforcement but also on a broader public health strategy that considers societal trends. Notably, recent evidence indicates a reduction in the perceived harmfulness of cannabis (Chiu et al. Reference Chiu, Hall, Chan, Hides and Leung2022) with rising vaping rates amongst adolescents and young adults (Pinho-Gomes et al. Reference Pinho-Gomes, Santos, Jones, Thout and Pettigrew2023). Declining perceptions of harm alongside increasing popularity of vaping (the usual method of ingestion of HHC) could contribute to the normalisation and continued use of HHC. This could potentially increase demand for mental health and addiction services and an increase in presentations with psychotic symptoms and disorders in young people. Consequently, educational initiatives should be organised to increase public awareness of the potential adverse sequelae linked to using HHC and its substitutes. Raising awareness in schools, community programmes and digital platforms could play a vital role in reducing experimentation and misuse.
Conclusion
We present two cases of psychotic illness in adolescents likely precipitated by HHC use. This semisynthetic cannabinoid had been widely sold as a legal product in Ireland until very recently, July 29th, 2025. Given the likely widespread use of HHC, all clinical assessments for a potential FEP or psychosis in adolescents or young adults should enquire specifically about the use of HHC and similar products. Toxicological profiles for HHC and emerging analogues should be enhanced to improve detection accuracy. Although Ireland’s HHC ban is an important step towards reducing youth exposure, its long-term effectiveness will depend on coordinated multiagency collaboration across the enforcement, public health,and education sectors. There is a need to develop a more proactive public health-oriented response to chemically similar cannabinoids that may emerge to bypass current controls.
Acknowledgements
The authors are grateful to the parents who gave informed consent for their children’s case histories to be included in this case series.
Funding statement
The research received no specific grant from any funding agency, commercial, or not-for-profit sectors.
Competing interests
None Ethical Standards: The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committee on human experimentation with the Helsinki Declaration of 1975, as revised in 2008.
Consent
Informed written consent was obtained from the parents of Cases 1 and 2.
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