Δ9-tetrahydrocannabinol: harmful even in low doses?
Authors: Carsten Hjorthøj, Christine Merrild Posselt
Journal: The Lancet Psychiatry (2020)

Cannabis is a substance that is shrouded in myth, paradox, and controversy. On the one hand, a host of literature indicates detrimental effects on areas such as mental health (eg, increased risk of schizophrenia and poorer prognosis among patients with psychiatric disorders who also use cannabis), risk of addiction, and psychosocial functioning.1Moore THM Zammit S Lingford-Hughes A et al.Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.Lancet. 2007; 370: 319-328Summary Full Text Full Text PDF PubMed Scopus (1632) Google Scholar, 2Marconi A Di Forti M Lewis CM Murray RM Vassos E Meta-analysis of the association between the level of cannabis use and risk of psychosis.Schizophr Bull. 2016; 42: 1262-1269Crossref PubMed Scopus (431) Google Scholar, 3Large M Mullin K Gupta P Harris A Nielssen O Systematic meta-analysis of outcomes associated with psychosis and co-morbid substance use.Aust New Zeal J Psychiatry. 2014; 48: 418-432Crossref PubMed Scopus (62) Google Scholar, 4Horwood LJ Fergusson DM Hayatbakhsh MR et al.Cannabis use and educational achievement: findings from three Australasian cohort studies.Drug Alcohol Depend. 2010; 110: 247-253Crossref PubMed Scopus (200) Google Scholar On the other hand, there has been an increase in public perception of cannabis as relatively harmless, as well as international movements to legalise cannabis for medicinal or recreational purposes.5Carliner H Brown QL Sarvet AL Hasin DS Cannabis use, attitudes, and legal status in the U.S.: a review.Prev Med. 2017; 104: 13-23Crossref PubMed Scopus (287) Google Scholar Of course, this does not necessarily constitute a paradox—benzodiazepines and opioids are also used both recreationally and medicinally, and with both positive (eg, reduction of pain or anxiety) and negative (eg, addiction or death) effects. However, the controversy appears to run deeper in the case of cannabis, probably because of the counterculture that has existed around the substance for the past 50 years. Cannabis is increasingly seen as harmless, perhaps because it is a natural product.5Carliner H Brown QL Sarvet AL Hasin DS Cannabis use, attitudes, and legal status in the U.S.: a review.Prev Med. 2017; 104: 13-23Crossref PubMed Scopus (287) Google Scholar Observed negative effects on mental health are, in this viewpoint, seen as stemming solely from self-medication. This controversy has also existed in the scientific community. Within a rather short time period, two systematic reviews were published in The Lancet.1Moore THM Zammit S Lingford-Hughes A et al.Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.Lancet. 2007; 370: 319-328Summary Full Text Full Text PDF PubMed Scopus (1632) Google Scholar, 6Macleod J Oakes R Copello A et al.Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies.Lancet. 2004; 363: 1579-1588Summary Full Text Full Text PDF PubMed Scopus (481) Google Scholar The first concluded that the associations between cannabis and psychosis were most likely explained by non-causal or selection mechanisms.6Macleod J Oakes R Copello A et al.Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies.Lancet. 2004; 363: 1579-1588Summary Full Text Full Text PDF PubMed Scopus (481) Google Scholar The second concluded that, although causality between cannabis and psychosis was difficult to establish, there was ample reason to be cautious because evidence was pointing in this direction.1Moore THM Zammit S Lingford-Hughes A et al.Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.Lancet. 2007; 370: 319-328Summary Full Text Full Text PDF PubMed Scopus (1632) Google Scholar Since then, much research has been published, and there appears to be a growing scientific consensus that cannabis does have a causal role in the development of psychosis. Indeed, the association appears to be bidirectional, so both hypotheses are probably correct.7Ferdinand RF Sondeijker F van der Ende J Selten J-P Huizink A Verhulst FC Cannabis use predicts future psychotic symptoms, and vice versa.Addiction. 2005; 100: 612-618Crossref PubMed Scopus (162) Google Scholar, 8Petersen SM Toftdahl NG Nordentoft M Hjorthøj C Schizophrenia is associated with increased risk of subsequent substance abuse diagnosis: a nation-wide population-based register study.Addiction. 2019; 114: 2217-2226Crossref PubMed Scopus (12) Google Scholar In some people, cannabis leads to incident psychosis, whereas in other people, psychosis leads to incident cannabis use. This growing scientific consensus is not reflected in the mainstream public discourses, which have a major effect on the political agenda to decriminalise or legalise cannabis. It also appears that, in many places (eg, several US states), the first thing to be legalised is medicinal cannabis followed by increasing decriminalisation and sometimes complete legalisation of cannabis. It is thus of utmost importance that the public and politicians are informed of the most up-to-date evidence on cannabis. Adding to the state of this evidence is the systematic review and meta-analysis by Guy Hindley and colleagues9Hindley G Beck K Borgan F et al.Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysis.Lancet Psychiatry. 2020; (published online March 17.)https://doi.org/10.1016/S2215-0366(20)30074-2Summary Full Text Full Text PDF PubMed Scopus (83) Google Scholar in The Lancet Psychiatry. The authors demonstrate that Δ9-tetrahydrocannabinol (THC) leads to an increase in total symptoms, which was assessed in nine studies, with ten independent samples, involving 196 participants: standardised mean change in scores (assessed with the Brief Psychiatric Rating Scale and the Positive or Negative Syndrome Scale) 1·10 (95% CI 0·92–1·28, p<0·0001). The effect sizes were also large for other symptoms (including general psychiatric symptoms), and were induced even with low doses of THC, somewhat similar to the doses often seen in medicinal cannabis, which we find extremely important and worrying. Moreover, the authors failed to find any clear evidence that concurrent administration of cannabidiol (CBD) reduced these symptoms. Indeed, such an ameliorating effect was observed in only one of four included studies. This finding is notable because CBD in particular is being touted as a potential wonder drug with antipsychotic, anxiolytic, and other properties.10Hurd YL Leading the next CBD wave—safety and efficacy.JAMA Psychiatry. 2020; (published online Jan 15.)DOI:10.1001/jamapsychiatry.2019.4157Crossref PubMed Scopus (18) Google Scholar Although it is quite possible that CBD will have some therapeutic applications (once proper randomised trials have been done), this supports suggestions that many of the initial reports and public discourses regarding the usefulness of both pure CBD and whole-plant-based extracts of cannabis might be somewhat exaggerated compared with what we can expect in clinical practice. Finally, although THC, alone or in combination with, for example, CBD might have a role in treating certain symptoms, caution should not be thrown to the wind. As Hindley and colleagues have clearly demonstrated, there are at least transient psychiatric symptoms associated with even relatively low doses of THC. Of course, this result should not be extrapolated as meaning that single doses of THC will eventually lead to schizophrenia or other severe disorders. However, it might be prudent to extrapolate and paraphrase the words of Moore and colleagues from their 2007 meta-analysis to apply to both recreational and medicinal use of THC-containing cannabis: “there is sufficient evidence to warn people that using THC could increase their risk of developing psychiatric symptoms or even a psychotic illness”.1Moore THM Zammit S Lingford-Hughes A et al.Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.Lancet. 2007; 370: 319-328Summary Full Text Full Text PDF PubMed Scopus (1632) Google Scholar We declare no competing interests. Psychiatric symptoms caused by cannabis constituents: a systematic review and meta-analysisA single THC administration induces psychotic, negative, and other psychiatric symptoms with large effect sizes. There is no consistent evidence that CBD induces symptoms or moderates the effects of THC. These findings highlight the potential risks associated with the use of cannabis and other cannabinoids that contain THC for recreational or therapeutic purposes. Full-Text PDF