Cannabis sativa has Δ⁹-tetrahydrocannabinol (Δ⁹-THC), isolated in the 1960s [¹], as its main psychoactive compound. The concentration of Δ⁹-THC in the different presentations of cannabis (marijuana, hashish, skunk) is proportional to the intensity of its toxic effects. In cannabis, considered to be the most consumed illicit substance in the world [²], increased concentrations of Δ⁹-THC have been reported in recent years [^3-5].

At the same time, there has been an increase in the number of patients reporting to specialized services with complaints related to the use of cannabis. A survey in the USA revealed that between 1992 and 1998 the demand for treatment at specialized services has doubled, with the percentage of admissions for the treatment of cannabis-related disorders (23%) approaching the admission rates relative to cocaine (27%) and heroine (23%), considering all drug-related hospitalizations [⁶].

The use of cannabis has been associated with several psychological, behavioral, and social problems [²]. Besides the chronic effects of the continued use of cannabis, such as dependence, abstinence, varying degrees of cognitive impairment, and increased risk of respiratory disorders, its acute effects have also been related to significant physical and mental health problems [⁷,⁸], and an increasing number of emergency admissions has been linked to cannabis use [⁹,¹⁰].

The intoxication by cannabis is associated with subjective symptoms of euphoria, perceptual distortion, continuous giggling, sedation, lethargy, impaired perception of time, difficulties in the performance of complex mental processes, impaired judgment and social withdrawal [¹¹]. In addition, physical signs of conjunctival hyperemia, increased appetite, dry mouth, and tachycardia can develop in the period of approximately two hours after the use of the substance [¹¹], corresponding to the plasmatic peak of Δ⁹-THC.

In general, the acute toxicity of cannabinoids is considered to be low. Nevertheless, there are reports of death by brain infarction - especially among teenagers - following the acute use of marijuana [¹²,¹³] as well as of cases of patients with severe sequelae resulting from this complication [¹⁴]. Similarly, there are reports of coma in children induced by the accidental intake of cannabis [¹⁵], in addition to cases of cardiac arrhythmia [^16-20], acute myocardial infarction [²¹], and transitory ischemic attacks [¹⁴]. Factors such as increased heart effort, elevated levels of catecholamine and carboxyhemoglobin in the blood, as well as the occurrence of postural hypotension are among the most commonly reported factors of cardiovascular disease associated with intoxication by cannabis [²²].

It is known that cannabis intoxication leads to impaired motor ability, attention, and short-term memory [⁸,²³]. In accordance with this, many studies have found a higher prevalence of cannabis use among drivers involved in accidents than in the general population [⁸].

Currently, there is consistent evidence that people who use cannabis on a regular basis have a higher proportion of acute psychiatric disorders, aggravated by other factors such as personality traits, pre-existing vulnerability, and substance use at an early age [²⁴]. First-time use and the dose of cannabis are among the main factors related to this occurrence [²³].

Panic and anxiety attacks are among the most commonly reported psychiatric symptoms related to cannabis intoxication and are often responsible for the discontinuation of the use of the substance [²³]. Acute psychotic episodes related to cannabis intoxication are described in terms of confusion, disorientation, amnesia, depersonalization, delusions, hallucinations, paranoid ideation, psychomotor agitation, labile affect, and hostility [²⁵]. These symptoms are usually gone after a maximum of one week abstinence [²⁶]. In some cases, psychotic episodes secondary to the use of cannabis can persist for a substantial period of time after the acute intoxication and may have some of the features of acute schizophreniform disorders [²⁴,²⁷,²⁸]. Further evidence is provided by a systematic review on longitudinal and population-based studies, which showed that cannabis use significantly increases the risk of developing psychotic illnesses in a dose-dependent manner [²⁹].

There is strong evidence that cannabis use can have major detrimental effects on the course of the illness when patients with a pre-existing psychotic condition continue to use the drug [³⁰]. In addition to worsening the outcome and exacerbating the symptoms, cannabis use by people with psychosis can lead to sudden behavioral disturbances such as increased proneness to violence, criminal activity, suspiciousness, and hallucinations [³¹].

Lately, attempts have been made to better understand the neurobiological mechanisms underlying cannabis-related disorders and the functioning of the endogenous cannabinoid system. There is increasing interest for the development of medications capable to reduce the morbidity of these disorders. Because marijuana intoxication is a major public health problem with a growing demand for assistance at emergency departments, the study of possible pharmacological interventions that might help in the management of the acute effects of cannabis use is of great clinical and social relevance.

This study is a bibliographic review on pharmacological interventions for the treatment of the acute effects of cannabis. The search for articles was performed on the PubMed, LILACS, and SciELO online databases using the search terms cannabis, intoxication, psychosis, anxiety, and treatment, and yielded a total of 174 matches. Additionally, an active search was conducted for related articles in the reference lists of the selected publications, which included case reports, controlled clinical trials, clinical trials of psychiatric and non-psychiatric medications, trials that promoted symptom reduction (physical, psychological or cognitive), and investigations related to the period of cannabis intoxication. Inclusion criteria were articles published in English, Spanish or Portuguese, no time limit up to October of 2011. Only those studies involving human samples were included. Taken together, the database and the hand search provided ten articles considered relevant for this review.

The results were subdivided according to interventions targetting the physiological and psychological acute effects of cannabis.

The analysis of research reports of pharmacological interventions against cannabis-related problems showed that only a few studies have been carried out on this subject. Ten studies that fulfilled the inclusion criteria consisted of case reports and controlled clinical trials.

No publications were found related to the treatment of panic attacks and manic and depressive syndromes specifically associated with cannabis intoxication. We predict that in emergency settings medications with acute therapeutic effects for these conditions are used. Thus benzodiazepines, such as lorazepam and alprazolam, recommended for the acute management of panic disorder [⁵⁴] can be used, but this requires research evidence for further confirmation. Similarly, manic and depressive syndromes, during the intoxication, can be managed by means of medications (benzodiazepines and antipsychotics) that attenuate important acute complaints like insomnia, anxiety, psychomotor agitation, and suicidal ideation. The use of antidepressants and mood stabilizers would be indicated only in the persistence of these symptoms, with duration beyond the intoxication period.

Cannabis intoxication is associated with significant physical and mental health impairment with resulting social costs; nonetheless, relatively few studies to date were aimed at investigating the possible pharmacological interventions in this condition [⁵⁵]. However scarce, the available evidence suggests that propranolol and rimonabant are valuable tools in the therapeutic arsenal for the management of the physiological (especially cardiovascular) and subjective intoxication effects of cannabis. Flumazenil and cannabidiol were also found to counteract comatose and anxious and psychotic states, respectively, although evidence in this regard still lacks strength.

Our systematic searches revealed that articles on intoxication by cannabis are scarce and report results based on small samples. Future studies evaluating pharmacological interventions directed at the attenuation of the several acute effects induced by cannabis and at promoting greater knowledge regarding its actions are urgently necessary and opportune in the face of the increasing challenge posed by such an important public health problem.

The authors declare that they have no competing interests.

JASC coordinated the study and drafted the manuscript. GND and JECH participated in the conception, design of the study and helped to draft manuscript. MHNC, ZA, AWZ and RMS contributed content knowledge and made contribuitions to the written manuscript. All authors read and approved the final manuscript.

GND is the recipient of a research grant from the National Council for Scientific and Technological Development (CNPq, Brazil). JASC (1C), JECH (2) and AWZ (1C) are recipients of CNPq Productivity Awards. The study was supported in part by the Research, Teaching, and Assistance Foundation of the Ribeirão Preto Medical School University Hospital (FAEPA, Brazil) and SGR2009/1435 (Departament d'Universitats Innovació i Empresa, Generalitat de Catalunya, Spain).