David W. Holt

The acute effects of synthetic intravenous Δ9-tetrahydrocannabinol on psychosis, mood and cognitive functioning

BACKGROUNDnRecent work suggests that heavy use of cannabis is associated with an increased risk of schizophrenia-like psychosis. However, there is a dearth of experimental studies of the effects of the constituents of cannabis, such as Delta9-tetrahydrocannabinol (THC). In a study of intravenous (i.v.) synthetic THC in healthy humans, we aimed to study the relationship of the psychotic symptoms induced by THC to the consequent anxiety and neuropsychological impairment.nnnMETHODnTwenty-two healthy adult males aged 28+/-6 years (mean+/-s.d.) participated in experimental sessions in which i.v. THC (2.5 mg) was administered under double-blind, placebo-controlled conditions. Self-rated and investigator-rated measurements of mood and psychosis [the University of Wales Institute of Science and Technology Mood Adjective Checklist (UMACL), the Positive and Negative Syndrome Scale (PANSS) and the Community Assessment of Psychic Experiences (CAPE)] were made at baseline and at 30, 80 and 120 min post-injection. Participants also completed a series of neuropsychological tests [the Rey Auditory Verbal Learning Task (RAVLT), Digit Span, Verbal Fluency and the Baddeley Reasoning Task] within 45 min of injection.nnnRESULTSnTHC-induced positive psychotic symptoms, and participant- and investigator-rated measurements of these were highly correlated. Participants showed an increase in anxiety ratings but there was no relationship between either self- or investigator-rated positive psychotic symptoms and anxiety. THC also impaired neuropsychological performance but once again there was no relationship between THC-induced positive psychotic symptoms and deficits in working memory/executive function.nnnCONCLUSIONSnThese findings confirm that THC can induce a transient, acute psychotic reaction in psychiatrically well individuals. The extent of the psychotic reaction was not related to the degree of anxiety or cognitive impairment.

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment

Community-based studies suggest that cannabis products that are high in Δ9-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ2=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.

Case series of individuals with analytically confirmed acute mephedrone toxicity.

Context.u2003Previous reports of acute toxicity/harm associated with mephedrone use have been based on self-reported mephedrone use; toxicological screening has not been undertaken in these cases to determine whether mephedrone has been used. Objective.u2003To report the first case series of analytically confirmed mephedrone-related acute toxicity. Materials and methods.u2003Serum samples were collected from individuals presenting to an emergency department (ED) with acute toxicity related to self-reported mephedrone use. Toxicological analysis, by gas-chromatography coupled with mass-spectrometry and liquid chromatography with tandem mass-spectrometry was performed to qualitatively confirm mephedrone use. Symptoms/signs of acute mephedrone toxicity and basic physiological parameters were extracted from the routine ED records. Results.u2003Acute mephedrone-related toxicity was analytically confirmed in seven male patients; the meanu200a±u200aSD age was 24.6u200a±u200a6.5 years (range 16–36 years). Agitation (four patients) was the most common symptom/sign reported; other common symptoms/signs included: palpitations (two patients); chest pain (two patients); self-limiting pre-hospital seizures (one patient) and headaches (one patient). The mean heart rate was 109.1u200a±u200a21.8 (range 80–140) beats per minute; one patient had a “severe” tachycardia (heart rate of ≥140u2009bpm). The mean systolic blood pressure was 153.0u200a±u200a39.6 (range 110–210) mmHg; three patients had clinically significant hypertension (systolic blood pressure ≥160u2009mmHg). Discussion.u2003These analytically confirmed acute mephedrone toxicity presentations had clinical features of toxicity consistent with an acute sympathomimetic toxidrome (e.g. hypertension, tachycardia and agitation). These findings are similar to the pattern of toxicity seen with other sympathomimetic recreational drugs such as 3,4-Methylenedioxymethamphetamine (MDMA) and cocaine. Conclusion.u2003The process for determining whether a novel psychoactive substance should be controlled often relies on demonstrated/proven acute harm associated with its use. It is important that clinical toxicologists undertake appropriate biological sampling and toxicological analyses in suspected cases of “novel psychoactive drug” toxicity. This will ensure that both clinicians and legislative authorities are informed of the confirmed pattern of toxicity associated with these drugs.

Collapse, reported seizure—and an unexpected pill

In May, 2006, on a Bank Holiday weekend, an 18-year-old woman presented to an inner-city London emergency department. She had been at a nightclub with friends and purchased tablets, which she understood to be Ecstasy or amfetamines, from a dealer. After ingesting fi ve tablets, she collapsed in the nightclub and appeared to have a seizure lasting 10 min. On arrival in the emergency department, she was agitated and had dilated pupils (8 mm), sinus tachycardia (156 bpm), and a blood pressure of 150/51 mm Hg. Her score on the Glasgow coma scale was 15 and she was apyrexial (35·9°C). She had no signifi cant past medical history and was on no regular medication. She was one of seven patients to attend the department that night with a similar presentation. We therefore considered it possible that she had taken a contaminated drug, or a substance not previously sold in the area; and we took a serum sample for analysis, in addition to treating the patient symptomatically with intravenous benzodiazepines (4 mg lorazepam followed by 15 mg diazepam). After 12 h, she was asymptomatic and discharged with advice to avoid recreational drugs. The serum sample was analysed by gas chromatography with mass-spectrometric detection (GCMS); 1-benzylpiperazine was detected at a concentration of 2·5 mg/L. Toxicological screening of the same serum sample did not detect the presence of other piperazines, other drugs, or ethanol. A tablet purchased by the patient (fi gure) was also analysed, and found to contain 1-benzylpiperazine. 1-benzylpiperazine is one of the piperazine family of drugs, initially developed as veterinary anthelmintic agents in the 1950s. Its chemical structure is similar to that of amfetamine. Piperazines are marketed in the UK, where they are legally available in shops and over the internet, as having similar eff ects to controlled recreational drugs; pills containing piperazines are known as “pep pills”. No reliable data are available on the consumption of piperazines in the UK, although one manufacturer claims that “over 20 million pills have been consumed in New Zealand with no deaths, or signifi cant lasting injuries”. However, in initial clinical trials of 1-benzylpiperazine, adverse eff ects similar to those of amfetamines were noted. A prospective study in New Zealand identifi ed adverse eff ects including nausea, vomiting, tachycardia, hypertension, anxiety, and agitation among 80 patients presenting to emergency departments after 1-benzylpiperazine ingestion. Seizures were reported in 15 (19%), at up to 8 h after ingestion. Three patients had potentially life-threatening recurrent seizures; ingestion of 1-benzylpiperazine by these patients was confi rmed by toxicological screening of their urine. Other potentially serious adverse eff ects included QTc prolongation (QTc duration 430–490 ms in 32 patients) and hyponatraemia (serum sodium concentration 118 mmol/L and serum osmolality 242 mmol/kg) in one patient. Clinicians should be aware of the potential presenting features of piperazine toxicity, particularly because commercially available urine toxicological screening kits for drugs of abuse may not detect piperazines. All patients with strongly suspected or reported ingestion of 1-benzylpiperazine should have an initial baseline ECG, to seek features of cardiotoxicity. They should be observed for up to 8 h after ingestion, because the onset of seizures can be delayed. Initial treatment should be based on the clinical presentation. Further management can require the advice of a clinical toxicologist.

Asymmetric and symmetric dimethylarginines are of similar predictive value for cardiovascular risk in the general population

OBJECTIVESnAsymmetric dimethylarginine (ADMA) has raised considerable interest, as it is an endogenous inhibitor of nitric oxide synthesis. While increased plasma levels of ADMA have been reported in different cardiovascular disease states, its association with symmetric dimethylarginine (SDMA) has not been evaluated in a prospective population-based study.nnnMETHODS AND RESULTSnWe performed a mass spectrometry-based analysis of ADMA and SDMA in the plasma of 572 participants of the Bruneck study. Levels of ADMA and SDMA were significantly correlated with each other (r=0.189, p<0.001). Age and parameters of renal function, however, showed a stronger influence on SDMA than on ADMA. Both ADMA and SDMA were predictive of cardiovascular disease in multivariate analysis and the associated hazard ratios over the 5-year observation period were of similar strength: 3.86 (1.36-10.9) and 7.91 (1.94-32.3) for ADMA and SDMA, respectively (p=0.011 and 0.004). Separate analyses focused on quintile groups of SDMA revealed that the increase in cardiovascular risk was mainly confined to the top category (>0.80 micromol/L).nnnCONCLUSIONnThis study argues against an exclusive ADMA effect in mediating cardiovascular risk. Instead, SDMA, its supposedly inactive counterpart, has similar diagnostic value in this large prospective cohort.

International Federation of Clinical Chemistry/International Association of Therapeutic Drug Monitoring and Clinical Toxicology working group on immunosuppressive drug monitoring.

Issues surrounding the measurement and interpretation of immunosuppressive drug concentrations have been summarized in a number of consensus documents. The Scientific Division of the International Federation of Clinical Chemistry has formed a working group in collaboration with the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. This paper sets out the goals of the working group in light of the developments that have occurred in the field of immunosuppressive drug monitoring since the publication of the last consensus documents.

Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study.

Intravenous (IV) Δ9-tetrahydrocannabinol (THC) induces transient psychotic symptoms in healthy subjects and in schizophrenic patients, but the psychotomimetic mechanism is unknown. One possibility is that THC stimulates dopamine (DA) release in the striatum. In this study we tested whether IV THC led to an increase in striatal DA release compared to placebo. We also investigated whether DA release and positive psychotic symptoms were related. Eleven healthy male volunteers completed two 123I-iodobenzamide ([123I]IBZM) single photon emission tomography (SPET) sessions and received IV THC (2.5u2009mg) or placebo in a randomized counterbalanced order, under double-blind conditions. Analysable data were obtained from nine participants. The Positive and Negative Syndrome Scale (PANSS) was used to rate psychotomimetic effects. Striatal binding index values were calculated using the occipital cortex as a reference region. Both the PANSS positive and general symptoms increased significantly at 30u2009min following IV THC. There were no significant differences in binding index in the caudate or putamen under THC compared to placebo conditions. Positive psychotic symptoms and DA release were unrelated. THC did not lead to a significant increase in DA release even though the dose was sufficient for participants to have psychotic symptoms. These findings do not support a central role for striatal DA in THC-elicited psychosis.

Disruption of Frontal Theta Coherence by Δ9-Tetrahydrocannabinol is Associated with Positive Psychotic Symptoms

The main ingredient in cannabis, Δ9-tetrahydrocannabinol (THC), can elicit acute psychotic reactions in healthy individuals and precipitate relapse in schizophrenic patients. However, the neural mechanism of this is unknown. We tested the hypothesis that THC psychopathology is related to changes in electroencephalography (EEG) power or inter-regional coherence. In a within-subjects design, participants (n=16) were given intravenous THC (1.25u2009mg) or placebo under double-blind conditions, during EEG recordings. Using fast-Fourier transform, EEG data were analyzed for power and coherence in the delta (1–3.5u2009Hz), theta (3.5–7u2009Hz), alpha (8–13u2009Hz), beta (14–25u2009Hz), low-gamma (30–40u2009Hz), and high-gamma (60–70u2009Hz) bands during engagement in the n-back test of working memory (WM). Compared with placebo, THC evoked positive and negative psychotic symptoms, as measured by the positive and negative syndrome scale (p<0.001) and slowed WM performance (p<0.05). Under THC, theta power was specifically reduced, (p<0.001) regardless of WM load; however, the reduction showed no relationship with psychotic symptoms or WM impairment. Coherence between bi-frontal electrodes in the theta band was also reduced by THC (p<0.05) and these reductions correlated with the change-in positive psychotic symptoms (rho=0.79, p<0.001). Bi-frontal specificity was suggested by the absence of a relationship between psychotic symptoms and fronto-parietal coherence. The results reveal that the pro-psychotic effects of THC might be related to impaired network dynamics with impaired communication between the right and left frontal lobes.

Dissociative and Sympathomimetic Toxicity Associated with Recreational Use of 1-(3-Trifluoromethylphenyl) Piperazine (TFMPP) and 1-Benzylpiperzine (BZP)

IntroductionThere is emerging evidence of increasing use of legally available synthetic compounds as recreational drugs. While there are some changes to legislation relating to these synthetic compounds, often the emergence of the agents outpaces the effect of the legislation to curb their use, and the legal status of these agents may change as more information on their toxicity becomes known. TFMPP [1-(3-trifluoromethylphenyl) piperazine] was initially temporarily controlled under Schedule I of the Controlled Substances Act in 2002 in the US, but following further review and lack of published information on toxicity, it was removed from this control in 2004. In addition, there are very few “user reports” of effects when TFMPP is taken alone or in combination with BZP [1-benzylpiperazine].Case reportsThree patients presented to our emergency department after ingesting 4 tablets thought to be 3,4-methylenedioxy-N-methylamphetamine (MDMA, street name “Ecstasy”) over the course of an evening. They presented with dissociative-type symptoms, nausea, and signs consistent with sympathomimetic toxicity. All 3 improved with conservative management and observation, within 12 hours of presentation. Serum analysis demonstrated the presence of TFMPP and BZP at concentrations of 263 ± 5.8 ng/mL (range 260–270 ng/mL) and 46.7 ± 15.3 ng/mL (range 30–60 ng/mL), respectively. No other recreational drugs were detected in an extended toxicological screen of blood and urine samples.DiscussionThis is the first case series of confirmed toxicity associated with recreational use of TFMPP in combination with BZP, with clinical features not consistent with BZP toxicity. In our view, the current legal status of TFMPP should be reviewed.

Substandard drugs: a potential crisis for public health

Poor‐quality medicines present a serious public health problem, particularly in emerging economies and developing countries, and may have a significant impact on the national clinical and economic burden. Attention has largely focused on the increasing availability of deliberately falsified drugs, but substandard medicines are also reaching patients because of poor manufacturing and quality‐control practices in the production of genuine drugs (either branded or generic). Substandard medicines are widespread and represent a threat to health because they can inadvertently lead to healthcare failures, such as antibiotic resistance and the spread of disease within a community, as well as death or additional illness in individuals. This article reviews the different aspects of substandard drug formulation that can occur (for example, pharmacological variability between drug batches or between generic and originator drugs, incorrect drug quantity and presence of impurities). The possible means of addressing substandard manufacturing practices are also discussed. A concerted effort is required on the part of governments, drug manufacturers, charities and healthcare providers to ensure that only drugs of acceptable quality reach the patient.