Mohini Ranganathan

The acute effects of cannabinoids on memory in humans: a review.

RationaleCannabis is one of the most frequently used substances. Cannabis and its constituent cannabinoids are known to impair several aspects of cognitive function, with the most robust effects on short-term episodic and working memory in humans. A large body of the work in this area occurred in the 1970s before the discovery of cannabinoid receptors. Recent advances in the knowledge of cannabinoid receptors’ function have rekindled interest in examining effects of exogenous cannabinoids on memory and in understanding the mechanism of these effects.ObjectiveThe literature about the acute effects of cannabinoids on memory tasks in humans is reviewed. The limitations of the human literature including issues of dose, route of administration, small sample sizes, sample selection, effects of other drug use, tolerance and dependence to cannabinoids, and the timing and sensitivity of psychological tests are discussed. Finally, the human literature is discussed against the backdrop of preclinical findings.ResultsAcute administration of Δ-9-THC transiently impairs immediate and delayed free recall of information presented after, but not before, drug administration in a dose- and delay-dependent manner. In particular, cannabinoids increase intrusion errors. These effects are more robust with the inhaled and intravenous route and correspond to peak drug levels.ConclusionsThis profile of effects suggests that cannabinoids impair all stages of memory including encoding, consolidation, and retrieval. Several mechanisms, including effects on long-term potentiation and long-term depression and the inhibition of neurotransmitter (GABA, glutamate, acetyl choline, dopamine) release, have been implicated in the amnestic effects of cannabinoids. Future research in humans is necessary to characterize the neuroanatomical and neurochemical basis of the memory impairing effects of cannabinoids, to dissect out their effects on the various stages of memory and to bridge the expanding gap between the humans and preclinical literature.

Cannabis and psychosis/schizophrenia: human studies

The association between cannabis use and psychosis has long been recognized. Recent advances in knowledge about cannabinoid receptor function have renewed interest in this association. Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative, and cognitive symptoms in some healthy individuals. Also clear is that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. The mechanisms by which cannabinoids produce transient psychotic symptoms, while unclear may involve dopamine, GABA, and glutamate neurotransmission. However, only a very small proportion of the general population exposed to cannabinoids develop a psychotic illness. It is likely that cannabis exposure is a “component cause” that interacts with other factors to “cause” schizophrenia or a psychotic disorder, but is neither necessary nor sufficient to do so alone. Nevertheless, in the absence of known causes of schizophrenia, the role of component causes remains important and warrants further study. Dose, duration of exposure, and the age of first exposure to cannabinoids may be important factors, and genetic factors that interact with cannabinoid exposure to moderate or amplify the risk of a psychotic disorder are beginning to be elucidated. The mechanisms by which exposure to cannabinoids increase the risk for developing a psychotic disorder are unknown. However, novel hypotheses including the role of cannabinoids on neurodevelopmental processes relevant to psychotic disorders are being studied.

Blunted Psychotomimetic and Amnestic Effects of |[Delta]|-9-Tetrahydrocannabinol in Frequent Users of Cannabis

Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Δ-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Δ-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of ‘high’; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Δ-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.

Cannabinoids and Psychosis

Recent advances in knowledge about cannabinoid receptor function have renewed interest in the association between cannabis and psychosis. Case series, autobiographical accounts, and surveys of cannabis users in the general population suggest an association between cannabis and psychosis. Cross-sectional studies document an association between cannabis use and psychotic symptoms, and longitudinal studies suggest that early exposure to cannabis confers a close to two-fold increase in the risk of developing schizophrenia. Pharmacological studies show that cannabinoids can induce a full range of transient positive, negative, and cognitive symptoms in healthy individuals that are similar to those seen in schizophrenia. There is considerable evidence that in individuals with an established psychotic disorder such as schizophrenia, exposure to cannabis can exacerbate symptoms, trigger relapse, and worsen the course of the illness. Only a very small proportion of the general population exposed to cannabis develop a psychotic illness. It is likely that cannabis exposure is a ‘component cause’ that interacts with other factors to ‘cause’ schizophrenia or other psychotic disorder, but is neither necessary nor sufficient to do so alone. Further work is necessary to identify the factors that underlie individual vulnerability to cannabinoid-related psychosis and to elucidate the biological mechanisms underlying this risk.

Dose-Related Behavioral, Subjective, Endocrine, and Psychophysiological Effects of the κ Opioid Agonist Salvinorin A in Humans

BACKGROUND Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA)-a highly selective agonist at the κ opiate receptor-is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans. METHODS In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological, and endocrine effects of 0 mg, 8 mg, and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia. RESULTS SA produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin, and reduced resting electroencephalogram spectral power. The SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits, or changes in vital signs. The effects were transient and not dose-related. SA administration was very well-tolerated without acute or delayed adverse effects. CONCLUSIONS SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with κ opiate receptor agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved, and to explore the basis for individual variability in its effects.

Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans

Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans. However, the neural correlates of these deficits have remained elusive. The current study examined the acute, dose-related effects of delta-9-tetrahydrocannabinol (Δ9-THC) on psychophysiological indices of information processing in humans. Healthy subjects (n=26) completed three test days during which they received intravenous Δ9-THC (placebo, 0.015 and 0.03 mg/kg) in a within-subject, double-blind, randomized, cross-over, and counterbalanced design. Psychophysiological data (electroencephalography) were collected before and after drug administration while subjects engaged in an event-related potential (ERP) task known to be a valid index of attention and cognition (a three-stimulus auditory ‘oddball’ P300 task). Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a. Δ9-THC did not have any effect on the latency of either the P300a or P300b, or on early sensory-evoked ERP components preceding the P300 (the N100). Concomitantly, Δ9-THC induced psychotomimetic effects, perceptual alterations, and subjective ‘high’ in a dose-dependent manner. Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations. Lastly, exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC, there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users. Overall, these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis, Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs. Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention, while leaving processing speed and earlier sensory ERP components intact. Collectively, the findings suggest that CB1R systems modulate top-down and bottom-up processing.

Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence.

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, D-serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors.

Lower β2*-Nicotinic Acetylcholine Receptor Availability in Smokers With Schizophrenia

OBJECTIVE There is a strong association between cigarette smoking and schizophrenia. Nicotines actions in the brain are mediated through nicotinic acetylcholine receptors. Those containing α(4) and β(2) subunits are the most abundant ones in the brain, have the highest affinity for nicotine, and are critical in mediating nicotines reinforcing properties. Healthy tobacco smokers have significantly higher levels of β(2)*-nicotinic acetylcholine receptors than do nonsmokers. However, in postmortem studies, smokers with schizophrenia do not show these higher levels. The purpose of this study was to measure β(2)*-nicotinic acetylcholine receptors in vivo and to relate levels to concurrent behavioral measures of smoking and schizophrenia. METHOD By using single-photon emission computed tomography with the β(2)*-nicotinic acetylcholine receptor agonist radiotracer [(123)I]5-IA-85380, the availability of receptors was measured in smokers with schizophrenia (11 men) and matched comparison smokers after 1 week of confirmed smoking abstinence. RESULTS Smokers with schizophrenia showed significantly lower (21%-26%) β(2)*-nicotinic acetylcholine receptor availability relative to comparison smokers in the frontal cortex, parietal cortex, and thalamus (in descending order). There was a specific and robust negative correlation between regional β(2)*-nicotinic acetylcholine receptor availability and negative symptoms. CONCLUSIONS These are the first in vivo findings of lower β(2)*-nicotinic acetylcholine receptor availability in smokers with schizophrenia. The relationship between β(2)*-nicotinic acetylcholine receptor availability and negative symptoms may explain the high rates of smoking in schizophrenia and the relationship between smoking and negative symptoms. Findings support the development of medications targeting the β(2)*-nicotinic acetylcholine receptor system for the treatment of negative symptoms.

Medical Marijuana: Is the Cart Before the Horse?

There is apressingneed todevelopnewmedications formany debilitating conditions. Novel approaches based onmarijuana or its constituent cannabinoids, if proven, could be added to the armamentarium of available treatments. In this issue of JAMA, reviews byWhiting et al1 and Hill2 provide detailedassessmentof thepharmacology, indications, benefits,adverseeffects,andlaws related tomedicalmarijuanaand thecannabinoids, and the results andconclusionsare consistent.There is someevidence to support the use of marijuana for nausea and vomiting related tochemotherapy, specificpain syndromes, andspasticity from multiple sclerosis. However, for most other indications that qualifyby state lawforuseofmedicalmarijuana, suchashepatitis C, Crohn disease, Parkinson disease, or Tourette syndrome, the evidence supporting its use is of poor quality. State laws vary widely regarding conditions for which marijuana is approvedandthedispensable legal limit.Bothreviewsraise important issues worthy of further discussion. First, for most qualifying conditions, approval has relied on low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion. Imagine if other drugs were approved through a similar approach. The US Food and Drug Administration (FDA) requires evidence from at least 2 adequately powered randomized clinical trials before approving a drug for any specific indication. For most of the conditions that qualify for medical marijuanause, theevidence fails tomeetFDAstandards. It has beenargued that the lackof high-quality evidence reflects the difficulty inconductingmarijuanaresearch intheUnitedStates. If so, the federal and state governments should support and encourage such research so that high-quality evidence canbe generated to guidedecisions aboutmedicalmarijuanause for the conditions forwhich the existing evidence is either insufficient or of poor quality. Second, there are inconsistencies in how medical conditionsarequalified formedicalmarijuanausewithina stateand between states. For example, in Connecticut, psoriasis and sickle cell disease but not Tourette syndrome qualify, even though the supporting evidence for all 3 conditions is uniformly of very lowquality. Similarly, posttraumatic stress disorder (PTSD) is approvedas aqualifying condition in somebut not all US states. These differences reflect inconsistencies in evaluatingandapplyingcurrentevidencetowarddecisionmaking about qualifying indications for medical marijuana use. Third,unlikemostFDA-approveddrugs that typicallyhave 1or2activeconstituents,marijuanaisacomplexofmorethan400 compounds including flavonoids and terpenoids and approximately 70 cannabinoids other than Δ9-tetrahydrocannabinol (THC)3.Thesecannabinoidshaveindividual, interactive,andeven entourageeffects(effectsofacompoundthatareonlyappreciable inthepresenceofothercompounds)thatarenotfullyunderstood andthatcontributetotheneteffectofmarijuana.Althoughclinical trials forsomeof thequalifyingconditionsandstudies inanimalmodelsof thoseconditionshavebeenconductedwith individual cannabinoids (eg, THCor cannabidiol [CBD]), given that marijuanahas somanyconstituents, the results of studieswith individualcannabinoids(eg,THCorCBD)cannotbeextrapolated tomarijuana and vice versa. In addition, unlike FDA-approved medicationsthathavearelativelyuniformcomposition,thecompositionofcannabispreparationscanvarysubstantiallyinitscontent of THC andCBD, such that precise dosingmaybe difficult. Giventhevariablecomposition,patientswillhavetoexperiment with different strains and doses to achieve the desired effects, withoutmuch input or oversight by physicians. Fourth, some individual cannabinoids are already commercially available in the form of dronabinol and nabilone. Thesedrugs are administeredorally, and somepublisheddata are available to guide dosing. In contrast, there are few data on dosing smoked medical marijuana for many of the qualifying medical conditions for which it is used. Fifth,while theacuteadverseeffectsofmarijuanaarequite well known, the effects of repeated exposure, aswould occur withmedicalmarijuana, need further study. Approximately 1 in 10 adult users of marijuana develops addiction, and this number is evenhigher amongadolescents.4Tolerance anddependence with accompanying down-regulation and desensitization of type 1 cannabinoid receptors occur with repeated exposure.5 Based on this profile, marijuana dosing will have to be increased over time to achieve the same effect. A distinct withdrawal syndrome is also well recognized. There is also a small but definite risk of psychotic disorder associated with marijuana use, as well as a significant risk of symptom exacerbations and relapse in patients with an establishedpsychoticdisorder.6Thus,explicitcontraindicationssuch as schizophrenia, bipolar disorder, or substance dependence need tobe identifiedalongwithmeasures tominimize the likelihoodthatpersonswithcontraindicationswouldbeable toobtain medical marijuana. Perhaps US states should establish clinical follow-upprogramstomonitor long-termoutcomesprospectively, especiallynegativeoutcomes (eg,newcasesofpsychosis) in patients with contraindications. Author Audio Interview at jama.com

Effects of Nicotine on the Neurophysiological and Behavioral Effects of Ketamine in Humans

Background: N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR) stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a non-competitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers. Methods: From an initial sample of 17 subjects (age range 18–55 years), 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects Positive and Negative Syndrome Scale, perceptual alterations Clinician Administered Dissociative Symptoms Scale, subjective effects Visual Analog Scale and auditory event-related brain potentials (mismatch negativity, MMN; P300) were assessed during each test session. Results: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target (P3b) or novel (P3a) stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. Conclusion: Nicotine failed to modulate ketamine-induced neurophysiological and behavioral effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.