Ben Gouaux

Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial

Despite management with opioids and other pain modifying therapies, neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals. Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception. We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV. This was a phase II, double-blind, placebo-controlled, crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy (DSPN). Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes; they continued on their prestudy analgesic regimens throughout the trial. Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting. Treatments were placebo and active cannabis ranging in potency between 1 and 8% Δ-9-tetrahydrocannabinol, four times daily for 5 consecutive days during each of 2 treatment weeks, separated by a 2-week washout. The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale (DDS) from a pretreatment baseline to the end of each treatment week. Secondary measures included assessments of mood and daily functioning. Of 127 volunteers screened, 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments. Among the completers, pain relief was greater with cannabis than placebo (median difference in DDS pain intensity change, 3.3 points, effect size=0.60; p=0.016). The proportions of subjects achieving at least 30% pain relief with cannabis versus placebo were 0.46 (95%CI 0.28, 0.65) and 0.18 (0.03, 0.32). Mood and daily functioning improved to a similar extent during both treatment periods. Although most side effects were mild and self-limited, two subjects experienced treatment-limiting toxicities. Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN.

Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers.

Background:Although the preclinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects, efficacy in the human pain state remains unclear. Using a human experimental pain model, the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin. Methods:In a randomized, double-blinded, placebo-controlled, crossover trial in 15 healthy volunteers, the authors evaluated concentration–response effects of low-, medium-, and high-dose smoked cannabis (respectively 2%, 4%, and 8% 9-&dgr;-tetrahydrocannabinol by weight) on pain and cutaneous hyperalgesia induced by intradermal capsaicin. Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure, and pain, hyperalgesia, tetrahydrocannabinol plasma levels, and side effects were assessed. Results:Five minutes after cannabis exposure, there was no effect on capsaicin-induced pain at any dose. By 45 min after cannabis exposure, however, there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose. There was no effect seen with the low dose, nor was there an effect on the area of hyperalgesia at any dose. Significant negative correlations between pain perception and plasma &dgr;-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects. There was no significant difference in performance on the neuropsychological tests. Conclusions:This study suggests that there is a window of modest analgesia for smoked cannabis, with lower doses decreasing pain and higher doses increasing pain.

Medical marijuana: clearing away the smoke.

Recent advances in understanding of the mode of action of tetrahydrocannabinol and related cannabinoid in-gredients of marijuana, plus the accumulating anecdotal reports on potential medical benefits have spurred increasing re-search into possible medicinal uses of cannabis. Recent clinical trials with smoked and vaporized marijuana, as well as other botanical extracts indicate the likelihood that the cannabinoids can be useful in the management of neuropathic pain, spasticity due to multiple sclerosis, and possibly other indications. As with all medications, benefits and risks need to be weighed in recommending cannabis to patients. We present an algorithm that may be useful to physicians in determining whether cannabis might be recommended as a treatment in jurisdictions where such use is permitted.

Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

Objective:The apolipoprotein E (APOE) &egr;4 allele enhances cerebral accumulation of &bgr;-amyloid (A&bgr;) and is a major risk factor for sporadic Alzheimers disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE &egr;4 genotype and cerebral A&bgr; deposition. Design:Clinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium. Methods:We used multivariable logistic regressions to model outcomes [A&bgr; plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE &egr;4 (allelic discrimination assay), older age (≥50 years), A&bgr; plaques, and their two-way interactions] and comorbid factors. Results:Isocortical A&bgr; deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE &egr;4 and older age were independently associated with the presence of A&bgr; plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 − 35.76 and 1.91−17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of A&bgr; plaques among APOE &egr;4 carriers (adjusted OR 30.00, 95% CI 1.41−638.63, P = 0.029, n = 15), but not in non-&egr;4 carriers (n = 57). Conclusion:The APOE &egr;4 and older age increased the likelihood of cerebral A&bgr; plaque deposition in HIV-infected adults. Generally, A&bgr; plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimers disease brains. Nonetheless, A&bgr; plaques were associated with HAND among APOE &egr;4 carriers. The detection of APOE &egr;4 genotype and cerebral A&bgr; deposition biomarkers may be useful in identifying living HAND patients who could benefit from A&bgr;-targeted therapies.

The veterans aging cohort study index is associated with concurrent risk for neurocognitive impairment.

Objective:The Veterans Aging Cohort Study (VACS) Index is predictive of mortality and combines age, traditional HIV biomarkers (HIV-1 plasma RNA and current CD4 count), and non-HIV biomarkers (indicators of renal and liver function, anemia, and hepatitis C coinfection). We examined the association between the VACS Index and HIV-associated neurocognitive impairment (NCI). Design and Methods:Participants included 601 HIV-infected adults enrolled in cohort studies at the University of California, San Diego, HIV Neurobehavioral Research Program (ages: 18–76 years; 88% male; 63% white; median current CD4 = 364 cells/mm3; 63% on antiretroviral therapy; AIDS = 64%). Biomarkers used in calculating the VACS Index were measured in prospectively collected blood samples using conventional laboratory methods. NCI was defined using global and seven domain deficit scores. Results:Higher VACS Index scores were associated with concurrent risk for global NCI [P < 0.001; odds ratio = 1.21, confidence interval (CI): 1.12 to 1.32], even when adjusting for psychiatric comorbidities. This relation was statistically significant for most cognitive domains in adjusted models. Furthermore, the VACS Index predicted concurrent NCI beyond nadir CD4 and estimated duration of infection. Older age, lower hemoglobin, and lower CD4 counts were the VACS components most strongly linked to NCI. Conclusions:The findings extend previous research on the potential usefulness of the VACS Index in predicting HIV-associated outcomes to include NCI. Although the effect size was relatively small, our findings suggest that demographic information, HIV-disease factors, and common comorbidities might each play important roles in the clinical manifestation of cognitive impairment among HIV-infected individuals. Additional research is needed to determine if a more sensitive and specific index can be developed.

Lifetime suicidal ideation and attempt are common among HIV+ individuals

BACKGROUND Estimates of the prevalence of lifetime suicidal ideation and attempt, and risks for new-onset suicidality, among HIV-infected (HIV+) individuals are not widely available in the era of modern combined antiretroviral treatment (cART). METHOD Participants (n=1560) were evaluated with a comprehensive battery of tests that included the depression and substance use modules of the Composite International Diagnostic Interview (CIDI) and the Beck Depression Inventory-II (BDI-II) as part of a large prospective cohort study at six U.S. academic medical centers. Participants with possible lifetime depression (n=981) were classified into five categories: 1) no thoughts of death or suicide (n=352); 2) thoughts of death (n=224); 3) thoughts of suicide (n=99); 4) made a suicide plan (n=102); and 5) attempted suicide (n=204). RESULTS Twenty-six percent (405/1560) of participants reported lifetime suicidal ideation and 13% (204/1560) reported lifetime suicide attempt. Participants who reported suicidal thoughts or plans, or attempted suicide, reported higher scores on the BDI-II (p<0.0001), and higher rates of current major depressive disorder (p=0.01), than those who did not. Attempters reported higher rates of lifetime substance abuse (p=0.02) and current use of psychotropic medications (p=0.01) than non-attempters. LIMITATIONS Study assessments focused on lifetime, rather than current, suicide. Data was not collected on the timing of ideation or attempt, frequency, or nature of suicide attempt. CONCLUSIONS High rates of lifetime suicidal ideation and attempt, and the relationship of past report with current depressed mood, suggest that mood disruption is still prevalent in HIV. Findings emphasize the importance of properly diagnosing and treating psychiatric comorbidities among HIV persons in the cART era.

HIV protease inhibitor exposure predicts cerebral small vessel disease

Objective:HIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND. Design:Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network. Methods:We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection. Results:We found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03–7.9) and 2.6 (95% CI 1.03–6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6–70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1–21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age. Conclusion:Protease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.

A pilot study of the effects of cannabis on appetite hormones in HIV-infected adult men

RATIONALE The endocannabinoid system is under active investigation as a pharmacological target for obesity management due to its role in appetite regulation and metabolism. Exogenous cannabinoids such as tetrahydrocannabinol (THC) stimulate appetite and food intake. However, there are no controlled observations directly linking THC to changes of most of the appetite hormones. OBJECTIVES We took the opportunity afforded by a placebo-controlled trial of smoked medicinal cannabis for HIV-associated neuropathic pain to evaluate the effects of THC on the appetite hormones ghrelin, leptin and PYY, as well as on insulin. METHODS In this double-blind cross-over study, each subject was exposed to both active cannabis (THC) and placebo. RESULTS Compared to placebo, cannabis administration was associated with significant increases in plasma levels of ghrelin and leptin, and decreases in PYY, but did not significantly influence insulin levels. CONCLUSION These findings are consistent with modulation of appetite hormones mediated through endogenous cannabinoid receptors, independent of glucose metabolism.

Antiretroviral therapy reduces neurodegeneration in HIV infection.

Objective:To determine the effect of virally suppressive antiretroviral therapy (ART) on cortical neurodegeneration and associated neurocognitive impairment. Design:Retrospective, postmortem observational study. Methods:Clinical neuropsychological and postmortem neuropathology data were analyzed in 90 HIV-infected volunteers from the general community who had never undergone ART (n = 7, ‘naive’) or who had undergone ART and whose plasma viral load was detectable (n = 64 ‘unsuppressed’) or undetectable (n = 19, ‘suppressed’) at the last clinical visit before death. Individuals were predominately men (74/90, 82%) with a mean age of 44.7 years (SD 9.8). Cortical neurodegeneration was quantified by measuring microtubule-associated protein (MAP2) and synaptophysin (SYP) density in midfrontal cortex tissue sections. Results:The suppressed group had higher SYP density than the naive group (P = 0.007) and higher MAP2 density than the unsuppressed group (P = 0.04). The suppressed group had lower odds of HIV-associated neurocognitive disorders than naive [odds ratio (OR) 0.07, P = 0.03]. Higher SYP was associated with lower likelihood of HIV-associated neurocognitive disorders in univariable (OR 0.8, P = 0.03) and multivariable models after controlling for ART and brain HIV p24 protein levels (OR 0.72, P = 0.01). Conclusion:We conclude that virally suppressive ART protects against cortical neurodegeneration. Further, we find evidence supporting the causal chain from treatment-mediated peripheral and central nervous system viral load suppression to reduced neurodegeneration and improved neurocognitive outcomes.

Preliminary Evidence for Feasibility, Use, and Acceptability of Individualized Texting for Adherence Building for Antiretroviral Adherence and Substance Use Assessment among HIV-Infected Methamphetamine Users.

The feasibility, use, and acceptability of text messages to track methamphetamine use and promote antiretroviral treatment (ART) adherence among HIV-infected methamphetamine users was examined. From an ongoing randomized controlled trial, 30-day text response rates of participants assigned to the intervention (individualized texting for adherence building (iTAB), n = 20) were compared to those in the active comparison condition (n = 9). Both groups received daily texts assessing methamphetamine use, and the iTAB group additionally received personalized daily ART adherence reminder texts. Response rate for methamphetamine use texts was 72.9% with methamphetamine use endorsed 14.7% of the time. Text-derived methamphetamine use data was correlated with data from a structured substance use interview covering the same time period (P < 0.05). The iTAB group responded to 69.0% of adherence reminder texts; among those responses, 81.8% endorsed taking ART medication. Standardized feedback questionnaire responses indicated little difficulty with the texts, satisfaction with the study, and beliefs that future text-based interventions would be helpful. Moreover, most participants believed the intervention reduced methamphetamine use and improved adherence. Qualitative feedback regarding the intervention was positive. Future studies will refine and improve iTAB for optimal acceptability and efficacy. This trial is registered with ClinicalTrials.gov NCT01317277.