Acute Effects of Cannabis on Cognition and Mobility in Older HIV-infected and HIV-Un-infected Women

The purpose of this study is to try to understand and explain why HIV-infected and uninfected women who use cannabis (marijuana) currently, or have used cannabis in the past, have higher risk of having experienced a fall in our earlier analyses in WIHS. This study will compare what happens when women are given cannabis compared with placebo, on measures of mobility, including walking speed under walking conditions that vary in terms of difficulty; for example normal walking and walking while reciting alternate letters of the alphabet, as well as measures of balance and cognition (for example attention, memory).

Cannabis is the most prevalent drug used by adults aged 50 and older in the U.S., after alcohol and tobacco. Recent trends show dramatic increases in cannabis use among older U.S. adults, and rising cannabis tetrahydrocannabinol (THC) content. Cannabis intoxication acutely alters short-term memory, attention span, verbal fluency, reaction time, and psychomotor control. Heavy long term cannabis use has been associated with lasting impairments in verbal learning, memory, and attention that correlate with duration of use; however, other studies have found that cognitive deficits from cannabis are reversible and related to recent exposure. But studies on cannabis exposure and cognition are age limited by including only adolescents through middle-aged adults; effects of acute and long-term cannabis use on cognition among older adults are virtually unknown. Given the rising potency and increasing frequency of cannabis use among older adults, studies systematically examining the risks and benefits of cannabis use in older adults are urgently needed. Cannabis use is particularly common in people living with HIV (PLWH), with 12- 56% prevalence rates compared to 9.5% in the general U.S. population. HIV has detrimental effects on both mobility and cognition, and similar to normal aging, mobility in patients with HIV may be influenced by cognitive function. Mild-to-moderate neurocognitive impairments (NCI), notably in attention and executive functions, remain highly prevalent and persist despite suppressive antiretroviral therapy, affecting almost half of PLWH. Little is known about the combined effects of cannabis use and HIV infection on cognition and mobility, particularly among older individuals. As the population of older PLWH continues to grow, co-occurring aging and HIV related declines in cognition and mobility will coincide; the effects of continued cannabis use In the Women's Interagency HIV Study (WIHS), it was found that current cannabis use was associated with over double the odds of single fall, and over 2.5 times the odds of multiple falls in 6 months; past cannabis use was associated with over 1.5 greater odds of single fall and multiple falls. Preliminary data shows that 40% of WIHS women (mean age 48) reported at least one fall over 2 years; current cannabis users had 1.7 times greater fall risk among HIV+ but not HIV-women. The hypothesis is that falls are related to acute effects of cannabis on attention and mobility, and that given subtle, pre-existing deficits associated with HIV infection, these acute cannabis effects may be more pronounced in HIV+ women, placing them at increased risks of falls. Whether this observed fall risk associated with cannabis use represents acute effects, or persistent effects of past cannabis use on cognition, balance, or mobility, or whether adverse effects of cannabis differ by HIV status merits further study in this aging population. The "Walking While Talking" (WWT) test requires individuals to walk while performing a secondary attention-demanding task (dual task), has been used to assess the interactions between cognition and gait, and provides a framework for evaluating the effect of divided attention, a facet of executive functions, on mobility. Increased dual task costs measured using WWT may help unmask subtle and latent cognitive abnormalities before they become clinically apparent by increasing the complexity of the walking condition, and predict falls, frailty, disability, and mortality among older community-residing adults. Because both cannabis use and HIV have been implicated in impairments in attention and executive functions, the WWT may be a quick and simple mobility stress test to identify subtle cognitive and motor effects of acute cannabis administration as a function of HIV status. The objective is to explore the mechanisms that underlie the increased fall risk associated with cannabis use. The effects of controlled administration of active (7.0% THC) and inactive (0.0%) cannabis in aging HIV+ women on stable HAART and HIV- controls enrolled on the WIHS will be compared. Endpoints will be balance, mobility, and cognition, including a cognitive-motor divided attention task (WWT). Specific aims and hypotheses are: To determine the acute effects of cannabis on balance and mobility among older HIV+ and HIV- women. These test will be performed within subject comparisons of performance on balance and mobility tests at two supervised visits, with administration of placebo vs. active cannabis in counter-balanced order. The hypothesis is that HIV+ women will have greater impairment on balance and mobility, especially on complex walking conditions that demand attention, with administration of active cannabis than HIV- women To determine the acute effects of cannabis on cognition among older HIV+ and HIV- women.HIV+ women will have greater impairment on cognitive testing, especially in attention, with administration of active cannabis than HIV- women.

7% delta9-THC cigarettes will be smoked by 'light the cigarette' (30 sec), 'get ready' (5 sec), 'inhale' (5 sec), 'hold smoke in lungs' (10 sec) and 'exhale.' Participants will smoke 3 puffs in this manner, with a 40-sec interval between each puff.

0% THC cigarettes will be administered to HIV negative women. Participants will be instructed to 'light the cigarette' (30 sec), 'get ready' (5 sec), 'inhale' (5 sec), 'hold smoke in lungs' (10 sec) and 'exhale.' Participants will smoke 3 puffs in this manner, with a 40-sec interval between each puff.

Mobility will be tested using the timed gait test. Gait speed is measured under normal walking and attention demanding measures.

Change in mobility as a function of timed gait from before cannabis to after cannabis which is the average of the 15 minute and 60 minute result.

Balance will be tested using functional reach test. Functional reach measures the distance the subject can reach in front of her from a standing position without losing balance.

The change in functional reach (in centimeters) will be measured from time 1 (30 minutes prior to cannabis) to the average of times 2 and 3 (15 min and 60 after cannabis)

Cognition will be tested using the number of correct suppressions on the sustained Attention to Response Task (SART). The hypothesis is that following active cannabis administration, HIV+ women will perform worse than HIV- women on cognitive testing of attention. The groups will not differ following inactive cannabis administration.

The change on the Sustained Attention to Response Task (number of correct suppressions) will be measured from time 1 (30 minutes prior to cannabis) to the average of times 2 and 3 (15 min and 60 after cannabis)

Inclusion Criteria: current cannabis use (within 6 months) based on self-report able to perform study procedures, including ability to ambulate independently adequate hearing and vision for HIV+ women use of stable HAART for at least 6 months. Exclusion Criteria: pregnancy current illicit drug use other than cannabis request for substance use treatment current parole or probation recent history of significant violent behavior (within 12 months) major current Axis I psychopathology (e.g.,bipolar disorder, suicide risk, schizophrenia) current use of psychiatric medication known to influence cognition significant uncontrolled medical illness (such as uncontrolled diabetes or hypertension, clinically significant laboratory abnormalities, liver function tests (LFTs)>3x upper limit of normal) history of active heart disease within 12 months history of dementia severe hand tremor history of Central Nervous System (CNS) diseases or injury poor English fluency. All participants will be consented and compensated for their effort as approved by the Institutional Review Boards (IRBs) of each participating institution (see human subjects).

Sharing of data generated by this study is an essential part of our proposed activities and will be carried out in terms of presentations at national and international scientific meetings as well as with publications in peer-reviewed journals. We would wish to make our results available to the community of scientists interested in understanding the consequences of substance use in older persons living with HIV, to foster future collaborative efforts and to avoid unintentional duplication of research.

The Data Analysis and Coordination Center (DACC) shares data to all investigators (internal and external) with Executive Committee (EC)-approved concept sheets. The concept sheet form requests information on the project background, specific aims and hypotheses, study design, laboratory and quality assurance methods, and plans for data analysis. All requests should be submitted online.