Adverse Events From Cannabis Administration

3.3.1. Physiological Cardiovascular

Acute cardiovascular effects of cannabis administration include tachycardia, slightly increased blood pressure when supine, orthostatic hypotension, increased cardiac output, and decreased left ventricular ejection fraction (32,33). These effects increase myocardial oxygen demand at the same time that oxygen delivery to tissues may be decreased because of the increased car-boxyhemoglobin from smoking. As a result, smoking one marijuana cigarette significantly reduces maximal exercise performance and exercise tolerance of physically healthy subjects (34) and patients with angina (35). However, in healthy subjects the acute cardiovascular effects of cannabis are mild, self-limiting, and rarely cause clinically significant adverse events (32,36-38).

Orthostatic hypotension may be associated with light-headedness and syncope (39). This may be minimized by ensuring that subjects are well hydrated (including encouraging fluid intake during cannabis administration), avoiding sudden changes in position, and keeping subjects seated with legs elevated during cannabis administration.

Acute cannabis administration is rarely associated with clinically significant ECG changes (32). Changes associated with tachycardia may be seen during monitoring, such as nonspecific, transient S-T segment or T-wave changes. Neurological

Acute neurological effects of cannabis administration include headache, tremor, impaired balance, and impaired gross and fine motor coordination (37,38,40). The latter, especially in conjunction with drowsiness, increases the risk of motor vehicle accidents, falls, and other unintended injuries (41). Physical activity by subjects under the influence of cannabis should be limited and performed only in a protected environment that minimizes the risk of injury. Subjects should be advised not to drive, operate machinery, or engage in other potentially hazardous activities until it is clear that their coordination (and mental alertness) has returned to normal. Pulmonary

Smoked cannabis causes bronchodilation (probably by THC) (42), pulmonary irritation from inhalation of the smoke, and increased absorption of carbon monoxide (43,44). The latter leads to elevated blood carboxyhemoglo-bin levels, resulting in decreased oxygen delivery to tissues. These effects rarely cause clinically significant adverse events with the limited exposure usually involved in cannabis administration research studies (45). However, even a single cannabis cigarette may trigger coughing or breathing difficulty (dysnpea) in a susceptible subject, e.g., one with active asthma or bronchitis.

Oral and intravenous THC cause bronchodilation (42) but are not associated with pulmonary adverse events. Other Physiological Effects

Acute cannabis administration may cause pupil constriction, conjunctival injection ("red eye"), and dry mouth. These effects are mild and self-limiting and do not require treatment (37). Dry mouth may be worsened by the smoked route of administration. It can be relieved by providing subjects with fluid to drink, sucking candy, or chewing gum.

3.3.2. Psychological Anxiety, Psychosis

Acute cannabis administration can cause a spectrum of adverse psychological effects, ranging from hypervigilance and anxiety, to panic, agitation, paranoid thinking, and psychosis (38,40). These are rare at the doses commonly used in research studies but are more likely to occur in susceptible individuals (46,47). Although controlled studies have not been done, susceptible subjects include those with preexisting psychopathology or a history of a psychiatric illness such as schizophrenia, schizoaffective disorder, major depression, manic depression (bipolar disorder), or anxiety disorder. Screening for these conditions relies largely on subject self-report and so may not always be completely reliable. Thus, it is prudent to conduct cannabis-administration studies in a setting where appropriate psychiatric intervention is promptly available. This should include facilities for safe physical restraint of agitated subjects and administration of parenteral medication. Cannabis-induced psychological effects usually subside within several hours and respond well to supportive reassurance and placement in a quiet environment. Severe agitation that makes the subject a danger to himself or others can be controlled with a benzodi-azepine sedative such as lorazepam (effective by both oral and intramuscular administration). Psychosis can be controlled with standard doses of antipsychotic (neuroleptics) medication. Psychomotor Performance

Acute psychomotor effects of cannabis administration include decreased postural balance (48,49), increased body sway (due to impaired equilibrium) (50), and increased tremor. Effects on simple and complex reaction time tasks are mixed, with some studies reporting impaired performance (51,52) and others showing no effect (50,53). Acute cannabis administration can also impair performance on the digit symbol substitution test (DSST) (9,13,49), Attention and Cognition

Cannabis administration acutely disrupts performance of complex tasks requiring continuous monitoring and the ability to shift attention rapidly between various stimuli (54,55). These same attentional abilities are required when operating a motor vehicle. Cannabis administration impairs performance on laboratory tests that model various components of driving (56) and increas-

es braking latency in a driving simulator (50). It also impairs performance on standardized tests used by law enforcement personnel to determine whether a person can safely drive (57,58). In tests of on-road driving, cannabis moderately increases lateral movement of the vehicle within the driving lane on a highway (59).

One of the most reliable effects of acute cannabis administration is the impairment of memory processes. Numerous studies have found that smoked marijuana decreased the number of words or digits recalled and/or increased the number of intrusion errors in either immediate or delayed tests of free recall (9,53,55,60). Using an extensive battery of cognitive tests, Block et al. (51) found that cannabis slowed response time for producing word associations, slowed reading of prose, and impaired tests of reading comprehension, verbal expression, and mathematics. Heishman et al. (31) also found that simple addition and subtraction skills were impaired by smoking one, two, or four cannabis cigarettes.

3.3.3. Addictive Risk

Addictive risk refers to the risk that cannabis administration during a research study might trigger or worsen cannabis abuse or dependence (6). It seems unlikely that the brief cannabis exposure involved with most research studies would be sufficient to have such an effect, especially in view of the fact that only 10% of regular cannabis users develop cannabis dependence (61,62). However, several steps can be taken to minimize whatever risk does exist. First, subjects with a history of abuse or dependence can be excluded on the grounds that they would be most susceptible (see Note 12). Second, the dose, frequency, and duration of cannabis administration in the research study should be no greater (and preferably less) than what subjects were using on their own prior to study participation. This removes any incentive to enter a study to gain more access to cannabis. Third, smoked cannabis, because it is considered to have the greatest abuse potential, should only be given to subjects with prior smoked cannabis experience.

4. Notes

1. To avoid some of the problems associated with the smoked route of administration (i.e., with inhalation of burning plant material), methods are being developed for inhalation of pure THC via either nebulizer or metered dose inhaler (63).

2. NIDA cigarettes can be ordered in writing from the Chemistry & Physiological Systems Research Branch, Division of Neuroscience & Behavioral Research, 6001 Executive Boulevard, MSC 9555, Bethesda, MD 20892-9555 (301 443-6275). US investigators must hold a valid Schedule I research license from the US Drug Enforcement Administration and have an approved IND from the US Food and Drug Administration.

3. The marijuana for NIDA cigarettes is grown under contract at the University of Mississippi, Oxford, MS. The plant material is sent to the Research Triangle Institute (RTI), Research Triangle Park, NC, where the marijuana leaves are stripped, cleaned, and rolled into cigarettes. RTI assays the cigarettes for THC content. Cigarettes are stored freeze-dried until shipped to an investigator. Cigarettes should be kept frozen in an air-tight container in order to maintain potency. Their moisture content prior to use should be raised by placing them above a saturated sodium chloride solution in a closed humidifier for 12-48 h.

4. Some investigators may accept a woman's self-report of reproductive status (e.g., hysterectomy, tubal ligation), abstinence from sexual activity, or use of contraception. However, it is prudent to confirm reproductive status with medical records and to have women with reproductive potential undergo pregnancy testing prior to study participation. Periodic pregnancy testing may be needed if the study extends over a period of time.

5. The validity of this prescreen approach depends on at least three factors. First, subjects' prior cannabis use should be by the same route of administration as used in the research study, e.g., a subject whose only prior cannabis was oral would not participate in a smoked cannabis study. This avoids exposing subjects to a route of administration that might produce more intense effects than they are used to. One concern in this regard is a route of administration, such as smoking, that produces rapid onset of positive psychological effects, thus increasing abuse liability and the potential for engendering or worsening cannabis abuse (64).

Second, the dosage, duration, and frequency of cannabis administration during research should not exceed that previously used by subjects. Obviously, the absence of adverse events following a single, low-dose use is not very reassuring with regard to the possibility of adverse events following higher-dose or more frequent cannabis administration.

Third, subjects must provide honest and accurate self-report about their prior experience with cannabis. Accuracy of self-report about illegal drug use is enhanced when subjects are aware that there will be objective confirmation by drug testing and when there are no adverse consequences for honest reporting (65-67). In the case of screening for a cannabis administration study, the adverse consequence for honest reporting may be exclusion from the study. Therefore, potential subjects who are aware of this connection may have a powerful incentive to withhold information. Thus, it is important to elicit the history of prior cannabis use and its adverse effects early in the screening process and without giving potential subjects clues, either overt or covert, about what types of responses will lead to inclusion or exclusion from the study. This can be done by collecting relevant information from questions embedded throughout larger questionnaires (rather than grouping all relevant questions together) and by couching questions broadly in terms of learning what to expect from cannabis administration in a particular subject.

6. There are no standardized measures of cannabis intoxication that have been used to assess the ability to give informed consent. The marijuana (M) scale of the Addiction Research Center Inventory (ARCI) has been used to measure the acute intoxicating effects of cannabis in research settings (e.g., ref. 25), but not as part of the subject consent process. In the latter setting, decisions about intoxication are based on clinical interview and judgment.

7. Typical questions measuring acute subjective effects of cannabis include "How high do you feel?", "How much of a good drug effect do you feel?", or "How stoned are you?" Questions can be presented either on paper (with subjects responding by marking with a pen) or on a computer screen (with responding by moving a cursor on the screen). Computer presentation is usually more efficient in terms of time and staff resources and eliminates data-entry errors. Subjects' attention and response to each question can be ensured by requiring that the cursor be moved slightly before any answer is recorded.

8. The M scale is scored by assigning one point for each "true" response and summing the points to obtain a total scale score. The 12 true-false statements that comprise the M scale are as follows: Things around me seem more pleasing than usual. I feel as if something pleasant had just happened to me. I have difficulty in remembering. I feel a very pleasant emptiness. My mouth feels very dry. Some parts of my body are tingling. I have a weird feeling. My movements seem slower than usual. I notice that my heart is beating faster. My thoughts seem to come and go. I notice my hand shakes when I try to write. I have an increasing awareness of bodily sensations.

9. The ARCI consists of 550 true-false statements comprising many empirically derived scales sensitive to the subjective effects of various psychoactive drugs. A widely used short form of the ARCI consists of 40 true-false statements that comprise three scales: morphine-benzedrine group (MBG), a measure of euphoria; pentobarbital-chlorpromazine-alcohol group (PCAG), a measure of sedation; and lysergic acid diethylamide (LSD), a measure of dysphoria and psychotomimetic changes (68).

10. Domains of psychomotor performance and tests shown to be sensitive to the acute effects of cannabis administration include (1) gross and fine motor abilities: body sway, one leg stand, hand steadiness, finger tapping; (2) eye-hand coordination: digit-symbol substitution, circular lights, rotary pursuit, pegboard, card sorting; (3) reaction time: visual or auditory simple (one stimulus) and choice (multiple stimuli). (For details about the tests and the effects of cannabis, see refs. 26-28.)

11. Domains of attention and cognition and tests shown to be sensitive to the acute effects of cannabis administration include (1) focused attention: simple and choice reaction time, digit-symbol substitution; (2) selective attention: letter search, Stroop color naming; (3) divided attention: various tests requiring simultaneous performance of a central and peripheral task, driving and flying simulators; (4) sustained attention: visual or auditory signal detection, continuous performance, vigilance; (5) learning: repeated acquisition and performance of response sequences, paired-associate learning, Buschke selective reminding; (6) memory: digit span, free recall, recognition memory, prose recall; (7) problem solving: mental arithmetic, spatial orientation, embedded figures; (8) reasoning: logical reasoning, creativity. (For details about the tests and the effects of cannabis, see refs. 26-28.)

12. In the absence of relevant data or controlled studies, there is a spectrum of practice regarding excluding subjects with a history of abuse or dependence. At one end are investigators who would exclude any subject with a family or lifetime personal history of any substance abuse or dependence (perhaps with the exception of nicotine dependence). At the other end are investigators who would exclude only subjects with current substance dependence. As with many other subject eligibility criteria for clinical research, there is usually an inverse relationship between strictness of the criterion and the availability of eligible subjects to enroll.

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