Lorcaserin Intra Venous Cocaine Effects

Background

Serotonin (5-HT) is one of three brain monoamines that are widely distributed in the brain
and play important roles in affect and goal-directed behaviors. Limbic structures that
underlie behavior motivated by palatable food and drugs of abuse receive dense projections
from brainstem serotonergic nuclei. In rats, light and sound cues associated with access to
cocaine strongly stimulate drug-seeking behavior. Agonists for the type 2C serotonergic
receptor (5-HT₂cR) attenuate this responding.8 Drug taking (cocaine self-administration) is
also attenuated at 5-HT₂cR agonist doses similar to those that decrease food-reinforced
responding and cause reductions in locomotor activity.

Lorcaserin is a novel and selective agonist of the 5-HT₂cR recently approved by the FDA for
weight loss therapy. It acts selectively at this receptor subtype with minimal activation of
5-HT₂ᴀR or 5-HT₂ᴃR receptors. Based on initial clinical studies leading to its approval,
lorcaserin is well tolerated and probably does not cause cardiac valve disease or other
serious side effects. Even so, given the potential for serious adverse events, the FDA has
limited its use to patients who are either obese or overweight with a medical complication
such as hypertension. Whether or not lorcaserin will become generally accepted as a
long-term treatment for obesity will depend on the results of ongoing post-marketing studies
of cardiovascular outcome data.

Rationale In preclinical studies, agonists for the 5-HT₂cR potently attenuate
cocaine-seeking behavior. Lorcaserin is a recently approved selective 5-HT₂cR agonist with
an acceptable safety profile in humans. No published studies have reported its effects on
cocaine-induced craving or drug-reinforced responding in humans.

Specific Aims:

1. Evaluate whether lorcaserin treatment attenuates the positive subjective effects of
cocaine and drug-reinforced behavior.

2. Determine whether active treatment modifies cocaine- or script- induced craving.

Methods This is a randomized, cross-over, double-blind, placebo-controlled, single-center,
multiple-panel evaluation of the potential for oral lorcaserin to modify cocaine
self-administration in a laboratory setting. Up to 32 non-treatment-seeking, regular cocaine
users will receive treatment with single doses of oral placebo, lorcaserin 10 mg (Panel 1),
or lorcaserin 20 mg (Panel 2). Script-guided imagery of autobiographical memories will be
developed based on experiences related to cocaine use, anger, and a neutral event. Following
treatment with lorcaserin, script-induced emotional states will be assayed. Sampling doses
of cocaine (0.0, 0.23, and 0.46 mg/kg) will be administered, and participants will choose
between self-administering additional intravenous doses or receiving monetary alternatives.
Detailed measures of the negative and positive subjective effects of intravenous infusions
will also be made. As noncontingent infusions of cocaine are administered, the
pharmacokinetics of cocaine and lorcaserin will be determined.

Inclusion Criteria:

1. Is non-treatment-seeking and has used cocaine regularly for at least six months.

2. Has used cocaine by a rapid route of administration (smoked or intravenous
injection), at least three times per week, for three of the preceding six weeks.

3. Is male or female, between 21 and 50 years old.

4. Is able to verbalize understanding of the consent form, able to provide written
informed consent, and verbalize willingness to complete study procedures.

5. Is agreeable to the study schedule and likely to complete all interventions and
measures.

6. Has a medical history, physical exam, and screening laboratory results that
demonstrate no contraindication to participation.

Exclusion Criteria:

1. Has a history of a medical adverse reaction to cocaine or other psycho stimulants,
including loss of consciousness, chest pain, cardiac ischemia, or seizure.

2. Has any current Axis I psychiatric disorder other than drug abuse or dependence.

3. Meets DSM-IV-TR criteria for dependence on opiates, benzodiazepines, alcohol, or
other sedative-hypnotics.

4. Has received opiate-substitution therapy within two months prior to enrollment.

5. Has a current or past history of seizure disorder other than febrile seizures,
including alcohol- or psycho stimulant- related seizures, or family history of
seizure disorder.

6. Has a diagnosis of adult asthma or chronic obstructive pulmonary disease.

7. Has had head trauma that resulted in neurological sequelae (e.g., loss of memory for
greater than 5 minutes).

8. Has a history of valvular heart disease, congestive heart failure, syncope,
bradycardia, or any other cardiac condition.

9. Has a condition that increases the risk of cocaine-induced hypertension or ischemic
heart disease, such as hypertension, hypercholesterolemia, renal disease (serum
creatinine > 1.4 mg/dl), diabetes (fasting glucose level ≥ 100 mg/dl).

10. Has a history of jaundice, hepatitis, or laboratory evidence of hepatic insufficiency
(total bilirubin ≥ 2.0, serum albumin ≤ 3.5 gm./dl); or current abnormalities of
liver function testing with serologic evidence of hepatitis (serology and coagulation
will be evaluated in individuals with aspartate transaminase or Alaine
aminotransferase > 40 IU/L).

11. History of priapism or conditions that would predispose to priapism (sickle cell
anemia, multiple myeloma, leukemia, Peyronie's disease, or other anatomical
deformation of the penis).

12. Currently being treated for erectile dysfunction.

13. Has an unstable medical condition, which, in the judgment of investigators, would
make participation hazardous, such as AIDS or active TB.

14. If female, is pregnant or lactating (nursing), not practicing adequate methods of
contraception, or planning to become pregnant within one month of conclusion of the
study.

15. Has current suicidal ideation as assessed by the SCID interview.

16. Has clinically significant ECG abnormalities, including QTc interval prolongation >
450 milliseconds in men or 480 milliseconds in women.

17. Has donated blood or participated in another clinical trial within 4 weeks of
enrollment.

18. In the opinion of investigators, is expected to fail to complete the study protocol
due to probable incarceration or relocation from the clinic area.

19. Has had known or suspected hypersensitivity to Lorcaserin.

20. Is currently being treated with an adrenergic receptor antagonist ('beta blocker').

21. Is currently receiving Lorcaserin, potential CYP2D substrates, or medications
associated with the serotonin syndrome or neuroleptic-malignant syndrome (see Tables
8 and 9).

22. Has a significant potential for violent behavior, as assessed by the Structured
Assessment of Violence Risk in Youth (SAVRY).23