Although cannabis may have potential therapeutic value, inhalation of a combustion product is an undesirable delivery system. The aim of the study was to investigate vaporization using the Volcano^s device as an alternative means of delivery of inhaled Cannabis sativa. Eighteen healthy inpatient subjects enrolled to compare the delivery of cannabinoids by vaporization to marijuana smoked in a standard cigarette. One strength (1.7, 3.4, or 6.8% tetrahydrocannabinol (THC)) and delivery system was randomly assigned for each of the 6 study days. Plasma concentrations of D-9-THC, expired carbon monoxide (CO), physiologic and neuropsychologic effects were the main outcome measures. Peak plasma concentrations and 6-h area under the plasma concentration–time curve of THC were similar. CO levels were reduced with vaporization. No adverse events occurred. Vaporization of cannabis is a safe and effective mode of delivery of THC. Further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system.

¹Community Consortium, Positive Health Program, San Francisco General Hospital, San Francisco, California, USA; ²Division of Hematology-Oncology, San Francisco General Hospital, San Francisco, California, USA; ³Department of Medicine, University of California, San Francisco, California, USA; ⁴Division of Neurology, San Francisco General Hospital, San Francisco, California, USA; ⁵Department of Neurology, University of California, San Francisco, California, USA; ⁶Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, California, USA. Correspondence: DI Abrams (dabrams@php.ucsf.edu)

Received 29 September 2006; accepted 25 February 2007; advance online publication 11 April 2007. doi:10.1038/sj.clpt.6100200

There was evidence of decreasing bioavailability and/or titration of THC intake with increasing strength of THC. The plasma THC AUC derived from the vaporizer normalized for the THC strength was highest at 1.7% THC (27.1 ng h/ml/%) and was progressively lower at higher THC strengths (3.4% THC: 20.5 ng h/ml/% and 6.8% THC: 14.3 ng h/ml/%; Table 1), suggesting higher bioavailability and/or more intensive puffing at lower THC potency. This decline was statistically significant (ratio: 0.87; 95% CI: 0.84, 0.90; Po0.001 per 1% increase in THC strength) and did not appear to differ between vaporization and smoking (ratio for interaction: 0.92; 95% CI: 0.79, 1.05; P ¼ 0.25) in a mixed model which included fixed effects for randomization, a linear term for THC strength, and a term for the interaction between these effects.

Figure 1 Plasma THC using vaporizer and smoked cannabis by THC strength (mean and 90% CI).

There was also evidence of titration of intake of THC with increasing THC strength based on puffing behavior. The number of puffs taken using smoked marijuana remained stable with increasing strength THC (mean puffs, 95% CI: 6.1 (4.8, 7.3), 5.9 (4.9, 6.8), and 6.4 (5.3, 7.6) for 1.7, 3.4, and 6.8% THC, respectively; mixed model analysis ratio: 1.01;

Subjective and safety observations

Self-reported high did not differ during vaporization com­pared to smoking overall (6-h AUC) or at any observation after consumption of cannabis (Figure 3). Self-reported high did increase significantly during both vaporization and smoking with increasing strength of THC (Po0.001).

Figure 2 Expired CO at each time point for each mode of administration and THC strength (mean and 95% CI).

for vaporized and smoked cannabis. This observation suggests either dose-dependant bioavailability or self-titra­tion of THC intake. Self-titration of drug intake means that smokers adapt their smoking behavior to obtain desired levels of THC from the particular delivery system, taking more puffs and/or inhaling more efficiently at lower compared to higher THC strengths. Supporting the idea of titration was the trend to take more puffs at lower THC concentrations of vaporized marijuana and the higher CO per puff at lower THC concentrations of smoked marijuana. The phenomenon of self-titration of psychoactive drug intake from an inhaled delivery system is well documented for nicotine from cigarette smoking,⁶ but to our knowledge has not been previously reported for marijuana.

Whereas smoking marijuana increased CO levels as expected for inhalation of a combustion product, there was little if any increase in CO after inhalation of THC from the vaporizer. This indicates little or no exposure to gaseous combustion toxins. Combustion products are harmful to health and reflect a major concern about the use of marijuana cigarettes for medical therapy as expressed by the Institute of Medicine. Although we did not measure other combustion products such as polycyclic aromatic hydrocarbons and oxidant gases, the observation of little or no CO exposure suggests little or no exposure to these other compounds. The vaporizer was well tolerated, with no reported adverse effects. Most subjects preferred the vaporizer compared to marijuana smoking, supporting its potential for medical therapy. Thus, the Volcano^s is an acceptable system and may provide a safer way to deliver THC than smoking marijuana cigarettes.

In summary, we provide data indicating that the availability of THC delivered by the Volcano^s vaporizer is comparable to that of marijuana cigarettes. Vaporization of marijuana does not result in exposure to combustion gases, and therefore is expected to be much safer than smoking marijuana cigarettes. The vaporizer was well tolerated and preferred by most subjects compared to marijuana cigarettes. The Volcano^s device is an effective and apparently safe vehicle for THC delivery, and warrants further investigation in clinical trials of cannabis for medicinal purposes.

METHODS Study patients. Participants were healthy adults between the ages of 21 and 45 years who were current cannabis users and had smoked cannabis within the past 30 days but in an amount totaling less than 10 cannabis cigarettes or the equivalent. Subjects with active substance abuse (e.g., recurrent or continuous drug and/or alcohol use) or diagnosed with marijuana dependence as defined in DSM-IV code no.

304.30. were excluded. Subjects were required to abstain from smoking cannabis for 48 h before their admission into the GCRC at San Francisco General Hospital (SFGH). The study was approved by the Institutional Review Board at the University of California San Francisco, the Research Advisory Panel of California, the Drug Enforcement Administration, the Food and Drug Administration, and the National Institute on Drug Abuse. Written informed consent was obtained from all patients. The trial was monitored by an independent Data Safety Monitoring Board (DSMB) established by the University of California Center for Medicinal Cannabis Research.

Study medication. The National Institute on Drug Abuse provided pre-rolled cannabis cigarettes, weighing on average 0.9 g and containing 1.7, 3.4, and 6.8% D-9-THC, respectively. The cigarettes were kept in a locked and alarmed freezer until they were dispensed to a locked freezer in the San Francisco General Hospital General Clinical Research Center where the in-patient study was conducted. The cigarettes were bisected; one half to be smoked and the contents of the other half to be vaporized. The half cigarettes were rehydrated in a humidifier overnight before their use. Patients were housed in a room with a fan ventilating to the outside. Research staff monitored patients during smoking sessions, weighed the cannabis cigarettes immediately before and after they were administered to patients, and returned all leftover material to the pharmacy. To maximize standardization of inhaled doses, patients followed the Foltin uniform puff procedure where inhalation for 5 s is followed by a 10 s breath hold, then exhalation; the entire process is repeated after 45 s.⁷ Study participants smoked or vaporized cannabis once a day. Subjects were instructed to continue puffing until they exhausted smoke or vapor from the delivery device or until they had inhaled as much as they could tolerate.

The vaporizer device. The Volcano^s vaporizer was obtained from Storz & Bickel GmbH & Company (Tuttlingen, Germany) and was employed according to the manual provided. The device works as a vaporizer that evaporates the active substances or aromas from plant material by using a hot airflow (Figure 4). Cannabis placed in the filling chamber is heated by the device to 1901C. The vaporized compounds are collected in the inflatable, detachable bag fitted with a mouthpiece and a one-way valve that allows the vapor to remain in the balloon until inhalation. It required two to three balloon inflations to vaporize each half cigarette. Subjects also followed the Foltin puff procedure when inhaling the vaporization product.

Study design and procedures. The study was a 6-day ‘‘proof of concept’’ pilot study to investigate the delivery of cannabinoids by way of vaporization of cannabis compared to cannabis smoked in a standard cigarette. The in-patient setting permitted us to measure plasma THC concentration over time and to rigorously assess the primary and secondary outcome variables in a controlled clinical environment.

Screening visit. Once a subject for the protocol had been identified, details of the study were carefully discussed and the subject was asked to read and sign a consent form. Subjects were asked questions about their medical history including psychiatric illness and substance abuse. Subjects were asked to abstain from smoking or ingesting cannabis 48 h before their hospitalization based on our prior studies which indicated that after 24 h of abstinence, plasma THC concentrations are sufficiently low so that the concentration-time curve could be determined after the experimental exposure.⁸

GCRC in-patient hospitalization (days 1–6). Subjects inhaled three strengths of cannabis (1.7, 3.4, and 6.8% THC) as smoked cigarettes and three as vaporized cannabis using the Volcano^s device. Half of one cigarette was inhaled via one of the two delivery systems on each of the 6 in-patient GCRC days. The uniform puff procedure described above was utilized to attempt to standardize inhalation. Blood was drawn at 2, 30, 60, 180, and 360 min after smoking on each of the 6 inhalation days to measure the concentrations of THC. Expired CO was measured using the Ecolyzer^s before inhalation, and 2, 30, 60, 180, and 360 min after inhalation.

Study by DI Abrams^1,2,3, HP Vizoso^1,3, SB Shade^1,3,CJay^4,5, ME Kelly^1,2,3 and NL Benowitz^3,6

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