Table 5 Studies of cannabinoids for anxiety in humans

D’Souza et al. 2004 [77]

22 healthy individuals (male: n = 14, female: n = 8), mean age = 29, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder

In a double-blind, randomised, and counterbalanced study, over three days, the dose effects of THC were characterized in healthy individuals who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder.

Volunteers participated in 1-3 test days, separated by at least 1 week. VAS scores were recorded 60 min before ingestion and at 10, 80 and 200 min post ingestion.

Visual Analog Scale for anxiety (VAS)

THC (2.5, 5.0 mg)

Intravenous

THC transiently increased VAS scores of ‘anxious’ and decreased VAS scores of ‘calm and relaxed’ in a dose dependent manner

D’Souza et al. 2008 [48]

30 frequent users of cannabis, (male: n = 21, female: n = 9), mean age = 24.8,

In a double-blind, randomized, placebo-controlled study over three days, the dose related effects of THC were observed in 30 frequent users of cannabis and 22 healthy controls.

Volunteers participated in 1-3 test days, separated by at least 1 week. VAS scores were recorded 60 min before ingestion and at 10, 80 and 200 min post ingestion.

Visual Analog Scale for anxiety (VAS)

THC (2.5, 5.0 mg)

Intravenous

THC transiently increased VAS anxiety scores in both groups. However, frequent users showed smaller increases in anxiety than controls.

Bergamaschi et al. 2011 [82]

6 males and 6 females were placed in each group. The mean age for each group was between 22.9 and 24.6.

Participants with SAD and an additional 12 controls were blindly allocated to receive CBD or placebo 1.5 h before a simulation public speaking test. At six time points during the test Visual Analogue Mood Scale, and Negative Self-Statement scale, and physiological measures were taken.

Baseline measurements were taken, followed by ingestion of CBD or placebo. Pretest measurements were made 80 min after ingestion and post-test measurements were made 15 and 35 min after the end of the speech.

Visual Analog Scale for anxiety (VAS)

CBD (600 mg)

Oral

CBD administration resulted in significantly reduced anxiety, cognitive impairment and discomfort, and significantly decreased hyper-alertness in anticipatory speech. The CBD group and the healthy controls had similar response profiles.

Crippa et al. 2011 [83]

10 males with of a mean age of 24.2

Participants with SAD who were given CBD or placebo, in a double-blinded crossover manner. Regional cerebral blood flow activity in the brain was then compared

Subjective ratings were made at five different time points: 30 min before drug ingestion, at the time of ingestion and at 60, 75 and 140 min (or after SPECT procedure) after ingestion

Functional neuroimaging, Statistical parametric mapping

CBD (400 mg)

Oral

Compared to the placebo CBD produced significantly lower subjective anxiety and modulated blood flow in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus, and right posterior cingulate gyrus

Zuardi et al. 1982 [18]

8 physically and mentally stable volunteers (male: n = 6, female: n = 2), mean age of 27.

Participants received in a double-blind procedure, THC, CBD or both cannabinoids together across five experimental sessions, separated by a minimum interval of one week.

Each volunteer participated in five experimental sessions, separated by a minimum interval of 1 week.

State-Trait Anxiety Inventory (STAI)

THC (0.5 mg/kg)

CBD (1.0 mg/kg)

THC + CBD (0.5 mg/kg + 1.0 mg/kg)

Oral

THC produced a large increase in anxiety. This was particularly antagonized when CBD was administered simultaneously

Fusar-Poli et al. 2009 [86]

15 healthy males, who had used cannabis 15 times or less in their life with a mean age of 26.67

THC, CBD or a placebo were administered in a double-blind, randomised manner. Functional magnetic resonance imaging (fMRI) was used to observed the brain while participants viewed images of faces that implicitly intended to induce varying levels of anxiety.

Subjects were studied on 3 separate occasions, each separated by a 1-month interval. Either THC, CBD or a placebo was ingested before each session.

State-Trait Anxiety Inventory (STAI), VAMS anxiety and tranquilization subscale

THC (10.0 mg)

CBD (600 mg)

Oral

THC resulted in increased anxiety being noted in the STAI score. Though CBD did not significantly change this rating, there was a trend (P = 0.06) for reduction in anxiety following CBD administration on the VAMS anxiety and tranquilization subscale.

Peters et al. 1976 [79]

Two groups, each consisting of 5 males and 5 females aged between 21 and 34. One group reported their marijuana use did not exceed twice per month over the past 3 to 4 years. The other group, reported using marijuana twice or more weekly during the same period.

THC was administered in a randomised, double blind procedure. The participants then filled out a 270 item questionnaire (SDEQ)

All 20 subjects were administered THC or a placebo on four separate occasions separated by at least 1 week. The SDEQ was undertaken 4.5 h after ingestion.

Subjective Drug Effects Questionnaire (SDEQ)

THC (0.2,0.4, 0.6 mg/kg)

Oral

THC was found to have a profound anxiogenic effect, with participants stating that they felt more tense, jittery and less in control

Karniol et al. 1974 [78]

40 male volunteers aged between 21 and 34. 22 stated that they had previous occasional use of cannabis

In a double-blind procedure, healthy male volunteers were assigned to one of eight experimental groups and in a double-blind procedure received THC, CBD or a mixture of both cannabinoids.

Pulse rate and a time production task (asked to produce a 60-sec interval, 10 times), was repeated before and after ingestion. At at 55, 95, 155 and 185 min after ingestion, subjects were asked questions about their feelings and sensations.

Reported anxiety and panic

THC (30.0 mg)

CBD (15.0, 30.0, 60.0 mg)

THC + CBD (30.0 mg + 15.0 mg, 30.0 mg + 30.0 mg, 30.0 mg + 60 mg)

Oral

THC provoked strong reactions, with four of the five subjects scoring their anxiety level as the maximum grade of four. CBD produced anxiogenic effects in two of the fifteen subjects. When CBD was given together with THC, the anxiogenic effects of THC were reduced.