Can lemon-smelling weed cause less anxiety than others?
The best findings from the study:
- Have you ever eaten mangoes to get higher? Maybe mash some lemonade to prevent anxiety
- Test subjects who vaped high levels of terpene limonene with their weed reported less anxiety in a small study
Leafly Ph.D. Nick Jikomes analyzes the new hype study on the odor molecule limonene below. Report your findings in the comments section.
The “entourage effect” is the idea that the psychoactive effects of cannabis result from a combination of different plant molecules. The idea is often used in the cannabis industry to explain the different effects that cannabis strains are said to have – each containing a different combination of THC, terpenes and other compounds. These claims have been largely theoretical, with limited empirical evidence showing that certain combinations of cannabinoids and terpenes reliably produce measurably different effects in humans.
However, a new study examines whether the common cannabis terpene limonene, when consumed alongside THC, produces different effects than THC alone.
Many types of grass contain some limonene
Limonene is one of the most common terpenes in commercial cannabis. Cannabis strains with the highest limonene content typically contain between 1 and 3 percent limonene by weight. Commercial THC-dominant cannabis flowers today often have THC levels in the 20-25% range, meaning the most limonene-rich strains have a THC to limonene ratio of around 20:1.
Limonene occurs naturally in many citrus fruits. On its own it has a pleasant citrus aroma. In a limited number of animal studies, an anxiolytic effect has been observed in rodents given limonene. Similar observations have been made in human studies, although the sample size was small or important controls were missing. Given that anxiety is a common side effect of THC – particularly when relatively large doses are consumed – it has been hypothesized that limonene may be able to mitigate these effects. If true, it would raise the possibility that THC-dominant strains with high levels of limonene may cause less anxiety than those with lower levels of limonene.
Limonene and THC vaporize – for science!
In this new study, Johns Hopkins researchers administered various combinations of THC, limonene, and a distilled water placebo to twenty human subjects in a double-blind experiment. Each person participated in several separate vaping sessions during which they received one of the following:
- Limonene alone (1 mg or 5 mg)
- THC alone (15 mg or 30 mg)
- THC + limonene together (15 or 30 mg THC + 1 mg limonene)
- THC + limonene together (15 or 30 mg THC + 5 mg limonene)
- THC + limonene together (30 mg THC + 15 mg limonene)
- Placebo (distilled water)
The test subjects were healthy adults who occasionally consumed cannabis. A Might Medic portable vaporizer (manufactured by Storz and Bickel) was used for administration. Subjects consumed 15 and 30 mg doses of THC because, based on previous research, these doses often produce small (15 mg THC) to medium/large (30 mg THC) psychoactive effects, with the larger dose expected to produce more would cause side effects such as anxiety. Researchers assessed participants using standardized questionnaires. In one of these questionnaires, the “Drug Effect Questionnaire”, test subjects are asked to rate various subjective drug effects on a scale from 0 to 100. Another, the State-Trait Anxiety Inventory (STAI-S), assessed their anxiety/distress levels before and after medication administration. The researchers also tracked heart rate, blood pressure and plasma levels of THC and limonene. (For more details on the study methods, including standardized procedures, see the article itself.)
What did they find? Did the presence of limonene influence the subjective effects of THC or reduce side effects such as anxiety and paranoia?
Three lime-dominant hype strains
And the results come
I recently spoke with the study's lead author, Dr. Ryan Vandrey of Johns Hopkins University talked about how his team designed the study and incorporated key controls. For one thing: the test subjects received the real molecules, not a burned version.
“We made sure that when we heated this device to this temperature, we didn't turn these things into something else,” Dr. Vandrey. “That's why we've taken great care to secure and work with our dosing methods. We specifically chose inhalation and vaporization so we can be sure our doses are delivered fully and completely.”
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THC consumption went as planned. The control placebo containing 0 mg THC caused no significant subjective effects, anxiety or paranoia, or changes in heart rate. Consuming 15 or 30 mg of THC triggered these changes, with the higher dose having greater effects on average.
“We selected two doses of THC, 15 milligrams and 30 milligrams, which provide a moderate to pretty damn high for the casual cannabis user.”
Dr. Ryan Vandrey, Johns Hopkins University
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But did consuming limonene along with THC produce different effects compared to the same dose of THC alone? Yes – if you maximize limonene.
When limonene was administered alone without THC, its effect did not differ from that of placebo.
However, when THC and limonene were administered simultaneously, the team saw differences compared to THC alone, but only at the highest limonene dose (15 mg).
Compared to 30 mg THC alone, consumption of 30 mg THC + 15 mg limonene resulted in lower subjective ratings of “anxious,” “paranoid,” and “unpleasant drug effect.”
The subjective ratings of “anxious” and “paranoid” were less than half of those observed at 0 mg limonene.
The subjective ratings of “anxious” and “paranoid” were less than half of those observed at 0 mg limonene.
Although the result was statistically significant at the highest dose of limonene (20 mg), the sample size (n=20) was small and it is not clear whether most subjects saw this effect or whether a small minority experienced large differences.
The presence of limonene did not affect physiological measurements such as heart rate, nor did it result in differences in the intensity of the subjective effects of THC or in THC blood levels.
“This is important … because it suggests that limonene does not somehow interfere with THC absorption. It doesn't change the pharmacology in any way. “It doesn’t block THC’s ability to bind to the cannabinoid receptor,” Dr. told me. Vandrey.
Could the test subjects recognize lemon?
Because limonene has a taste and odor and affects vapor quality, blinding may have been a problem, especially with higher doses of limonene.
In other words, if the subjects could taste or smell that terpene, or noticed that the vapor felt different, it could have influenced their experience.
According to Dr. However, according to Vandrey, the team's drug delivery design reduced the subjects' ability to tell what they were consuming by taste or sight.
“We did everything we could to maintain blindness in this study,” he said. “The drugs were sealed in the vaporizer, but they couldn't see it, they couldn't smell it or anything like that.”
The entourage effects of weed remain difficult to determine
Although the results of Vandrey's study proved to be statistically significant, the magnitude of the effect was quite modest. Co-administration of THC with 15 mg limonene resulted in a reduction in anxiety, but not with 1 mg or 5 mg limonene.
It is important to note an important caveat: the subjects did not consume whole plant cannabis products like the ones we can buy in pharmacies. They only consumed certain combinations of THC and/or limonene.
The moderate effects they saw were only seen with 30 mg of THC with 15 mg of limonene, which is a THC:limonene ratio of 2:1. This is not a combination found in commercial cannabis flowers. Expect a THC:limonene ratio of around 20:1 even for the strains with the highest limonene content.
Taken at face value, the results of the Johns Hopkins study suggest that maximum limonene intake may reduce anxiety.
However, they do not prove that limonene-rich, THC-dominant cannabis purchased from a dispensary contains enough limonene to achieve the same goal.
If limonene or other cannabis terpenes can indeed reliably modulate the effects of THC in commercially available cannabis products, future research must focus on them. Such products contain more complex mixtures of THC and a variety of terpenes and other molecules, many of which are present in small amounts. Does the “entourage effect” really explain all of the effects of weed? To be sure, researchers need to carefully measure the effects of real things.
For more details on this study, see my full conversation with Dr. Ryan Vandrey. Mind & Matter is a scientific column by Nick Jikomes, PhD, exploring how psychoactive drugs affect the mind and body. It is inspired by the long-form science podcast, Mind and matter.
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