Understanding Biphasic Response Curves

What are biphasic response curves and why do they confound cannabis dosing and overall treatment for millions of patients and lifestyle consumers? Read on to learn!

One biochemical aspect of some, but not necessarily all, cannabinoids and terpenes is something that scientists call a biphasic response curve (also called hormesis or biphasic dose response and related to multiphasic response curves). Chemicals and drugs that exhibit such a response curve display an efficacy that is dose dependent. At low doses, the molecules present a particular effect (or no effect whatsoever), while at a stronger dose they deliver a different (and sometimes polar opposite) effect.

A good example of this dynamic is THC. This phytocannabinoid displays a biphasic response curve with respect to anxiety. At low doses, it reduces anxiety and perceived stress. At stronger doses, however, THC can increase anxiety and even cause disorientation and panic attacks. Other cannabinoids, such as CBD and CBC, also display biphasic response curves with respect to particular effects (appetite, anxiety, changes in systemic inflammation, etc.).

"Most wellness practitioners and consumers are acclimated to a dynamic equating higher doses with a greater response," said New Mexico-based clinical practitioner and author of the 2016 book An Inflammation Nation Dr. Sunil Pai, MD in a 2020 interview with Vegas Cannabis Magazine. "However, with CBD and terpenes from hemp oil, it is actually the opposite!," said Pai.

Pai explained that, unlike many conventional drugs and therapies, more is not necessarily better when it comes to the most appropriate dosing for cannabinoids such as CBD. “Think of a key that’s necessary to open a door. Only a small, gentle turn of the lock is required to open the door and enter the house. A bulldozer isn’t required to knock down the door and surrounding wall!,” said Pai.

Dr. Sunil Pai, author of An Inflammation Nation

Pai also described the importance of not only the size/volume of a dose, but also the frequency of dosing throughout the day. While a patient may require a certain amount of a cannabinoid over a 24 hour period, the efficacy of the treatment will vary (targeting different places on the response curve) depending on frequency of administration. "Improvements from CBD are better when it is consumed more frequently throughout the day, versus a larger dose once per day," recommended Pai.

According to Boston-based clinical physician Dr. Peter Grinspoon, MD, dosing is heavily influenced by biphasic response curves. "I always caution patients to start low and go slow. Anxiety is a good example of a negative side effect because the dose response generally tends to be biphasic," said Grinspoon during an interview. "In other words, in low doses, THC can decrease anxiety; in higher doses, however, it can do the opposite, exacerbating anxiety."

Research on Biphasic Response

According to a a 2012 research study entitled "Biphasic Effects of Cannabinoids in Anxiety Responses," a number of cannabinoids display biphasic response curves for several aspects of their medicinal efficacy, including “processes such as feeding behavior, motor activity, motivational processes and anxiety responses.”

A 2018 study entitled "Biphasic Effects of THC in Memory and Cognition" investigated the efficacy and biochemical mechanisms surrounding the endocannabinoid anandamide and the phytocannabinoid THC. The study revealed the biphasic response of THC with respect to multiple areas of its efficacy, including neurogenesis (the ability to repair or grow fresh nerve cells) and memory.

The study reported how the specific experience of an individual is determined by not only the biphasic responses of cannabinoids such as anandamide, but also subjective characteristics, such as age. Reported the study, "THC modulates memory and cognition in a biphasic and age‐dependent manner: In old animals, low concentrations improve memory and cognition while high concentrations impair these functions; in young animals, even a low concentration is detrimental."