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Cannabis stands at the crossroads of culture, medicine, and legality as a plant full of myth and enigma. It has been part of human civilization for centuries, taking on various uses and perceptions in diverse societies. From ancient rituals to modern medicine, cannabis has traversed a complex journey, inspiring both fascination and controversy.

The cannabis plant is more than just a botanical curiosity; it symbolizes human fascination and exploration. Its story crosses geographical boundaries and societal norms, intertwining civilizations. While cannabis has been revered for its potential medicinal properties, its tumultuous legal landscape has led to debates and regulatory shifts around the world.

Throughout this article, we aim to chart the history of cannabis, explore its fundamental characteristics, decode its active constituents and their effects on the human body, and explore the intricate molecular biology behind its effects.

What is Cannabis?

Cannabis, also known as marijuana or Indian hemp, is a herbaceous plant native to the Himalayan plateau. The genus Cannabis includes three species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Due to widespread cultivation, cannabis now has a cosmopolitan distribution and can be found everywhere. Carl Linnaeus classified the plant in 1753, and it has been historically cultivated primarily for seed oil, industrial fiber, and recreational and medicinal uses [1].

The Recreational and Medicinal use of Cannabis throughout History

The history of cannabis is intimately tied to the history of humanity. Throughout history, humans have utilized hemp for many different purposes.


The domestication of cannabis (or hemp) likely coincided with the emergence of agriculture in Central Asia and Southeast Asia, before its cultivation extended to other geographical regions. The finding of sophisticated plaited basketry made of C. sativa in Czech Paleolithic sites stands as the oldest evidence of cannabis use dating back 26,000 years [2]. Similarly, findings of C. sativa in Neolithic sites in Taiwan suggest its utilization in that region approximately 12,000 years ago [3].

The recreational use of cannabis may have been around since ancient times [4]. The discovery of its psychoactive properties may have occurred by accident, possibly when cannabis plants were burnt accidentally by natural causes [5]. Various strains of cannabis originated from human cultivation, some for textile fiber production, and others as psychedelic drugs for religious use [4].

Ancient Civilizations

C. sativa flowers and resins have been used in Indian and Tibetan Hinduism and tantric Buddhism traditions to facilitate meditation and spiritual communication [6]. According to Buddhist folklore, Siddhartha Gautama ate only Bhang during his six years of asceticism [7]. Some authors claim the word “cannabis” is present in Semitic languages like Hebrew, recurrently appearing in passages of the Old Testament. Notably, references in Exodus, Isaiah, Jeremiah, and Ezekiel detail the use of cannabis as incense and sacred oil [8].

Five thousand years ago, Cheng Nung compiled the first Chinese pharmacopeia. This historical text prescribed cannabis for fatigue, rheumatism, and malaria. Additionally, cannabis seed oil is recommended for eczema, psoriasis, and inflammatory diseases in traditional Chinese medicine [8,9]. In ancient civilizations, hemp's medicinal properties were documented in clay tablets of Assyria and the Egyptian Ebers Papyrus dating to circa 3,000 years ago [10,11].

The Classical Era

The ancient Greeks and Romans were well aware of the medicinal properties of cannabis [12]. Herodotus described its use among Indians, while Diodorus Siculus mentioned ancient Egyptian women using hemp for pain relief and mood enhancement [13]. Roman historian Pliny the Elder reported the use of C. sativa roots to ease pain [14]. A Greek physician, Pedacius Dioscorides, also described the benefits of cannabis and its medical applications [15].

The Middle Ages

Cannabis was mainly utilized in the Middle Ages for its fibers' strength and resistance, although it was still used for recreational and medicinal purposes [4]. Hemp was also used in magic and traditional medicine, which prompted Pope Innocent VIII to condemn witchcraft and hemp use in a papal bull in 1484 [16]. In the following centuries, traders and merchants from Africa and India introduced Europeans to cannabis and its properties. Colonialists also spread the use and knowledge of hemp in America with their arrival and settlement [4].

Modern Times

Oriental culture and philosophy permeated Western societies throughout the 19th century, rekindling interest in cannabis. At that time, there were many cannabis consumer clubs, frequented by renowned authors like Charles Baudelaire, Honoré de Balzac, Alexandre Dumas, and Gustave Flaubert [17]. Jacques Joseph Moreau, a French physician, studied cannabis' effect on mental illness [18]. Additionally, the plant was introduced as an analgesic, anti-inflammatory, anti-emetic, and anti-convulsant in English medicine [19].

Prohibition and Medical Use

Despite cannabis' numerous beneficial effects described by physicians and traditional medicine, its psychoactive effects caused its prohibition in Western societies. However, indigenous peoples and shamans continued to use it in traditional ways [4]. As a result of its beneficial properties, cannabis is now considered a medicinal product and legal in numerous countries. Evidence regarding its effects is increasing, resulting in new medical applications. Cannabis is now being studied for its potential role in treating a variety of medical conditions, such as immune disorders or infectious diseases. It is also being studied as a potential treatment for certain forms of cancer [20].

In the fascinating history of hemp, we have seen how human societies and cannabis have intertwined. To explore the potential medical applications of cannabis, we will next delve into the molecular basis of cannabis effects. Let’s discuss the endocannabinoid system and the cannabinoid receptors.

The Endocannabinoid System

The endocannabinoid system (ECS) is pivotal in nervous system development and modulation of neuronal activity. The ECS encompasses endogenous cannabinoids (endocannabinoids), cannabinoid receptors, and the proteins transporting, synthesizing, and degrading endocannabinoids [21].

Endocannabinoids are endogenous signaling lipids that activate cannabinoid receptors. Two of the most well-studied endocannabinoids are 2-arachidonoyl glycerol (2-AG), a full agonist of cannabinoid receptors, and anandamide (N-arachidonoyl ethanolamine, AEA), a partial agonist of cannabinoid receptors. Similar to phytocannabinoids, endocannabinoids do not only interact with cannabinoid receptors but can also bind to other kinds of receptors [21].

Cannabinoid Receptors

The cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) are G-protein coupled receptors. These receptors translate external signals (such as light, peptides, lipids, etc.) into specific cellular responses in eukaryotes [22].

  • CB1 receptors: These receptors are widely distributed in the central nervous system, associated with both glutamergic and GABAergic neurons. The activation of these receptors inhibits GABA and glutamate release and increases potassium and calcium ion channel activity. Therefore, CB1 receptor activation modulates neurotransmitter release in a dose-dependent manner [22].
  • CB2 receptors: Closely related to the CB1 receptors, CB2 receptors are predominantly expressed by immune system cells and by astrocytes and microglia in the nervous system. Activation of CB2 receptors maintains bone mass, triggers neurodefense functions, and reduces inflammation [22].

Endocannabinoid Function

The ECS is not a defined, isolated system. In contrast, it interacts with many other systems and elements within the organism. Although it is known to play an essential role in the nervous system, there are still many questions that remain unanswered. Consequently, the knowledge gathered by recent research can still be considered preliminary and incomplete. This section of the article will discuss the potential functions of cannabinoids in different physiological processes.

  • Memory: Animal studies have shown contradictory effects on memory and learning. The ECS plays a modulatory role in these cognitive processes and the dichotomic results obtained may suggest an effect of environmental and stress factors on cannabinoid memory and learning regulation [23].
  • Appetite: Endocannabinoids such as 2-AG and AEA stimulate appetite and food intake both in animals and humans [24].
  • Immune system: Endocannabinoids have been shown to affect various immune cell types, thus modulating the immune response [25].
  • Pain: Palmitoylethanolamide, an endocannabinoid, has been shown to reduce pain [26]. In addition, preclinical studies show endocannabinoid effects in pain alleviation depending on the model [27].
  • Sleep: Endocannabinoids are known to induce sleep as well as modulate the length of sleep phases and their stability [28].

Having learned about the ECS and endocannabinoids, let's examine how cannabinoids, the bioactive compounds of cannabis, affect our bodies. Cannabinoids interact with the ECS and are believed to have therapeutic potential. They are being studied for their potential to treat various medical conditions, including pain, inflammation, and nausea.

Chemical Composition of Cannabis: Cannabinoids

The cannabis plant produces more than 568 distinct compounds, encompassing more than 100 cannabinoids or phytocannabinoids, a unique class of organic molecules with a polyphenolic structure [29,30]. Here are some cannabinoids that interact with human cannabinoid receptors:

  • Δ9-tetrahydrocannabinol (THC)
  • Cannabidiol (CBD)
  • Δ9-tetrahydrocannabinolic acid (THCA)
  • Cannabidiolic acid (CBDA)

Cannabinoids interact with a wide variety of human receptors [31]. As well as cannabinoid receptors, cannabinoids may interact with other human receptors, such as serotonin receptors and vanilloid-type transient receptor potential channels. Euphoria, motor impairment, analgesia, and immunomodulation are some of the physiological effects induced by cannabinoids through their interaction with these receptors [32-34].

How do Phytocannabinoids work?

Several neural processes are mediated by endocannabinoids, which function as neurotransmitters. Due to their structural resemblance to endocannabinoids, phytocannabinoids like THC bind to the cannabinoid receptors and other receptors within the body, activating similar responses.

Potential therapeutic uses of Cannabinoids

By activating the ECS, THC and other cannabinoids have remarkable therapeutic potential in the treatment of a wide range of diseases and disorders.

Among the various diseases in which cannabinoids have shown a certain degree of efficacy are multiple sclerosis, epilepsy (CBD has been shown effective as an anti-convulsant, especially in children), nausea (cannabinoids are approved in some countries as a drug to prevent chemotherapy-induced nausea), neuropathic pain, and post-traumatic stress syndrome [35]. Finally, some cannabinoids may be effective in treating specific types of cancer.

In addition to alleviating the unwanted side effects of antineoplastic drug regimens, plant-based, endogenous, and synthetic cannabinoid compounds have shown promising results in decreasing tumor burden. Cannabinoids have shown efficacy both alone and in combination with antineoplastic drugs. The effects of these compounds are mediated by various receptors and ligands as well as by modulating signaling pathways involved in cancer pathology hallmarks. The emerging evidence for phytocannabinoid anticancer effects is promising, but not enough clinical trials have been conducted [36].

Adverse effects

Due to their potential use as therapeutic agents, cannabinoids have been studied in various preclinical and clinical studies to assess their efficacy and safety. In general, the reported adverse effects from therapeutic cannabinoids are rare and mild [37-39].

Cannabis in Health Optimization Medicine and Practice (HOMe/HOPe)

The HOMe/HOPe Academy has an Advanced Practice module dedicated to cannabis. It includes a deep dive into the physiology cannabinoids that are in use now and others that are just breaking into clinical practice.

If you are considering integrating cannabinoids into your clinical practice, you must have a comprehensive understanding of the endocannabinoid system and how to modulate it effectively.

Check out the Cannabis module in the Advanced HOMe/HOPe Course here.


Plants have played an important role in human history since the beginning of time. From the moment human beings appeared on the surface of the Earth, we explored the surrounding environment. Besides being a source of food, plants have also been used as medicines. Ancient societies realized the therapeutic potential of certain botanical specimens. Modern science is now confirming some of this ancient knowledge, translating it into potential therapeutic strategies. Cannabis is perhaps the perfect example of the fascinating history of humans' relationship with plants and its potential impact on modern medicine.

Written by Ferran Riaño-Canalias, PhD



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