While it’s true that psychedelic compounds like LSD and MDMA were initially synthesized in laboratory settings, others, like psilocybin and mescaline, are derived from plants and have been used medicinally for millennia. 

There are differences between natural and synthetic psychedelics, of course, but perhaps not in the ways we tend to assume. You might be wondering, if their chemical action is similar, what differentiates “natural” from “synthetic” psychedelics? Is one better than the other for therapeutic use? Is one type safer than the other? 

Here, we’ll explore both natural and synthetic psychedelics, what sets them apart, and what unites them. Then we’ll discuss why intended outcome, preparation, and set and setting are actually more important factors than choosing between natural versus synthetic psychedelics. 

Defining “Natural or Organic” 

Since much of our discussion hinges on the distinction between natural and synthetic psychedelics, it’s important to be specific from the start. “Natural” is a term that gets bandied around quite a bit today, often in a way that’s misleading, or even outright disingenuous. This is partly due to the fact that there is no legal definition of “natural” or “all-natural,” allowing advertisers to subtly manipulate our perception of natural products and ingredients.

The dictionary defines natural as “existing in or caused by nature; not made or caused by mankind.” In this loose definition, we can see pretty quickly that “natural” doesn’t necessarily mean “beneficial.” A plant named Belladonna, for instance, fits this definition but is highly toxic to humans and many animals. It’s important to understand that natural doesn’t inherently mean better.

For the purposes of our discussion here, natural psychedelics are those derived from plants. This includes entheogens like ayahuasca, which is made with the combined products of multiple plants or plant-based ingredients. Synthetic psychedelics, on the other hand, are those that have been created (or synthesized) in a controlled setting. This setting might be a laboratory or a clinical practice but is not always the case. 

Before we go further, it’s important to note that there are three categories of both natural and synthetic psychedelics. Serotonergic psychedelics produce their effects by engaging with the brain’s serotonin receptors.

Empathogens, also sometimes called entactogens, improve our ability to form interpersonal connections. Dissociatives produce an effect that allows us to shift our perspectives outside of ourselves, broadening our understanding and consciousness. For a more in-depth look, check out our article on how psychedelics work in the brain. 

As we compare and contrast natural and synthetic psychedelics, it’s important to understand that the proximity of one chemical or another to nature doesn’t make it inherently better or worse. Despite their unique origins, many of these compounds have relatively similar structures and affect the brain in related ways. However, different hallucinogenic properties, intensities, and durations may produce vastly different experiences. The intention and context in which they are consumed also play a role.

Types of Natural Psychedelics

Natural psychedelics include plant-derived entheogens like mescaline or peyote, psilocybin, ayahuasca, and some forms of DMT. These compounds differ from one another in both structure and origin, but share key elements that allow them to behave similarly in the brain. Each of these compounds, like most natural psychedelics, engage with the brain’s serotonin receptors.

There are thousands of different plants and fungi that produce psychedelic compounds. There’s even a species of toad whose skin secretions contain a form of DMT called 5-MEO-DMT. The sources of psychedelics can vary quite greatly, from fungi to shrubs and even roots. 

For example, there are over 200 fungi species that contain psilocybin, the hallucinogenic compound, and are collectively known as ‘magic mushrooms’. The following is a very abbreviated list of the most well-known natural psychedelics in America. 


Mescaline is derived from the peyote or San Pedro cacti, native to parts of southwestern US and Mexico. The cacti, scientifically referred to as Lophophora williamsii and Echinopsis pachanoi respectively, produce small button-like growths when cut. 

These growths are then harvested and chewed or brewed into a bitter-tasting tea. For many reasons (including Western interest in “novelty” peyote trips and the slow growth rate of the cacti), both are considered vulnerable to extinction. 


Ayahuasca is a psychedelic beverage brewed from several different entheogenic plants. While the exact brew varies according to geography and tradition, the core ingredients remain fairly consistent. The Banisteriopsis caapi vine and the leaves of Psychotria viridis, or the catruna shrub, are combined together, along with other plants and herbs, and brewed into a tea that produces a profound psychedelic experience when ingested orally. The primary psychedelic ingredient in ayahuasca is DMT, an endogenous psychedelic.


Psilocybin, perhaps the best-known natural psychedelic, comes from various different species of mushroom and other fungi, with various strains of psilocybe cubensis being the most well-known. These mushrooms have a deep history in Central and South American culture and it is believed that psilocybin mushrooms played a big role in Aztec tradition. 

Hieroglyphs have also been found in Africa and Europe, suggesting that multiple continents have used psychedelics for religious ceremony. Today, psilocybin mushrooms are decriminalized in three U.S. cities (Denver, CO, Santa Cruz, CA, and Oakland, CA) and are currently undergoing FDA approved clinical studies to treat severe depression. 

Types of Synthetic Psychedelics

Unlike natural psychedelics, synthetic psychedelics are produced by human efforts in a controlled or semi-controlled setting. Synthetic psychedelics include compounds like LSD, MDMA, and ketamine, among others. 

Some, like ketamine, are Schedule III drugs, which means there is some medical use. The other substances in this list are Schedule I, meaning they have no medical benefit and a high rate of abuse, despite an overwhelming amount of modern research that suggests the contrary.


LSD is a synthesized version of a natural compound in parasitic rye fungus that was discovered by Albert Hoffman when he was seeking to create a pharmaceutical respiratory and circulation stimulant. Five years later, he would accidentally discover it’s psychedelic effects, and human society was never the same. 

Research into LSD’s therapeutic use was prevalent until it’s illegal designation in the 1960s. LSD produces an intensely visual experience and a rather longer trip, anywhere from 8-12+ hours. It is a potent chemical as the effective dose is a miniscule amount (roughly 125 micrograms).


MDMA is commonly known as ‘ecstasy’ or ‘molly’ and perhaps has the most controversial history in the United States as it was a major psychedelic target of the War on Drugs. And though health risks are present, especially for those with preexisting heart or respiratory conditions, it has been shown to be safe under the correct supervision. 

MDMA is known to increase prosocial behaviors and has been used as a relationship therapy aid until it’s ban in the 1960’s. In recent years, it has been designated by the FDA as a ‘breakthrough’ therapy in treating PTSD


Ketamine has been used as an anesthetic since the 1950’s for a wide variety of surgical and medical procedures. Because of it’s Schedule III status, it is available for “off-label” use under the direct supervision of a medical professional. As such, ketamine assisted therapy clinics have opened up across the country to help patients address treatment resistant depression among a list of other mental health conditions. 

Ketamine is dissociative, meaning that it can temporarily disconnect the functions of the mind and body. Though it sounds alarming, this can produce meditative and contemplative states that can contribute to long term healing and is generally safe under proper care. At higher dosages, ketamine can produce vivid hallucinations. 

Differences Between Natural and Synthetic Psychedelics

Though there are many commonalities between natural and synthetic psychedelics, there are some major differences that affect how the substances are consumed today. One clear distinction is their history of use, as most synthetic substances have been discovered within the last century whereas natural psychedelics have been used throughout human history

What this means is that natural psychedelics tend to have more tradition and historical context, especially when it comes to ceremonial, religious, or spiritual use. Therefore, western medicine has limited exposure to these natural plants and fungi, though new research may change all that. 

Without this cultural backdrop, synthetic psychedelics have been used more recreationally. Though a change in public perception has led to a resurgence of intentional and healing psychedelic use, regardless of whether they are derived from man or nature. 

Another major difference lies in the form factor of the psychedelics themselves. Natural psychedelics come from plants and fungi, and users encounter them in this form as well (a dried mushroom or an herbal brew for example). Synthetic substances are man-made and often come in the form of liquids or powders. 

Human error can play a factor in their creation, but what’s more is that synthetic substances are more easily adulterated with fillers and additives in an effort to increase volume, and therefore, profit. And with the illegality of these drugs, there is no regulation or oversight into how they are produced. Most often, the user is unaware and may be ingesting other unknown and potentially harmful chemicals. 

Because of this, synthetic psychedelics may present different risks than their natural counterparts. This doesn’t mean that synthetic psychedelics are inherently dangerous, or that they are intrinsically harmful. 

However, it does mean that choosing to use synthetic psychedelics may carry its own set of unique risks, depending on their source. Though not 100% foolproof, a drug-testing kit and reliable scale can help you determine what’s in your substance before you consume. 

And perhaps the most important distinction is that certain psychedelics are more successful in treating specific conditions, both natural and synthetic. The man-made nature of synthetic psychedelics doesn’t preclude them from providing therapeutic benefits. 

MDMA (synthetic) has been shown to be effective in relationship therapy and in treating anxiety; both MDMA and psilocybin (natural) can be more conducive to alleviating symptoms of PTSD. Ketamine (synthetic) can help address severe depression. And both psilocybin (natural) and DMT (synthetic) have had results in helping alleviate fear of death in people with terminal conditions. 

Why Intention and Context Are More Important

While different psychedelics produce different types of experiences and states of consciousness, most compounds are more alike than they are different. Instead of focusing on natural versus synthetic, we would argue that both can create significant experiences in one’s healing journey. Picking the right substance largely depends on the goals you are trying to achieve. 

Are you seeking to alleviate a mental health condition? Are you looking to navigate a major life change? Are you wanting to perform better at work? A particular psychedelic substance may be more suited to help you achieve your individual outcome. We’ve put together an extensive guide that covers how to choose the best psychedelic based on your desired outcome.

Situational factors also play a role in your experience. Set (mindset) and setting (physical surroundings) have been shown to greatly impact your trip. Are you in a clear and motivated mindset or have you been stressed about a particular event or situation? Do you feel well-rested or fatigued? Do you have a safe, comfortable, and uninterrupted place to have your psychedelic experience? What about a trained trip sitter or guide to help keep you safe? 

These questions are important for any psychedelic endeavor, natural or synthetic. What’s even more critical is the intention, preparation and effort you make before and after the event to turn your mystical experience into meaningful life change.   

Both natural and synthetic psychedelics can be used for therapeutic benefit, with great results. However, there are unique considerations and preventable risks associated with each. The goal of a psychedelic experience is to heal, not to harm, and it is important to undertake such an experience with all the necessary preparation.

Sound complex? That’s because it is. And that’s why Psychedelic Passage exists. We can provide you with information and coaching support to not only make your journey smoother but increase its potential impact while lowering your risk of harm.

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