Many healthcare providers anticipate clinical effects of synthetic cannabinoids from what is known about cannabis (marijuana) and the endogenous cannabinoid system. However, clinical experience suggests otherwise. The acute clinical effects that follow smoking marijuana have been well documented [1, 2]. These effects include anxiety, panic reactions, depressive feelings, euphoria, relaxation, perceptual alterations, time distortion, intensified sensory experiences, infectious laughter, talkativeness, impaired attention, short-term memory and psychomotor function, and sinus tachycardia. After discovery of the CB1 cannabinoid receptor and anandamide, pharmacology of the endogenous cannabinoid system has been characterized, and research efforts have yielded xenobiotics that interact with most of the main endogenous cannabinoid system elements [3]. The CB1 cannabinoid receptor is one of the most abundantly expressed of the neuronal receptors, and has high density within the basal ganglia. One of the most striking effects of cannabinoids is the depression of locomotor activity by inhibition of c-aminobutyric acid (GABA) uptake at striatopallidal and striatonigral terminals, by inhibition of dopamine uptake in the striatum, and by a decrease in glutamate release from the nucleus subthalamicus terminals; inhibiting the firing of the substantia nigra. Mechanisms leading to catalepsy include decreased GABA reuptake into the presynaptic terminal by cannabinoids resulting in an increase in GABA concentration in the synaptic cleft and potentiation of inhibitory GABA action on the nigrostiatal pathway [4]. In mice, anandamide produces a pharmacological profile similar to that of the classical cannabinoid receptor agonists, including analgesia, hypothermia, hypomobility, and catalepsy, which constitutes the ‘‘mouse tetrad,’’ and is classically considered a signature of cannabimimetic activity [4]. The acute clinical effects that follow smoking herbs sprayed with synthetic cannabinoids [e.g., disorientation, agitation, paranoia/fear, combativeness, hallucinations, hyperreflexic, myoclonic jerks, fasciculations, gait disturbance, collapse/syncope, seizures (status), xerostomia, sweating, hypertension, and mydriasis] are, for the most part, unlike the acute clinical effects that follow smoking marijuana. These effects are inconsistent with the effects of endocannabinoids on CB1 receptors and contradict the cannabimimetic signature observed in animals [5–11]. The contrasting clinical effects may be due to the fact that synthetic cannabinoids are not delta-9-tetrahydrocannabinol (THC), are devoid of cannabidiol, have a higher affinity for cannabinol receptors and higher potency than THC, have longer half-lives than THC, have active metabolites, have contaminants, or, is there something more...? Interestingly, while some THC effects may be attenuated (e.g., anxiety) when cannabidiol is co-administered with THC in a controlled study environment, there is little evidence to suggest cannabidiol attenuates the effects of synthetic cannabinoids [12]. We have read with interest an article published in this Journal [Uchiyama et al. (2013) Forensic Toxicol 31:223–240], in which an ongoing survey of designer drugs in the Japanese illegal market revealed structures of newly detected synthetic cannabinoids, detected but known synthetic cannabinoids, and related compounds [13]. We were intrigued by Figure 1 in the article, and noted in the L. Yip (&) R. C. Dart Rocky Mountain Poison and Drug Center, 990 Bannock Street, Denver, CO, USA e-mail: Luke.Yip@rmpdc.org